CN103476403A - Controlled release formulations of opioids - Google Patents

Abstract

Pharmaceutical formulations containing opioid components that each has a release profile. The components may provide immediate or controlled release of the opioid. The invention is also directed to methods of controlling release of one or more opioid compounds and methods of treating pain.

Description

Opioid controlled release preparation

the cross reference of related application

The application requires the priority of the U.S. Provisional Application series number 61/386,277 that JIUYUE in 2010 submits on the 24th and the U. S. application series number 13/024,319 of submitting on February 9th, 2011, and the two equal integral body is quoted and added this paper.

Technical field

The present invention relates to the pharmaceutical preparation that comprises the opioid component, described opioid component has release characteristic spectrum (profile) separately.Described component can provide opioid and release or controlled release.The invention still further relates to the controlled release method of one or more opioid compounds and the method for the treatment of pain.

Background technology

Opioid is to be usually used in treating a class lenitive prescription drugs of various acute and chronic, moderates to severe pain.Yet opioid can be rapidly absorbed and be discharged by body system by the metabolism inactivation.In order to treat the patient, the patient of severe pain particularly, opioid administration often need to be with interval frequently, and dosed administration to be to maintain opioid effective steady-state blood level carefully, thereby continuous analgesia is provided.Otherwise, opioid blood level Possible waves and cause very poor and inconsistent pain relief.

These difficulties relevant to opioid administration show the opioid therapy of needs exploitations, the fluctuation that it can maintain opioid consistent level in blood and avoid pain relief after administration.

Summary of the invention

The present invention relates to be used for the treatment of the pharmaceutical preparation of pain, described pharmaceutical preparation comprises such component, and described component comprises the opioid compound and has different release characteristic spectrums.The invention still further relates to the controlled release method of one or more opioid compounds and the method for the treatment of pain.

Pharmaceutical preparation of the present invention can comprise one or more components, and described component has one or more release characteristic spectrums, and wherein at least one described component comprises the compound with opioid receptor agonist activity.Have therein in a kind of embodiment of component of surpassing, described component can have identical release characteristic spectrum, or described component can have different release characteristic spectrums.

In some embodiments, compound with opioid receptor agonist activity can have for μ (" μ ", morphine receptor), σ (" σ ", phencyclidine receptors), κ (" κ ", ketone group cyclazocine (ketocyclazocine) receptor) or the agonist activity of δ (" δ ", endorphinlenkephalin receptor) Opioid Receptors.This compounds can comprise morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, paramorphan (dihydromorphine), oxymorphone, their mixture or their salt.In certain embodiments, component can comprise two kinds of opioid compounds of different proportion.In specific embodiments, component can comprise morphine and oxycodone or their salt of about 3:2 weight ratio.

In some embodiments, described component can have and releases characteristic spectrum or release characteristics spectrum.

In certain embodiments, described preparation can comprise one or more extra components, for example at least 2 kinds, at least 3 kinds, at least 4 kinds or at least 5 kinds of components.In some embodiments, described one or more extra components can comprise one or more active substances.In some embodiments, described one or more active substances can be the compounds with opioid receptor agonist activity.In some embodiments, described one or more active substances can be one or more non-opioid analgesic compounds, or one or more non-opioid analgesic compounds and one or more have the compound of opioid receptor agonist activity or the mixture of the acceptable salt of their pharmacy, ester or prodrug.In certain embodiments, described one or more active substances can be that one or more mix the opioid compound, or one or more mix the opioid compound and one or more have the compound of opioid receptor agonist activity or the mixture of the acceptable salt of their pharmacy, ester or prodrug.

In embodiments of the invention, described pharmaceutical preparation can comprise one or more opioid components, and wherein at least one described opioid component is to comprise opioid controlled release opioid component.In certain embodiments, described opioid is selected from morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, paramorphan (dihydromorphine), oxymorphone, their mixture and their salt.In specific embodiments, described opioid is oxycodone or its salt.

In certain embodiments, described pharmaceutical preparation about 4.5-is provided after repeat administration approximately 8 hours to the time (T of maximum opioid plasma concentration _max).In specific embodiments, T after repeat administration _maxfor about 5-approximately 6 hours or approximately 6 hours.

In some embodiments, described release components about 13-is provided after repeat administration approximately 16 hours to the time (T of minimum oxycodone plasma concentration _min).In specific embodiments, T after repeat administration _minfor approximately 14 hours.In some embodiments, repeat administration carries out in limit.

In some embodiments, while measuring in USP I type device under 37 ° of C in water with 50rpm, the stripping of described pharmaceutical preparation discharged approximately 20% opioid of about 0-after 2 hours, perhaps after 4 hours, discharge approximately 60% opioid of about 15-, perhaps after 6 hours, discharge approximately 80% opioid of about 25-, perhaps after 8 hours, discharge approximately 85% opioid of about 35-, perhaps after 10 hours, discharge approximately 95% opioid of about 45-, or discharged approximately 100% opioid of about 60-after 12 hours.

In certain embodiments, when described pharmaceutical preparation comprises about 2mg opioid, described pharmaceutical preparation can provide the average maximal plasma concentration (C of the about 3ng/mL of about 1-or about 2ng/mL after repeat administration _max).In some embodiments, repeat administration can carry out in limit.In certain embodiments, after single-dose, about 0-is the area under curve (AUC of 24 hours approximately ₂₄) can be the about 23.0nghr/mL of about 14.7nghr/mL-, or the about 21.0nghr/mL of about 15.8nghr/mL-, or the about 19.7nghr/mL of about 17.1nghr/mL-.

In certain embodiments, when described pharmaceutical preparation comprises about 5mg opioid, described pharmaceutical preparation can provide the average C of the about 7ng/mL of about 3-or about 5ng/mL after repeat administration _max.In some embodiments, repeat administration can carry out in limit.In certain embodiments, after single-dose, AUC ₂₄can be the about 62.8nghr/mL of about 40.2nghr/mL-, or the about 57.2nghr/mL of about 43.2nghr/mL-, or the about 53.7nghr/mL of about 46.7nghr/mL-.

In certain embodiments, when described pharmaceutical preparation comprises about 10mg opioid, described pharmaceutical preparation can provide the average C of the about 15ng/mL of about 5-or about 10ng/mL after repeat administration _max.In some embodiments, repeat administration can carry out in limit.In certain embodiments, after single-dose, AUC ₂₄can be the about 125.9nghr/mL of about 80.5nghr/mL-, or the about 114.8nghr/mL of about 86.6nghr/mL-, or the about 107.7nghr/mL of about 93.7nghr/mL-.

In certain embodiments, when described pharmaceutical preparation comprises about 20mg opioid, described pharmaceutical preparation can provide the average C of the about 30ng/mL of about 10-or about 20ng/mL after repeat administration _max.In some embodiments, repeat administration can carry out in limit.In certain embodiments, after single-dose, AUC ₂₄can be the about 259.3nghr/mL of about 166.0nghr/mL-, or the about 236.6nghr/mL of about 178.5nghr/mL-, or the about 222.0nghr/mL of about 193.0nghr/mL-.

In certain embodiments, when described pharmaceutical preparation comprises about 40mg opioid, described pharmaceutical preparation can provide the average C of the about 55ng/mL of about 25-or about 40ng/mL after repeat administration _max.In some embodiments, repeat administration can carry out in limit.In certain embodiments, after single-dose, AUC ₂₄can be the about 528.9nghr/mL of about 338.5nghr/mL-, or the about 482.3nghr/mL of about 363.9nghr/mL-, or the about 452.7nghr/mL of about 393.5nghr/mL-.

In certain embodiments, when described pharmaceutical preparation comprises about 80mg opioid, described pharmaceutical preparation can provide the average C of the about 110ng/mL of about 50-or about 80ng/mL after repeat administration _max.In some embodiments, repeat administration can carry out in limit.In certain embodiments, after single-dose, AUC ₂₄can be the about 1356.9nghr/mL of about 868.4nghr/mL-, or the about 1237.5nghr/mL of about 933.5nghr/mL-, or the about 1161.5nghr/mL of about 1009.5nghr/mL-.

In some embodiments, described pharmaceutical preparation provides the average minimum oxycodone plasma concentration (C of the about 40ng/mL of about 0.5-or the about 15ng/mL of about 4-after repeat administration _min).In some embodiments, repeat administration carries out in limit.

In certain embodiments, described pharmaceutical preparation comprises the second controlled release opioid component.In some embodiments, described the second controlled release opioid component comprises the opioid be selected from following group: morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, paramorphan (dihydromorphine), oxymorphone, their mixture and their salt.

In certain embodiments, described pharmaceutical preparation comprises and releases the opioid component.In some embodiments, the described opioid component of releasing comprises the opioid be selected from following group: morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, paramorphan (dihydromorphine), oxymorphone, their mixture and their salt.In other embodiments, the described opioid of releasing in the opioid component is morphine or its salt.In other embodiments, in described preparation, the weight ratio of total morphine or its salt and total oxycodone or its salt is that about 3:2 morphine or its salt are than oxycodone or its salt.

In certain embodiments, described pharmaceutical preparation comprises the second opioid component and the 3rd opioid component, and wherein: (a) described the second opioid component for to release the opioid component and to comprise the opioid with kappa agonist activity; And (b) described the 3rd opioid component is controlled release opioid component and comprises the opioid with MU agonist activity.In some embodiments, the opioid with kappa agonist activity is oxycodone or its salt, and the opioid with MU agonist activity is morphine or its salt.

In certain embodiments, described controlled release opioid component comprises morphine or its salt.In some embodiments, described controlled release opioid component packet content is about 3:2 weight ratio morphine or its salt and oxycodone or its salt.

In embodiments of the invention, described pharmaceutical preparation can comprise one or more opioid components for the people of these needs is arranged, wherein said one or more opioid components comprise one or more release characteristic spectrums, and at least one described opioid component is the controlled release opioid component that comprises oxycodone or its salt; When the oxycodone of the accumulated dose that comprises about 2mg or its salt, pharmaceutical preparation provides approximately approximately 6 hours or the about T of 6 hours of 7.5 hours or about 5-of about 4.5-after repeat administration _max, and the AUC of the about 23.0nghr/mL of about 14.7nghr/mL-or the about 21.0nghr/mL of about 15.8nghr/mL-or the about 19.7nghr/mL of about 17.1nghr/mL-is provided after single-dose ₂₄.Repeat administration can carry out in limit.

In certain embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 2mg oxycodone or its salt, and has the AUC with 2mg ₂₄proportional AUC ₂₄.In some embodiments, accumulated dose AUC ₂₄with 2mg AUC ₂₄linear ratio.

In certain embodiments, when the oxycodone of the accumulated dose that comprises about 2mg or its salt, described pharmaceutical preparation provides the C of the about 3ng/mL of about 1-or about 2mg after repeat administration _max.In some embodiments, repeat administration carries out in limit.In some embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 2mg oxycodone or its salt, and has the C with 2mg _maxproportional C _max.In some embodiments, accumulated dose C _maxwith 2mg C _maxlinear ratio.

In certain embodiments, when the accumulated dose that comprises about 2mg, described pharmaceutical preparation provides about 13-after the repeat administration about T of 16 hours _min.In some embodiments, repeat administration carries out in limit.

In embodiments of the invention, described pharmaceutical preparation can comprise one or more opioid components for the people of these needs is arranged, wherein said one or more opioid components comprise one or more release characteristic spectrums, and at least one described opioid component is the controlled release opioid component that comprises oxycodone or its salt; When the oxycodone of the accumulated dose that comprises about 5mg or its salt the time, described pharmaceutical preparation provides approximately approximately 6 hours or the about T of 6 hours of 7.5 hours or about 5-of about 4.5-after repeat administration _max, and the AUC of the about 62.8nghr/mL of about 40.2nghr/mL-or the about 57.2nghr/mL of about 43.2nghr/mL-or the about 53.7nghr/mL of about 46.7nghr/mL-is provided after single-dose ₂₄.Repeat administration can carry out in limit.

In certain embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 5mg oxycodone or its salt, and has the AUC with 5mg ₂₄proportional AUC ₂₄.In some embodiments, accumulated dose AUC ₂₄with 5mg AUC ₂₄linear ratio.

In certain embodiments, when the oxycodone of the accumulated dose that comprises about 5mg or its salt, described pharmaceutical preparation provides the C of the about 7ng/mL of about 3-or about 5ng/mL after repeat administration _max.In some embodiments, repeat administration carries out in limit.In some embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 5mg oxycodone or its salt, and has the C with 5mg _maxproportional C _max.In some embodiments, accumulated dose C _maxwith 5mgC _maxlinear ratio.

In certain embodiments, when the oxycodone of the accumulated dose that comprises about 5mg or its salt, described pharmaceutical preparation provides about 13-after the repeat administration about T of 16 hours _min.In some embodiments, repeat administration carries out in limit.

In embodiments of the invention, described pharmaceutical preparation can comprise one or more opioid components for the people of these needs is arranged, wherein said one or more opioid components comprise one or more release characteristic spectrums, and at least one described opioid component is the controlled release opioid component that comprises oxycodone or its salt; When the oxycodone of the accumulated dose that comprises about 10mg or its salt the time, described pharmaceutical preparation provides approximately approximately 6 hours or the about T of 6 hours of 7.5 hours or about 5-of about 4.5-after repeat administration _max, and the AUC of the about 125.9nghr/mL of about 80.5nghr/mL-or the about 114.8nghr/mL of about 86.6nghr/mL-or the about 107.7nghr/mL of about 93.7nghr/mL-is provided after single-dose ₂₄.Repeat administration can carry out in limit.

In certain embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 10mg oxycodone or its salt, and has the AUC with 10mg ₂₄proportional AUC ₂₄.In some embodiments, accumulated dose AUC ₂₄with 10mg AUC ₂₄linear ratio.

In certain embodiments, when the oxycodone of the accumulated dose that comprises about 10mg or its salt, described pharmaceutical preparation provides the C of the about 15ng/mL of about 5-or about 10ng/mL after repeat administration _max.In some embodiments, repeat administration carries out in limit.In some embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 10mg oxycodone or its salt, and has the C with 10mg _maxproportional C _max.In some embodiments, accumulated dose C _maxwith 10mg C _maxlinear ratio.

In certain embodiments, when the oxycodone of the accumulated dose that comprises about 10mg or its salt, described pharmaceutical preparation provides about 13-after the repeat administration about T of 16 hours _min.In some embodiments, repeat administration carries out in limit.

In embodiments of the invention, described pharmaceutical preparation can comprise one or more opioid components for the people of these needs is arranged, wherein said one or more opioid components comprise one or more release characteristic spectrums, and at least one described opioid component is the controlled release opioid component that comprises oxycodone or its salt; When the oxycodone of the accumulated dose that comprises about 20mg or its salt the time, described pharmaceutical preparation provides approximately approximately 6 hours or the about T of 6 hours of 7.5 hours or about 5-of about 4.5-after repeat administration _max, and the AUC of the about 259.3nghr/mL of about 166.0nghr/mL-or the about 236.6nghr/mL of about 178.5nghr/mL-or the about 222.0nghr/mL of about 193.0nghr/mL-is provided after single-dose ₂₄.Repeat administration can carry out in limit.

In certain embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 20mg oxycodone or its salt, and has the AUC with 20mg ₂₄proportional AUC ₂₄.In some embodiments, accumulated dose AUC ₂₄with 20mg AUC ₂₄linear ratio.

In certain embodiments, when the oxycodone of the accumulated dose that comprises about 20mg or its salt, described pharmaceutical preparation provides the C of the about 30ng/mL of about 10-or about 20ng/mL after repeat administration _max.In some embodiments, repeat administration carries out in limit.In some embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 20mg oxycodone or its salt, and has the C with 20mg _maxproportional C _max.In some embodiments, accumulated dose C _maxwith 20mg C _maxlinear ratio.

In certain embodiments, when the oxycodone of the accumulated dose that comprises about 20mg or its salt, described pharmaceutical preparation provides the approximately T of 8 hours after repeat administration _min.In some embodiments, repeat administration carries out in limit.In some embodiments, described pharmaceutical preparation is formulated as the accumulated dose that is different from about 20mg oxycodone or its salt, and has the C with 20mg _minproportional C _min.In some embodiments, accumulated dose C _minwith 20mg C _minlinear ratio.

In embodiments of the invention, described pharmaceutical preparation can comprise one or more opioid components for the people of these needs is arranged, wherein said one or more opioid components comprise one or more release characteristic spectrums, and at least one described opioid component is the controlled release opioid component that comprises oxycodone or its salt; When the oxycodone of the accumulated dose that comprises about 40mg or its salt the time, described pharmaceutical preparation provides approximately approximately 6 hours or the about T of 6 hours of 7.5 hours or about 5-of about 4.5-after repeat administration _max, and the AUC of the about 528.9nghr/mL of about 338.5nghr/mL-or the about 482.3nghr/mL of about 363.9nghr/mL-or the about 452.7nghr/mL of about 393.5nghr/mL-is provided after single-dose ₂₄.Repeat administration can carry out in limit.

In certain embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 40mg oxycodone or its salt, and has the AUC with 40mg ₂₄proportional AUC ₂₄.In some embodiments, accumulated dose AUC ₂₄with 40mg AUC ₂₄linear ratio.

In certain embodiments, when the oxycodone of the accumulated dose that comprises about 40mg or its salt, described pharmaceutical preparation provides the C of the about 55ng/mL of about 25-or about 40ng/mL after repeat administration _max.In some embodiments, repeat administration carries out in limit.In some embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 40mg oxycodone or its salt, and has the C with 40mg _maxproportional C _max.In some embodiments, accumulated dose C _maxwith 40mg C _maxlinear ratio.

In certain embodiments, when the oxycodone of the accumulated dose that comprises about 40mg or its salt, described pharmaceutical preparation provides about 13-after the repeat administration about T of 16 hours _min.In some embodiments, repeat administration carries out in limit.

In embodiments of the invention, described pharmaceutical preparation can comprise one or more opioid components for the people of these needs is arranged, wherein said one or more opioid components comprise one or more release characteristic spectrums, and at least one described opioid component is the controlled release opioid component that comprises oxycodone or its salt; When the oxycodone of the accumulated dose that comprises about 80mg or its salt the time, described pharmaceutical preparation provides approximately approximately 6 hours or the about T of 6 hours of 7.5 hours or about 5-of about 4.5-after repeat administration _max, and the AUC of the about 1356.9nghr/mL of about 868.4nghr/mL-or the about 1237.5nghr/mL of about 933.5nghr/mL-or the about 1161.5nghr/mL of about 1009.5nghr/mL-is provided after single-dose ₂₄.Repeat administration can carry out in limit.

In certain embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 80mg oxycodone or its salt, and has the AUC with 80mg ₂₄proportional AUC ₂₄.In some embodiments, accumulated dose AUC ₂₄with 80mg AUC ₂₄linear ratio.

In certain embodiments, when the oxycodone of the accumulated dose that comprises about 80mg or its salt, described pharmaceutical preparation provides the C of the about 110ng/mL of about 50-or about 80ng/mL after repeat administration _max.In some embodiments, repeat administration carries out in limit.In some embodiments, described pharmaceutical preparation is formulated as oxycodone or its salt of the accumulated dose that is different from about 80mg oxycodone or its salt, and has the C with 80mg _maxproportional C _max.In some embodiments, accumulated dose C _maxwith 80mg C _maxlinear ratio.

In certain embodiments, when the oxycodone of the accumulated dose that comprises about 80mg or its salt, described pharmaceutical preparation provides about 13-after the repeat administration about T of 16 hours _min.In some embodiments, repeat administration carries out in limit.

One or more controlled release methods with compound of opioid receptor agonist activity that absorb for the people comprise the pharmaceutical preparation that administration comprises one or more components, wherein said one or more opioid components comprise one or more release characteristic spectrums, and at least one described opioid component is to comprise opioid controlled release opioid component.In certain embodiments, the pharmaceutical preparation to people's administration is pharmaceutical preparation of the present invention.

The method for the treatment of people's pain comprises the pharmaceutical preparation that administration comprises one or more components, wherein said one or more opioid components comprise one or more release characteristic spectrums, and at least one described opioid component is to comprise opioid controlled release opioid component.In certain embodiments, the pharmaceutical preparation to people's administration is pharmaceutical preparation of the present invention.

The accompanying drawing explanation

Figure la and 1b provide the schematic diagram of two embodiments of opioid preparation of the present invention.

Fig. 2 is provided for the target release characteristic spectrum of granule of the oxycodone coating of opioid preparation of the present invention.

Fig. 3 is provided for the target release characteristic spectrum of granule of the morphine coating of opioid preparation of the present invention.

The use that Fig. 4 is provided for opioid preparation of the present invention is the target release characteristic spectrum of the oxycodone granule of strange L30D-55 coating especially.

Fig. 5 provides the target release characteristic spectrum that in opioid preparation of the present invention, total oxycodone discharges.

Fig. 6 is provided for total oxycodone of of the present invention pair of opioid coated tablet and the target release characteristic spectrum that morphine discharges.

Fig. 7 provides the schematic diagram confirmed for the preparation of the method for oxycodone granule of the present invention.

Fig. 8 provides the schematic diagram confirmed for the preparation of the method for oxycodone core granule of the present invention.

Fig. 9 provides the schematic diagram confirmed for the preparation of the method for morphine core granule of the present invention.

Figure 10 provides and confirms for coating the schematic diagram for the method for morphine of the present invention or oxycodone core granule.

Figure 11 provides the schematic diagram confirmed for the preparation of the method for of the present invention pair of opioid coated tablet.

Figure 12 provides the flow chart (embodiment 2) for the preparation of the middle oxycodone granule of the prolongation release of clinical research.

Figure 13 provides in latter 72 hours for the treatment of two kinds of opioid preparations of the present invention (preparation A and preparation B) and reference preparation (with Oxy

20mg (oxycodone CR) is the MS of administration altogether 30mg (morphine CR)) oxycodone plasma concentration characteristic spectrum.

Figure 14 provides in latter 24 hours for the treatment of two kinds of opioid preparations of the present invention (preparation A and preparation B) and reference preparation (with Oxy

20mg (oxycodone CR) is the MS of administration altogether

30mg (morphine CR)) oxycodone plasma concentration characteristic spectrum.

Figure 15 provides the oxycodone blood plasma characteristic spectrum of expection, the administration of the opioid preparation of the present invention of its multiple dose from 12 hours intervals.

Figure 16 provides the oxycodone blood plasma characteristic spectrum of expection, and it is from the administration of the opioid preparation of the present invention with various dose administration intensity of multiple dose.

Figure 17 provides the oxycodone blood plasma characteristic spectrum of expection, the administration of the opioid compound formulation of the present invention (releasing+controlled release) of its multiple dose from 12 hours intervals.

Figure 18 provides the oxycodone blood plasma characteristic spectrum of expection, and it is from the administration of the opioid compound formulation of the present invention (releasing+controlled release) with various dose administration intensity of multiple dose.

Figure 19 provides the release characteristic spectrum of morphine sulfate, its use from different % coating levels (a) RS/RL=90/10 and (b) quaternary amine ylmethyl acrylate copolymer (AmmonioMethacrylate Copolymer) Type B (RS) of RS/RL=80/20 and the coating spheroidal particle (beadlet) that comprises morphine sulfate and oxycodone hydrochloride of A type (RL) coating ratio.

Figure 20 provides the release characteristic spectrum of oxycodone hydrochloride, its use from different % coating levels (a) RS/RL=90/10 and (b) the quaternary amine ylmethyl acrylate copolymer Type B (RS) of RS/RL=80/20 and the coating spheroidal particle that comprises morphine sulfate and oxycodone hydrochloride of A type (RL) coating ratio.

Figure 21 provides the release characteristic spectrum of the morphine sulfate in the enteric coated tablet (using the quaternary amine ylmethyl acrylate copolymer Type B (RS) of 90/10 ratio and 50% coating spheroidal particle of A type (RL)) of different % enteric coating levels.

Figure 22 provides the release characteristic spectrum of the oxycodone hydrochloride in the enteric coated tablet (using the quaternary amine ylmethyl acrylate copolymer Type B (RS) of 90/10 ratio and 50% coating spheroidal particle of A type (RL)) of different % enteric coating levels.

That Figure 23 provides is low, in or the release characteristic spectrum of the morphine sulfate in the enteric coated tablet (10% and 15% coating level) of high rigidity level.

That Figure 24 provides is low, in or the release characteristic spectrum of the oxycodone hydrochloride in the enteric coated tablet (10% and 15% coating level) of high rigidity level.

Figure 25 provides the release characteristic spectrum of oxycodone hydrochloride, the coating spheroidal particle that comprises oxycodone hydrochloride of its acrylate copolymer Type B of quaternary amine ylmethyl from the use RS/RL=85/15 of different % coating levels (RS) and A type (RL) coating ratio.

Figure 26 provides the release characteristic spectrum of oxycodone hydrochloride, the coating spheroidal particle that comprises oxycodone hydrochloride of its acrylate copolymer Type B of quaternary amine ylmethyl from the use RS/RL=80/20 of different % coating levels (RS) and A type (RL) coating ratio.

Figure 27 provides the release characteristic spectrum of oxycodone hydrochloride, the coating spheroidal particle that comprises oxycodone hydrochloride of the quaternary amine ylmethyl acrylate copolymer Type B (RS) of its use RS/RL=80/20 from different % coating levels and RS/RL=85/15 and A type (RL) coating ratio.

The specific embodiment

The controlled release that the present invention relates to the compound with opioid agonist activity by absorbing for the people is alleviated pharmaceutical preparation and the method for acute or chronic pain.Pharmaceutical preparation of the present invention and method can provide effective analgesia to the patient, reduce or eliminate the side effect of not expecting of experience usually when the administration of opioid analgesic compounds simultaneously.Controlled release due to compound, can obtain the release of compound substantial constant speed in special time, corresponding to the required dosage for the treatment of of considering, adhere to strict dosage thereby can carry out, for example need to be with interval every day of setting of administration medicine several times nearly.

An aspect of of the present present invention relates to the pharmaceutical preparation that comprises one or more components, and described component has one or more release characteristic spectrums, and wherein at least one described component comprises the compound with opioid receptor agonist activity and has the release characteristics spectrum.Another aspect of the present invention relates to pharmaceutical preparation of the present invention to people's administration that these needs are arranged.

Preparation as herein described and method are used for treating dissimilar pain, comprise neuropathic pain and nociceptive pain, body pain and visceral pain.In various embodiments, preparation as herein described and method are lost pain and thalamus pain syndrome (central pain) after being used for treating diabetic neuropathy, trigeminal neuralgia, herpes.Neuropathic pain is normal to coexist with nociceptive pain, and compound of the present invention and salt can be used for treatment mixing pain status, the i.e. combination of nerve and nociceptive pain.For example, damaged tissue and neural wound, burn (burned skin and teleneuron) and outside nerve compression can cause nerve and nociceptive pain.The example of outside nerve compression comprises the tumor nerve compression and from the sciatica that is pressed in supraneural intervertebral disk hernia.In other embodiments, described preparation and method are used for treating lumbago, cancer pain, osteoarthritis pain, fibromyalgia and postoperative pain.In various other embodiments, described preparation is used for treating pain, osteodynia and the joint disease relevant to inflammation with method.Preparation of the present invention and method can be used for the pain that caused by the various diseases situation for the treatment of, include but not limited to operation or post-traumatic pain, the pain relevant to internal disease etc.

The present invention includes can administration so that two kinds of opioid preparations to be provided.The objective of the invention is to activate some Opioid Receptors in brain by a kind of opioid, and at some time point, the second opioid is arrived after receptor is occupied by the first opioid.The tablet that the two opioid prolongations of design discharge is to complete this point.For example, in the preparation that comprises oxycodone and morphine, need to postpone morphine release until oxycodone in receptor place at least one half an hour, and preferably over 1 hour.Also need to again supply oxycodone for taking in brain to eliminate identical substantially speed from the CNS chamber.Approximate mutually in the granule component that the delay of expection oxycodone and rate of release should discharge in the improvement of delay as herein described and the preparation (such as but not limited to the Tablet and Capsula agent) that mixes this.

Compound with opioid receptor agonist activity

The component of described pharmaceutical preparation can comprise the compound with opioid receptor agonist activity.This compounds can have for μ-, κ-, σ-or the agonist activity of delta-opioid receptor (receptor subtype that comprises other classification).Compound with opioid receptor agonist activity can be naturally occurring, semisynthetic or complete synthesis opiate compound, its derivant or analog, or the acceptable salt of its pharmacy, ester or prodrug.Naturally occurring opiate is the alkaloid compound of finding in the resin of Semen Papaveris, and comprises morphine, codeine and thebaine.Semi-synthetic or complete synthesis opiate includes but not limited to paramorphan (dihydromorphine), heterocodeine, dihydrocodeine, Hydromorphone (dihydrornorphinone), dihydrocodeinone, 3,6-diamorphine, hydromorphone (morphinone), 6-desoxymorphine, heroin, oxymorphone, oxycodone, 6-methylene-paramorphan (dihydromorphine), hydrocodone, etorphine, bupemorphine, naloxone or naltrexone.

Compound with μ-opioid receptor agonist activity can include but not limited to morphine (and on structure relevant analog and derivant), alvimopan, buprenorphine, codeine, the 6-desomorphine, paramorphan (dihydromorphine), Dilauid, dihydrocodeine, dihydrocodeinone, 3, the 6-diamorphine, 6-methylene-paramorphan (dihydromorphine), diphenoxylate, drotebanol, (-)-Eseroline, etorphine, fentanyl, hydrocodone, levophenacylmorphan, methadone, oxymorphone, nicomorphine, Pethidine, picenadol, tapentadol hydrochloride, thebaine and trimebutane.

Compound with κ-opioid receptor agonist activity can include but not limited to asimadoline, butorphanol, bremazocine, cyclazocine, dextromethorphan, dynorphin, enadoline, ketazocine, nalbuphine, Na Fula coffee, norbuprenorphine, oxycodone, pentazocine, salvinorinA, 2-methoxymethyl salvinorin B and ethoxyl methyl thereof and the homologue of fluorine ethoxyl methyl, spiradoline and replace fluorine many.

Compound with delta-opioid receptor agonist activity can include but not limited to deltorphin, ethoxymetopon, leu-enkephalin, met-enkephalin, mitragyna speciosa (kratom), 9-methoxycorynantheidine., mitragynine-pseudoindoxyl, N-phenethyl-14-norbuprenorphine, Norclozapine and 7-spiroindanyloxymorphone.

In certain embodiments, described compound is selected from morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, paramorphan (dihydromorphine), oxymorphone, their mixture and the acceptable salt of their pharmacy.

Salt includes but not limited to hydrochlorate, sulfate, disulfate, tartrate, nitrate, citrate, biatrate, phosphate, malate, maleate, hydrobromate, hydriodate, fumarate, succinate etc.

The component of described pharmaceutical preparation can comprise and surpass a kind of compound, wherein saidly surpasses a kind of compound and exists with certain weight ratio.For example, described component can comprise two kinds of compounds, and wherein said compound exists with 2:1,2:2,2:3,2:5,3:1 or 3:4 weight ratio.

In specific embodiments, described compound is morphine and the oxycodone of about 3:2 weight ratio, or their pharmaceutical salts.The pharmaceutical composition of inclusion compound can be with the total amount administration up to 18mg morphine and the every dosage of 12mg oxycodone, the morphine that described compound comprises about 3:2 weight ratio and oxycodone, or their pharmaceutical salts.In some embodiments, the pharmaceutical preparation of inclusion compound can be with the amount administration up to about 600mg morphine or its pharmaceutical salts and about 400mg oxycodone or its pharmaceutical salts every day, the morphine that described compound comprises about 3:2 weight ratio and oxycodone, or their pharmaceutical salts.

Release characteristic spectrum and the feature of component

At least one component in described pharmaceutical preparation comprises the compound with opioid receptor agonist activity and has the release characteristics spectrum.

Described preparation can comprise extra component, and what wherein said extra component can have a described compound releases characteristic spectrum or release characteristics spectrum.

As used herein, the release characteristic spectrum that the release that refers to wherein the compound for absorbing there is no delay " released " in term.

As used herein, term " controlled release " refers to wherein to have with the release of releasing characteristic spectrum and compare compound the release characteristic spectrum of modification.The type of release characteristics spectrum comprises delayed release, extends release and pulse release characteristic spectrum.

As used herein, term " delayed release " refers to that wherein the release of the compound for absorbing has the release characteristic spectrum of delay.

As used herein, term " extend discharge " referred to the release characteristic spectrum that wherein reactive compound discharges with such speed: at approximately 8 hours or approximately 10 hours or approximately 12 hours or approximately 15 hours or approximately 20 hours or approximately 24 hours or approximately 30 hours or approximately in 35 hours or even longer time, blood level maintains in therapeutic domain, but lower than poisonous level.According to release characteristic spectrum of the present invention, term " extends and discharges " with " releasing " and " delayed release " release characteristic spectrum to be distinguished.As used herein, " postponing-extend to discharge " refers to the wherein hangover of reactive compound, but still than " discharging " release characteristic spectrum, extends longer release characteristic spectrum.

As used herein, term " pulse release " refers to that wherein compound discharges the release characteristic spectrum for absorbing with interval.

Release component

Releasing component can provide the approximately 1%-of the accumulated dose of compound approximately 50% to send by described pharmaceutical preparation.For example, release component can provide compound accumulated dose at least about 5% or about 10%-approximately 30% or about 45%-approximately 50% by described formulation delivered.In optional embodiment, release component provide compound accumulated dose approximately 2,4,5,10,15,20,25,30,35,40,45 or 50% by described formulation delivered.

Releasing component can be to decompose rapidly the mixture of the composition to discharge the opioid compound after administration.This can adopt for example form of granule, particle, powder, liquid and granule.

Release components

Release components can provide the approximately 30-95% of the accumulated dose of compound to send by described pharmaceutical preparation.For example, release component can provide compound accumulated dose approximately 70-90% or approximately 80% by described pharmaceutical preparation, send.In optional embodiment, release components provide compound accumulated dose approximately 30,35,40,45,50,55,60,65,70,75,80,85,90 or 95% by described formulation delivered.

Release components can have after repetition or single-dose about 1-approximately 25 hours, or the about T of 20,17,15,12,11,8,6,5,4,3,2 or 1 hours after administration _max.

In certain embodiments, release components can have after repeat administration the approximately about about T of 6 hours after 6 hours or repeat administration of about 5-after 8 hours or repeat administration of about 4.5- _max.

Release components can have after repeat administration about 10-approximately 25 hours, or the about T of 12,13,14,15,16,17,18,19 or 20 hours after administration _min.

In certain embodiments, release components can have after repeat administration the approximately about T of 14 hours after 16 hours or repeat administration of about 13- _min.

While measuring in USP I type device under 37 ° of C in water with 50rpm, the stripping of release components discharged approximately 20% compound or its salt of about 0-after 2 hours, perhaps after 4 hours, discharge approximately 60% compound or its salt of about 15-, perhaps after 6 hours, discharge approximately 80% compound or its salt of about 25-, perhaps after 8 hours, discharge approximately 85% compound or its salt of about 35-, perhaps after 10 hours, discharge approximately 95% compound or its salt of about 45-, or discharged approximately 100% compound or its salt of about 60-after 12 hours.

Release components can comprise the about 80mg compound of about 2mg-.When release components comprises about 2mg, described release components can provide the average C of the about 3ng/mL of about 1-or about 2ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 23.0nghr/mL of about 14.7nghr/mL-, or the about 21.0nghr/mL of about 15.8nghr/mL-, or the about 19.7nghr/mL of about 17.1nghr/mL-.

When release components comprises about 5mg, described release components can provide the average C of the about 7ng/mL of about 3-or about 5ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 62.8nghr/mL of about 40.2nghr/mL-, or the about 57.2nghr/mL of about 43.2nghr/mL-, or the about 53.7nghr/mL of about 46.7nghr/mL-.

When release components comprises about 10mg, described release components can provide the average C of the about 15ng/mL of about 5-or about 10ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 125.9nghr/mL of about 80.5nghr/mL-, or the about 114.8nghr/mL of about 86.6nghr/mL-, or the about 107.7nghr/mL of about 93.7nghr/mL-.

When release components comprises about 20mg, described release components can provide the average C of the about 30ng/mL of about 10-or about 20ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 259.3nghr/mL of about 166.0nghr/mL-, or the about 236.6nghr/mL of about 178.5nghr/mL-, or the about 222.0nghr/mL of about 193.0nghr/mL-.

When release components comprises about 40mg, described release components can provide the average C of the about 55ng/mL of about 25-or about 40ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 528.9nghr/mL of about 338.5nghr/mL-, or the about 482.3nghr/mL of about 363.9nghr/mL-, or the about 452.7nghr/mL of about 393.5nghr/mL-.

When release components comprises about 80mg, described release components can provide the average C of the about 110ng/mL of about 50-or about 80ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 1356.9nghr/mL of about 868.4nghr/mL-, or the about 1237.5nghr/mL of about 933.5nghr/mL-, or the about 1161.5nghr/mL of about 1009.5nghr/mL-.

In some embodiments, release components provides the average C of the about 40ng/mL of about 0.5-or the about 15ng/mL of about 4-after repeat administration _min.

In certain embodiments, T _max, T _min, average C _maxand C _mincan after by repeat administration in limit, determine.As used herein, term " stable state " means that the blood plasma level of given medicine reaches, and uses the described medicine with post dose that it is maintained to certain level, this level or higher than minimum effective treatment level and lower than the minimum poisonous blood plasma level of compound.For opioid analgesic, as oxycodone, minimum effective treatment level can partly be determined by the amount that realizes pain relief in given patient.The technical staff of medical domain will appreciate that pain measurement is highly subjective, and huge individual variation can occur between the patient.Obviously, after the administration of each dosage, concentration is by maximum and then be down to minimum.

Stable state can be described below: in time t=0 (time of the first dosed administration) concentration C, be also 0.Then concentration, by the first maximum, then is down to the first minimum.In concentration, be down to before 0, by another dosed administration, thereby the increase for the second time of concentration is not since 0.On the basis of this first concentration minimum, by after the second dosed administration, curve negotiating the second maximum (it is on the first maximum), and be down to the second minimum (it is on the first minimum).Therefore, due to the progressively accumulation of repeated doses and relevant active substance, the blood plasma curve progressively rises, until it is stablized to the point that absorbs and eliminate balance.Absorption and elimination balance and the concentration continuous this state vibrated between the maximum of the minimum and definition of definition is called stable state.

The active substance of component

Described one or more extra components can comprise one or more active substances.For example, described active substance can be any compound with opioid receptor agonist activity as this paper discussion.

Described active substance can also comprise one or more non-opioid analgesic compounds, or one or more non-opioid analgesic compounds and one or more have the compound of opioid receptor agonist activity or the mixture of the acceptable salt of their pharmacy, ester or prodrug.Non-opioid analgesic compounds can play a role and carry out alleviating pain with other mechanism by irrelevant with being bonded to Opioid Receptors.For example, described non-opioid analgesic compounds can be non-steroid class anti-inflammatory compound (NSAID), and the example includes but not limited to that piroxicam, lornoxicam (lomoxicam), tenoxicam, salicylic acid (aspirin) and other Salicylates are as diflunisal; The 2-arylpropionic acid is coughed up acid, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen as ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen (flubiprofen), ketoprofen, copper; Positive aryl-anthranilic acid is as mefenamic acid (metenamic acid) and meclofenamic acid; Aryl-alkanoic is as diclofenac, aceclofenac, acemetacin, etodolac, indomethacin (idomethacin), sulindac and tolmetin etc.; Perhaps their mixture.

Non-opioid analgesic compounds can also be COX-1 or cox 2 inhibitor compound, include but not limited to celecoxib (

), etoricoxib, Lu meter Kao former times, parecoxib, rofecoxib, valdecoxib or their mixture.Non-opioid analgesic can also be the calcium channel bonding agent as gabapentin or lyrica, or their derivant, analog or prodrug, or their mixture.

In certain embodiments, non-analgesic compounds is gabapentin ester (Solzira ^tM), its prodrug that is gabapentin, chemistry 1-[[[[1-(2-methyl-l-oxopropoxy) ethyoxyl by name] carbonyl] amino] methyl] Cyclohexaneacetic acid.The structure of gabapentin, lyrica and gabapentin ester is as follows:

Described active substance can also be that one or more mix the opioid compound, or one or more mix the opioid compound and one or more have the compound of opioid receptor agonist activity or the mixture of the acceptable salt of their pharmacy, ester or prodrug.Mixing the opioid compound is the compound by by the joint component, two or more opioid compound covalent bond are formed together.The joint component can be stable, or can be hydrolyzed to provide parent opioid compound under physiological condition.Mixing opioid compound is described in the people's such as Holaday that submit on February 18th, 2009 U.S. Provisional Application series number 61/153,537.Mix the opioid compound and also be described in the people's such as Portoghese No. WO2006/073396th, International Patent Application Publication.

Mixing the opioid compound can comprise two or more that connect by covalency joint component and have the compound of opioid receptor agonist activity.Mix the opioid compound and can also comprise the compound with opioid receptor agonist activity that is connected to non-opioid active substance (including but not limited to non-opioid analgesic compounds as described above).In some embodiments, described non-opioid active substance is gabapentin, lyrica or gabapentin ester.

Mix the opioid compound and can comprise two or more opiate compounds that are bonded together by the covalency joint.Described opiate compound can include but not limited to opiate compound mentioned above.

Reactive compound can, by various chemical bondings to the joint component, preferably not hinder the position of the biologic activity of active substance on active substance.Usually, active substance can be bonded to by the reactive group on reactive compound joint or can be activated with the position bonding with the joint component reaction.

The component preparation

In order to obtain the component of pharmaceutical composition as herein described, with debita spissitudo, use the combination of excipient so that the pharmacokinetics of characteristic and expectation to be provided.Excipient for pharmaceutical composition as herein described is commercially available, and lists in USP or NF.Selection contributes to every kind of activity to release the function of component and purpose and contributes to the excipient of final component.The technical staff will appreciate that the concentration of these excipient used can undesirably increase or reduce to increase or reduce the particular characteristics in final opioid preparation.Coating material used herein is commercially available USP or the NF of being listed in also, and USP or NF quote and add this paper.

Be used for preparing technology that compound as herein described-opioid extends release tablet and be the combination of known process for preparing medicine.The unit process of releasing for the preparation of every kind of activity is for several commercially available products, but so large-scale.Prepare two importances that compound-opioid extends release tablet and be preparation and the performance of the granule that the improvement of dissimilar delay discharges.In the example of two opioid oxycodones/morphine compounds product, the preparation of the morphine granule that the oxycodone granule that the improvement of delay discharges and the improvement of delay discharge and the importance of performance are similar.These should be identical with the granule performance of free-pouring not tabletting after the tablet compacting.This key character preferably completes to avoid adding cracking and the brittle fracture of depressing coating during the tablet compacting by abundant plasticizing coating network.

The material that adds the compound for releasing component can be but be not limited to microcrystalline Cellulose, corn starch, pregelatinized Starch, potato starch, rice starch, carboxymethyl starch sodium, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, ethyl cellulose, chitosan, the hydroxyl chitosan, the methylolation chitosan, crosslinked chitosan, crosslinked carboxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivative (carbopol, especially strange etc.), Polyethylene Glycol is as low-molecular-weight PEG (PEG2000-10000) and have 20, the high molecular weight PEGs (Polyox) of the molecular weight that 000 dalton is above.These materials can be useful with the scope existence of 1.0-60% (W/W).

In addition, it can be useful having other compositions in this system, so that the stripping of ancillary drug or the decomposition of component after picked-up or administration.These compositions can be surfactants, as sodium lauryl sulphate, single sodium glycerinate, Arlacel-80, Arlacel-80, polyoxyethylene sorbitan monooleate dehydration, tristerin, glycerin mono-fatty acid ester, only son's acid glyceride, one of non-ionic surface active agent is as the pluronic gram line of surfactant, any other material that perhaps there is surface active properties, or any combination of above-mentioned substance.These materials can exist with the ratio of 0.05-15% (W/W).

Material in release components is identical with the material of releasing in component, but has extra polymer to be integrated into component, or as the coating on granule or granule.The kind that can be used for the material of this purpose can be but be not limited to ethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, carboxymethyl cellulose, methylcellulose, nitrocellulose, especially strange R and especially strange RL, carbopol or have the Polyethylene Glycol that surpasses 8,000 daltonian molecular weight.These materials can exist with the concentration of 4-20% (W/W).

In certain embodiments, component can have the delayed release characteristic spectrum of pH sensitivity or the delayed release characteristic spectrum of non-pH sensitivity.Material in the delayed release component of pH sensitivity can be identical with the material of releasing in component, but have extra polymer to be integrated into component, or as the coating on granule or granule.The kind that can be used for the material of this purpose can be but be not limited to CAP, other phthalates of strange L and cellulose derivative especially.These materials can exist with the concentration of 4-20% (W/W).

Material in the delayed release component of pH sensitivity can be identical with the material of releasing in component, but have extra polymer to be integrated into component, or as the coating on granule or granule.The kind that can be used for the material of this purpose can be but the Polyethylene Glycol (PEG) (carbowax, Polyox), wax that are not limited to have the above molecular weight of 4,000 dalton as white beeswax or Cera Flava, paraffin, acrylic acid derivative (especially strange), propylene glycol and ethyl cellulose.Usually, these materials can exist with the scope of the 0.5-25% (W/W) of this component.

Pharmaceutical preparation

Described pharmaceutical preparation can comprise one or more components, and described component has one or more release characteristic spectrums.Every kind of component can comprise identical compound, can comprise different compounds or their mixture (for example, in same preparation, some components have identical compound, and other components have different compounds).In addition, component can comprise active substance as described herein.

For example, described preparation can comprise at least one component, and wherein said a kind of component has the release characteristics spectrum.

Described preparation can also comprise at least two kinds of components (the first and second components), and wherein every kind of component has different release characteristic spectrums.For example, the second in described at least two kinds of components starts to discharge wherein contained compound at least 1 hour after the first component, and the beginning discharged thus generally is no more than generation in 6 hours after since the first component, discharging compound.

Described preparation can also comprise at least three kinds of components (first, second, and third component).The first component can be to release component, and the beginning that discharges thus compound does not basically postpone after described preparation administration.The second and the 3rd component is release components, thereby the release of compound can postpone.Release components can be the delay component of pH sensitivity or non-pH sensitivity, and this depends on the type of preparation.The compound discharged from the delayed release component can postpone until start after releasing component release compound.For example, the compound discharged from second component can be from releasing compound that component the discharges C can reaching serum _maxafter time reach C _max.The compound discharged from the 3rd component can be at the C of the compound discharged from second component _maxreach afterwards the C in serum _max.

In certain embodiments, release component and can approximately produce the C of the compound discharged thus in 2 hours at about 0.5- _max, and second component produces the C of the compound discharged thus in being no more than approximately 4 hours _max.In general, the C of such second component _maxcan after described preparation administration, be no earlier than 2 hours reaches; Yet, can reach C in the short period by the concentration of adjusting excipient as herein described and/or coating _max, in order to obtain the preparation of the pharmacokinetic characteristic spectrum with expectation.

In certain embodiments, discharging compound since the 3rd component can be after the first and second components discharges compound.The C of the compound discharged from the 3rd component in some embodiments, _maxcan in 8 hours, reach.

Described preparation can also comprise at least 4 kinds of components (the first, second, third and the 4th component), and every kind in described at least 4 kinds of components has different release characteristic spectrums.For example, the compound of every kind of release from described at least 4 kinds of different components can reach C at different time _max.

Described preparation can also comprise at least 5 kinds of components (first, second, third, fourth and fifth component).The first component can be the first compound or first group of compound release component, and the second and the 3rd component can be the release components of the first compound or first group of compound.The 4th and BSA can be the release components of the second compound or second group of compound.For example, in certain embodiments, the first compound can be oxycodone, and the second compound can be morphine.

In certain embodiments, described preparation can be capsule form, the component of the tablet that comprises separation or a form.Therefore; for example, releasing component can be tablet or a form, and release components can be other tablets or a form; it provides the wherein controlled release of contained compound separately, thereby reaches the C of the compound discharged from each or the tablet that comprises granule at different time _max, and reach the C of described preparation in being less than 12 hours _max.

In certain embodiments, described pharmaceutical preparation itself comprises the release characteristics spectrum.For example, can after described preparation administration, approximately in 20,17,15,12,11,8,6,5,4,3,2 or 1 hours, reach the C of all compounds that discharge from described preparation _max.In some embodiments, can after described preparation administration, be less than in 2,1 or 0.5 hours and reach C _max.In other embodiments, can after described component administration, be greater than in 4.5,5,6,7,8,9 or 10 hours and reach C _max.

Described preparation can repeat or single-dose after the there is about 1-about T of 25 hours _max, or there is the approximately T of 20,17,15,12,11,8,6,5,4,3,2 or 1 hours after administration _max.

In certain embodiments, T _maxcan be about 4.5-after repeat administration approximately 8 hours, or about 5-approximately 6 hours, or approximately 6 hours.In some embodiments, repeat administration carries out in limit.

Described preparation can comprise the about 100mg compound of about 1mg-, or can comprise the about 80mg compound of about 2mg-.When described preparation comprises about 2mg, described release components can provide the average C of the about 3ng/mL of about 1-or about 2ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 23.0nghr/mL of about 14.7nghr/mL-, or the about 21.0nghr/mL of about 15.8nghr/mL-, or the about 19.7nghr/mL of about 17.1nghr/mL-.

When described preparation comprises about 5mg, described release components can provide the average C of the about 7ng/mL of about 3-or about 5ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 62.8nghr/mL of about 40.2nghr/mL-, or the about 57.2nghr/mL of about 43.2nghr/mL-, or the about 53.7nghr/mL of about 46.7nghr/mL-.

When described preparation comprises about 10mg, described release components can provide the average C of the about 15ng/mL of about 5-or about 10ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 125.9nghr/mL of about 80.5nghr/mL-, or the about 114.8nghr/mL of about 86.6nghr/mL-, or the about 107.7nghr/mL of about 93.7nghr/mL-.

When described preparation comprises about 20mg, described release components can provide the average C of the about 30ng/mL of about 10-or about 20ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 259.3nghr/mL of about 166.0nghr/mL-, or the about 236.6nghr/mL of about 178.5nghr/mL-, or the about 222.0nghr/mL of about 193.0nghr/mL-.

When described preparation comprises about 40mg, described release components can provide the average C of the about 55ng/mL of about 25-or about 40ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 528.9nghr/mL of about 338.5nghr/mL-, or the about 482.3nghr/mL of about 363.9nghr/mL-, or the about 452.7nghr/mL of about 393.5nghr/mL-.

When described preparation comprises about 80mg, described release components can provide the average C of the about 110ng/mL of about 50-or about 80ng/mL after repeat administration _max.After single-dose, AUC ₂₄can be the about 1356.9nghr/mL of about 868.4nghr/mL-, or the about 1237.5nghr/mL of about 933.5nghr/mL-, or the about 1161.5nghr/mL of about 1009.5nghr/mL-.

In certain embodiments, C _mincan approximately appearance in 18 hours of about 12-after the administration component in limit.In some embodiments, C _mincan after described preparation administration, approximately within 12,13,14,15,16,17,18,19 or 20 hours, occur.In some embodiments, C _mincan after described preparation administration, be less than approximately and occur in 10,9,8,7,6,5 or 4 hours.In some embodiments, C _mincan after described preparation administration, be greater than approximately and occur in 14,15,16,17,18,19 or 20 hours.In specific embodiments, surpass the C approximately occurred in 12 hours after administration _mincan after the preparation administration that not yet is absorbed into blood flow, reach approximately and occur in 1,2,3 or 4 hour.

In certain embodiments, described preparation can have after repeat administration about 10-approximately 25 hours, or the about T of 12,13,14,15,16,17,18,19 or 20 hours after administration _min.

In certain embodiments, described preparation can have after repeat administration the approximately about T of 14 hours after 16 hours or repeat administration of about 13- _min.

In some embodiments, described preparation can provide the average C of the about 40ng/mL of about 0.5-or the about 15ng/mL of about 4-after repeat administration _min.

While measuring in USP I type device under 37 ° of C in water with 50rpm, the stripping of described preparation discharged approximately 20% compound or its salt of about 0-after 2 hours, perhaps after 4 hours, discharge approximately 60% compound or its salt of about 15-, perhaps after 6 hours, discharge approximately 80% compound or its salt of about 25-, perhaps after 8 hours, discharge approximately 85% compound or its salt of about 35-, perhaps after 10 hours, discharge approximately 95% compound or its salt of about 45-, or discharged approximately 100% compound or its salt of about 60-after 12 hours.

Be to be understood that this class term means that described preparation designs and be intended to produce the release of so more late beginning when openly preparation starts to discharge after another component in this article.Yet this area is known, although such design and intention are arranged, some " seepages " of compound may occur." seepage " like this is not " release " as used herein.

In specific embodiments, described pharmaceutical preparation can comprise one or more components, two kinds of opioid compounds that described one or more components comprise 2:1,2:2,2:3,2:5,3:1 or 3:4 weight ratio.In certain embodiments, described component can comprise morphine and the oxycodone of about 3:2 weight ratio.

For example, described pharmaceutical preparation can comprise release components and release component, the mixture that described release components comprises morphine and oxycodone, and the described component of releasing comprises oxycodone.In some embodiments, release the T of the oxycodone in component _maxcan be for absorbing latter approximately 10 minutes to approximately 1 hour.In other embodiments, T _maxfor approximately 10 minutes to approximately 30 minutes or 45 minutes.Release components can discharge with slower speed in the longer time.For example, in some embodiments, release components can discharge the morphine of effective dose and the mixture of oxycodone in 12 hours.In other embodiments, release components can discharge morphine and the oxycodone of effective dose in 4 hours or in 8 hours.In other embodiments, release components can discharge morphine and the oxycodone of effective dose in 15,18,24 or 30 hours.

In some embodiments, the active substance of more late release can be from the pharmaceutical preparation pulse release, thereby the pulse of compound discharges at interval after the picked-up said preparation.For example, in certain embodiments, release components can discharge the active substance of the more late release of the first pulse in about 0.5-1 hour after picked-up, then after picked-up, approximately after 4 hours, discharges the second pulse, and approximately after 8 hours, discharges the 3rd pulse of medicine after picked-up.

The preparation preparation

On the one hand, described pharmaceutical composition is the Tablet and Capsula for oral administration.These tablets or capsule can comprise conventional excipients as binding agent, filler, lubricant, disintegrating agent or wetting agent.On the one hand, according to method well known in the art by tablet or capsule coating.

Best, be alterable height shape during compacting for the pelletize of this purpose, thereby minimize as far as possible before release time of appointment any seepage from the coating granule.In one embodiment, can expect to there is of short duration hysteresis, or the initial burst delay, or divide middle release oxycodone in the regiment headquarters of releasing of described preparation.In some embodiments, tablet weight is less than about 500mg, about 450mg, about 400mg, about 350mg, about 300mg, about 250mg, about 200mg, about 150mg, about 100mg, about 50mg, about 25mg or about 10mg, and drug load is approximately 20%, approximately 15%, approximately 10%, approximately 5% (w/w) of preparation or still less.In one embodiment, purpose is to have tablet size as far as possible efficiently, and excellent homogeneity and the integrity of the granule in tablet is provided simultaneously.

Disintegrating agent for tablet of the present invention is not particularly limited, as long as it is the disintegrating agent for pharmaceutical preparation.Example can comprise crospovidone, crystalline cellulose, has the hydroxypropyl cellulose of low degree of substitution, cross-linking sodium carboxymethyl cellulose, carboxymethylcellulose calcium, carboxyl Starch Sodium, carboxymethyl starch sodium, potato starch, wheaten starch, corn starch, rice starch, partially pregelatinized starch and hydroxypropyl starch.Can use in these disintegrating agents one or both or more kinds of.Crospovidone particularly preferably.For the kind of the disintegrating agent of coating granule of the present invention can with granule in used identical or different.

The example that is used for the acceptable additive of pharmacy of tablet of the present invention can comprise excipient, lubricant, pH adjusting agent, mask agent, sweeting agent, acidulant, cold-producing medium, foaming agent, antiseptic, fluidizing reagent, antioxidant, coloring agent, stabilizing agent, surfactant, buffer agent, spice, binding agent and solubilizing agents for drugs.Those skilled in the art can list the instantiation of these additives immediately.

These additives can suitably be formulated in the coating in granule, outside the granule with the disintegrating agent coating, at disintegrating agent and in all these, as long as they do not damage advantage of the present invention.

Any lubricant for pharmaceutical preparation can unrestrictedly use.The example that is used for the lubricant of tablet of the present invention can comprise light anhydrous silicic acid, magnesium stearate, stearic acid, calcium stearate, aluminium stearate, aluminum monostearate, sucrose fatty acid ester, Polyethylene Glycol, sodium stearyl fumarate, octadecanol, Talcum, titanium dioxide, aqueous silicon dioxide, magnesium silicate, synthetic aluminium silicate, calcium hydrogen phosphate, hardened castor oil, hardened rapeseed oil, Brazil wax, Cera Flava, microwax and sodium lauryl sulphate.Can use in these lubricants one or both or more kinds of.In these lubricants, preferably use one or more lubricants that are selected from light anhydrous silicic acid and magnesium stearate.Especially, preferably be contained in the combination of the intragranular silicic acid anhydride magnesium stearate outer with being included in granule.

When described preparation is tablet form, the shape of tablet does not have specific limited, as long as prepared without difficulty by its preparation facilities that can utilize common preparation facilities or have some modifications.The disc of the general concept of tablet can be thought representative instance.Whole size is not particularly limited.For example, shorter diameter (diameter of disk tablet) is adapted in the scope of 6-20mm, preferably 8-12mm.Thickness also is not particularly limited, but is suitably for 1-10mm, preferably 2-8mm.

In some embodiments, can expect to have initial short delay, this adds tablet to complete by the delayed release coating that will also be used as mask agent.If expectation, this coating can be that white is coloured transparent or opaque.If expectation, identification NDC code (U.S.) or similar identification code also can be imprinted on tablet.

Compound for tablet of the present invention can be used the coatings such as film coating agent, excipient, binding agent, lubricant, and this depends on its characteristic, and can add plasticizer.

Anti-abuse characteristic

In another aspect of this invention, pharmaceutical composition as herein described has and can be used for stoping them for generation of may be for the compositions of non-medical application or as the characteristic of Drug abuse.

Have a mind to or be not intended to intervene (tamper) prolongation delivery formulations can send rapidly heavy dose (the slow release product being converted into to the result of releasing form) and produce far-reaching various serious and life-threatening side effect, comprise respiration inhibition and exhaustion, calmness, cardiovascular collapse, stupor and dead.

Addict and leisure junkie are usually used and extend the opioid discharged by various route of administration.Common method comprises (a) parenteral (for example, intravenous injection), (b) intranasal (for example, sucking) and (c) discontinuity or repeat tablet or the capsule of the complete or crushing of orally ingestible.

A kind of pattern of abuse comprises from component extracts opioid, and this is to be used for intravenous injection by first tablet or capsule for example, being mixed with suitable solvent (, water or alcohol), then filtering and/or extract the opioid component from mixture.Abuse extends the opioid another kind of pattern discharged and comprises that medicine is water-soluble, pure or another " leisure solvent " discharges and the orally ingestible content to accelerate it, in order to peak concentration and maximum euphoric effect are provided.

Term " intervention " means by any operation of machinery, heat and/or chemical mode, it changes the physical characteristic of component, for example, slow release form if, opioid is disengaged for releasing, perhaps make opioid agonist can be used for improper purposes, as passed through optional administration, as parenteral.Intervention can be for example by crushing, shearing, grinding, mechanical extraction, solvent extraction, solvent soaking, burning, heating or their any combination.

In the context of the present invention, term " abuse ", " opioid agonist abuse " or " abuse of opioid dosage forms " comprise that when having guided the effect of such opioid agonist other drug is intermittently used alone or in combination, lie fallow and use and the life-time service opioid agonist: (i) with the amount that does not meet the standard medical practice or method and the approach of putting into practice by not meeting standard medical; (ii) outside the scope of the detailed description of the use provided qualified medical professionalism personage; (iii) outside qualified medical professionalism personage's supervision; (iv) outside the suitably used description of the approval provided in the legal manufacturer of medicine; (v) not in the component for the concrete approval of medical application as medicament; (vi) strong desire arranged and make great efforts to obtain; (vii) evidence of mandatory use is arranged; (viii) obtain by handling medical system, comprise that forgery medical history, symptom intensity, disease severity, patient identity, doctor do shopping, prescription is forged; (ix) impaired use is controlled; (x) no matter injury; (xi) by purchasing from non-medical treatment source; (xii) by selling or being transferred to non-healthcare supply chain by individuality; (xiii) the mood change purpose that medical treatment is not ratified or do not expected.

Term " anti-abuse ", " abuse stops " and " stoping abuse " commutative use in the context of the present invention, and comprise such pharmaceutical composition and method: (i) opposing, stop, dissuasion, reduce, postpone and/or obstruct and have a mind to, be not intended to or accidental physical manipulation or intervene component (for example, crushing, shear, grind, chew, stripping, melt, the pin puncture, suck, be blown into, by machinery, heat and chemical method, extract and/or filter); (ii) opposing, stop, have a mind to, be not intended to or accidentally use outside the suitably used description of dissuasion, the approval that reduces, postpone and/or obstruct outside the scope of detailed description of the use provided qualified medical professionalism personage, outside qualified medical professionalism personage's supervision and provide in the legal manufacturer of medicine or the abuse component (for example, intravenous is used, intranasal is used, suck use and orally ingestible so that peak concentration to be provided); (iii) opposing, stop, dissuasion, reduce, postpone and/or obstruct and have a mind to, be not intended to or accidentally prolongation of the present invention discharged to the form that component is converted into more instant-free; (iv) opposing, stop, dissuasion, the pain patients that reduces, postpone and/or obstruct leisure junkie, addict and have an addiction disease seek having a mind to or iatrogenic increase of physiology and psychological effects; (v) opposing, stop, dissuasion, reduce, postpone and/or obstruct and attempt stealthily component being given third party's (for example,, in beverage); (vi) opposing, stop, dissuasion, reduce, postpone and/or obstruct and attempt by handling medical system and obtaining component from non-medical treatment source; (vii) opposing, the mood change purpose that stops, tries to stop, reduces, postpones and/or obstruct component to sell or be transferred to non-healthcare supply chain and do not ratify or do not expect for medical treatment; (viii) opposing, stop, dissuasion, reduce, postpone and/or obstruct and have a mind to, be not intended to or physics, pharmacy, pharmacology and/or medical science characteristic that accidentally trial otherwise changes the component of manufacturer's expectation.

When intervening the component of pharmaceutical preparation, pharmaceutical preparation reduces release the amount of the opioid agonist that form discharges, and this reduces again opioid glad, happy, strengthening, award, mood change and the poisonous effect of component.

In specific embodiments, if intervene, use some excipient as polyvinylpyrrolidone (Kollidon30) or CREMOPHORE EL (Cremophor EL ^tM) or sodium lauryl sulphate produce disabled colloid substance.Add aqueous or water-alcohol solvent and can make the excipient of pulverizing and medicinal mixture become colloid substance, this extracts and causes difficulty easily opioid.The breast of mixed methyl acrylate copolymer and cellulosic polymer is floating is the example that causes the main component of this feature of the present invention.

The additive method that produces the opioid combination of anti-abuse provides in U.S. publication application US20090082466, and its instruction integral body is quoted and added this paper.

The preparation administration

An aspect of of the present present invention is a kind of method that is used for the treatment of pain, and described method comprises administration preparation as herein described.

Described preparation can be such as by any following route of administration administration: Sublingual, oral cavity, through mucous membrane, transdermal, parenteral, oral etc.In certain embodiments, can prepare in the mode that is applicable to oral administration by described preparation.Therefore, for example, for oral administration, every kind of component can be used as granule, granule, powder, liquid or particle, and then it forms the single medicine product, for example, in capsule, or is embedded in tablet, or is suspended in liquid for oral administration.As used herein, terms " formulation " also refers to the single medicine product that comprises at least one component.

In certain embodiments, described preparation is used for oral administration, and can or be many units chemical species for tablet or capsule form.Described preparation can be applicable to oral administration 1-6 time every day, every day 1-4 time usually, and as every day 1-3 time, 2 times, or once a day.In the context of this article, term " once a day " is intended to mean only pharmaceutical composition to be administered once every day, so that the compound that obtains effective therapeutic dose is to provide suitable treatment to reply.

The final dose of the compound that the administration by described preparation provides can be about 100mg, about 95mg, about 90mg, about 85mg, about 80mg, about 75mg, about 70mg, about 65mg, about 60mg, about 55mg, about 50mg, about 45mg, about 40mg, about 35mg, about 30mg, about 25mg, about 20mg, about 15mg, about 12mg, about 10mg, about 8mg, about 5mg, approximately 4, mg, about 3mg, about 2mg or about 1mg by weight.

The dosage of opioid compound depends on predetermined substance, the human or animal's of use combination treatment age, body weight condition etc.All of these factors taken together is well known to a person skilled in the art.

embodiment

Can more easily understand the present invention with reference to following examples, embodiment provides rather than in order to limit the present invention by the mode of explanation.

Embodiment 1: the opioid component

Exploitation is for the component of pharmaceutical preparation, as shown in table 1-8.

Table 1: target component 1 (oxycodone):

¹the amount of every, the solids content based on dispersion

²between processing period, remove

Table 2: target component 1 (morphine):

¹the amount of every, the solids content based on dispersion

²between processing period, remove

Table 3: target component 2 (oxycodone):

¹the amount of every, the solids content based on dispersion

²between processing period, remove

Table 4: target component 2 (morphine):

¹the amount of every, the solids content based on dispersion

²between processing period, remove

Table 5: target component 3 (oxycodone):

¹the amount of every, the solids content based on dispersion

²between processing period, remove

Table 6: target component 3 (morphine):

¹the amount of every, the solids content based on dispersion

²between processing period, remove

Table 7: target component 4 (oxycodone):

¹the amount of every, the solids content based on dispersion

²between processing period, remove

Table 8: target component 4 (morphine):

¹the amount of every, the solids content based on dispersion

²between processing period, remove

Embodiment 2: the pharmacokinetic characteristic spectrum of opioid preparation

A., oxycodone preparation with following pharmacokinetic characteristic spectrum is provided.Utilize the method described in the figure shown in Fig. 7-11 to obtain the pharmacokinetic characteristic spectrum by the concentration of adjusting excipient.This 8mg oxycodone preparation has the C of 8 hours _maxc with 14 hours _min.

B., oxycodone preparation with following pharmacokinetic characteristic spectrum is provided.Utilize the method described in the figure shown in Fig. 7-11 to obtain the pharmacokinetic characteristic spectrum by the concentration of adjusting opioid compound and excipient.This 8mg oxycodone preparation has the C of 6 hours _maxc with 16 hours _min.

C., two opioid oxycodone/morphine preparations with following pharmacokinetic characteristic spectrum are provided.Utilize the method described in the figure shown in Fig. 7-11 to obtain the pharmacokinetic characteristic spectrum by the concentration of adjusting opioid compound and excipient.This 8mg oxycodone/4mg morphine preparation has the C of two kinds of opioid 6-20 hours _max, and two kinds of C of opioid 15-26 hour _min.

D., two opioid oxycodone/morphine preparations with following pharmacokinetic characteristic spectrum are provided.Utilize the method described in the figure shown in Fig. 7-11 to obtain the pharmacokinetic characteristic spectrum by the concentration of adjusting opioid compound and excipient.This 18mg morphine/12mg oxycodone preparation has the C of 6 hours _maxc with 16 hours _min.

Embodiment 3: preparation extends the middle preparation of release

Preparation has the prolongation formed as shown in Tables 9 and 10 and discharges a middle preparation A and B.

Table 9: preparation A:

* USP=American Pharmacopeia; The NF=NF

Table 10: preparation B:

* USP=American Pharmacopeia; The NF=NF

The preparation process of mix preparation illustrates in the flow chart of Figure 12.In order to prepare described preparation, oxycodone hydrochloride, microcrystalline Cellulose and polyvinylpyrrolidone (Kollidon30) are sieved into separately to collection container by hand by the #20 mesh sieve.The mixture sieved is transferred to the pelletize bowl of high shear granulator and is dry mixed 3 minutes.

The granulation solution of purifying waste water that comprises that to mix with CREMOPHORE EL is sprayed into the pelletize bowl with constant rate of speed, with low speed impeller or low speed copped wave, mixing is set.Continue the granulation mixture of visual evaluation gained, and when needed extra purifying waste water is sprayed on agglomerate.

Then utilize extruder and plate spheronizator to make extruded-round as a ball process of granulation mixture.The agglomerate that will wet sieves and evenly clamp-ons the marmurizing bowl by 0.8mm, and here extrudate forms the granule of suitable size.

Utilize fluid bed drying comminutor granule is dried to≤3% loss on drying (LOD) test target.In order to obtain preferred part, a dry stainless steel sift by #20 and #40 order size is sieved into to double-layer polyethylene liner fiber drums for storing until the granule spray coating.

Then utilize fluidized bed dryer to make granule carry out spray coating.In rustless steel container, utilize pneumatic helical oar blender that the coating component is mixed into to isopropanol/water solution at least 1 hour, until obtain settled solution.In independent rustless steel container, by enteric-coated component is mixed and prepared enteric coating solution until obtain settled solution at least 1 hour with pneumatic blender.The polymer coating spray solution, on granule, is continued to monitor to spraying condition simultaneously.The granule completed is put into to double-layer polyethylene liner fiber drums for storing until lubricated in processing (work-in-process).

Stainless steel sift by lubricated granule by #18 and #40 order size to be to obtain preferred part, and puts into double-layer polyethylene liner fiber drums for storing until tablet mixes.

Embodiment 4: the pharmacokinetics test of preparation A and B

Method

Carry out single dose, three periods, three orders, three process crossing research with oral administration relatively as described in Example 3 preparation A or B or reference preparation (with 20mg (oxycodone CR) is the MS of administration altogether

the oxycodone pharmacokinetic characteristic spectrum of individual human 30mg (morphine CR)).

Each is individual participates in a series of three periods, wherein comprises examination and registration before (i) administration each period, (ii) administration of preparation, and (iii) sample collection and following up a case by regular visits to after administration.Individual each the time interim acceptance different preparations, and which kind of order administration is random division to determine preparation with.

Before administration, examination and registration comprise physical examination and the record of individual life sign.By opioid antagonists naltrexone (50mg) administration in 0.5 hour before administration.Collect blood sample after 10 minutes and 0.5,1,2,3,4,5,5.5,6,6.5,7,8,10,12,14,18,21,24,48 and 72 hour after the preparation administration.

Measure morphine and oxycodone in the blood plasma of blood sample with tandem mass spectrometry (LC/MS/MS) by liquid chromatograph, confirm to contain following scope:

Morphine 0.25-100ng/mL

Oxycodone 50-50,000pg/mL

Result

At the sample collecting time point, the mean plasma concentration of oxycodone is as shown in Figure 13 (whole 72 hours) and Figure 14 (first 24 hours).With reference preparation, compare, preparation A causes higher oxycodone blood plasma level in 5-16 hour after processing, although after this blood plasma level is generally lower.On the other hand, in processing, within latter 6 hours, also continue whole 48 hours, preparation B compares with reference preparation and produces approximately identical or larger oxycodone blood plasma level.During during this period of time, the blood plasma level large 30% that the oxycodone blood plasma level average specific reference preparation that preparation B provides provides.

These data are used for presenting oxycodone blood plasma characteristic spectrum, due to this preparation by administration multiple dose B, as shown in Figure 15 and 16.Figure 15 illustrates the oxycodone blood plasma characteristic spectrum of the preparation B of 4 dosage of administration, and is presented under this dosage regimen, and the oxycodone blood plasma level can be maintained at about the about 20ng/mL of 7-.

Figure 16 illustrates can be by the oxycodone blood plasma characteristic spectrum due to various dose administration intensity, and concentrates on the single dose that blood plasma level reaches multiple dose scheme after stable state; Stable state is characterised in that crest and trough consistent in multiple dose blood plasma characteristic spectrum.Figure 16 is presented under stable state, C _maxcan inform the intensity of pharmaceutical quantities.

Figure 17 and 18 illustrates the projection of oxycodone blood plasma characteristic spectrum of preparation of the complex that comprises immediate release formulations (10%) and preparation B (90%) of multiple dose.Figure 17 confirms the oxycodone blood plasma characteristic spectrum of the compound formulation of 4 dosage of administration, and is presented under this dosage regimen, and the oxycodone blood plasma level can be maintained at about the about 19ng/mL of 10-.

Figure 18 illustrates the oxycodone blood plasma characteristic spectrum that can cause after the administration of the compound formulation of various dose administration intensity.Figure 18 concentrates on the single dose that blood plasma level reaches multiple dose scheme after stable state, and stable state is characterised in that crest and trough consistent in multiple dose blood plasma characteristic spectrum.Projection Display under stable state, C _maxbe less than dosage.

The comparison of the comparison of the oxycodone blood plasma characteristic spectrum of preparation A and reference preparation and the oxycodone blood plasma characteristic spectrum of preparation B and reference preparation is as shown in table 11 and 12.

Table 11: comparative formulations A and reference preparation

?	Preparation A	Reference preparation
			AUC t[pg·hr/mL]	167077.87±18761.51	194706.30±41996.62
C max[pg/mL]	24410.50±4864.72	20525.70±4520.50
			T max[h]	5.00(2.00–6.00)	3.00(2.00–5.00)

Table 12: comparative formulations A and reference preparation

?	Preparation B	Reference preparation
			AUC t[pg·hr/mL]	180846.58±22868.36	194706.30±41996.62
C max[pg/mL]	16471.00±3543.53	20525.70±4520.50
			T max[h]	5.75(5.00–12.0)	3.00(2.00–5.00)

Although the AUC of preparation A and B _taUC lower than reference preparation _tbut, the AUC of preparation A and B _trespectively within 14% and 7%.And, the T of preparation A and B _maxall be greater than the T of reference preparation _max, this is also unexpected.

Embodiment 5: have oxycodone-morphine the controlled release mixture oxycodone release compositions

Prepare the oral component tablet of oral administration solid according to preparing the known standard method in tablet field, its core that comprises 5.0mg oxycodone hydrochloride and 5.0mg morphine sulfate is as active component and quaternary amine ylmethyl acrylate copolymer, hypromellose, lactose, magnesium stearate, PEG400, polyvinylpyrrolidone, sodium hydroxide, sorbic acid, octadecanol, Talcum, titanium dioxide and glyceryl triacetate.By the outside of tablet controlled release preparation coating, described controlled release preparation comprises 10mg oxycodone hydrochloride and gelatin, hypromellose, corn starch, Polyethylene Glycol, polyoxyethylene sorbitan monoleate, iron oxide red, silicon dioxide, sodium lauryl sulfate (dodium laurel sulfate), sucrose, titanium dioxide and iron oxide yellow.The gained tablet is administered for to alleviating pain to the patient, and causes effectively analgesia and the respiration inhibition of morphine induction does not occur.

Embodiment 6: the conventional method for preparing controlled release preparation

The mode that below preparation is described by example provides, for the preparation of the controlled release compressed tablets that comprises morphine sulfate and oxycodone hydrochloride.

The preparation of granule core

By active drug substance (morphine sulfate and oxycodone hydrochloride), microcrystalline Cellulose, USP and PVP K30, NF is respectively by the manual collection container that is sieved into of #20 mesh sieve.The mixture sieved is proceeded to high shear granulator as the pelletize bowl of PMA-25 or PMA-65 and is dry mixed 3 minutes.

Will be by the purifying waste water of former mixing, USP and CREMOPHORE EL, the granulation solution of the solution composition of NF is sprayed into the pelletize bowl and with low speed impeller/low speed copped wave, mixing is set with constant rate of speed.Visual evaluation pelletize result on continuous foundation, and if need, by extra purifying waste water, USP is sprayed on agglomerate.When granulation stage finishes, take out sample and test for the process of water content.

After having sampled, pelletize is entered and extrude round as a ball process, use Luwa extruder and plate spheronizator or equivalent.The agglomerate that will wet sieves and evenly clamp-ons the marmurizing bowl by 0.8mm, and here extrudate forms the granule of suitable size.

Fluid bed drying to≤5% the loss on drying (LOD) of utilizing suitable GPCG-3, GPCG-5 for procedure parameter or equivalent to carry out granule is tested target.A dry stainless steel sift by #20 and #40 order size is sieved into to double-deck PE-liner fiber drums to obtain preferred part for storing until a spray coating at goods.

Improve the preparation that discharges the coating spheroidal particle

Utilize pneumatic helical oar blender that quaternary amine ylmethyl acrylate copolymer and triethyl citrate are mixed into to isopropanol/water solution contained in rustless steel container at least 1 hour until obtain settled solution.Then Talcum is added to container, continuous stirring.Utilize suitable procedure parameter to carry out the bed spray coating of core granule with the GPCG-5Wurster that is furnished with the 1.0mm nozzle.

The preparation of enteric coating spheroidal particle

In independent container, by rustless steel container, with pneumatic blender mixed methyl acrylic copolymer and triethyl citrate, within least 1 hour, preparing enteric coating solution.Then Talcum is added to container, continuous stirring.Polymer coating solution is sprayed to complete on spheroidal particle continuously with constant rate of speed, continue to monitor spraying condition simultaneously.The enteric coating spheroidal particle is put into to double-layer polyethylene liner fiber drums for storing until lubricated at goods.

The stripping method of testing of embodiment 7. controlled release preparations

The stripping method of testing is designed to for example, use together with automatization stripping sampling station (, Varian VK8000).If such instrument is unavailable, can carry out suitable adjustment with manual draw samples.

Device: USP<711 > install 2 (oars)

Automatization's stripping sampling station

Container size/type: about 1000mL/ clear glass, round bottom container

Rotary speed: about 50rpm all the time

The stage 1 (acid phase) of medium and volume: 0-2 hour:

Under 37.0 ± 0.5 ° of C, 750mL acidic leaching medium A keeps 2 hours

The stage 2 (buffer stage) of 2-11 hour:

1000mL under 37.0 ± 0.5 ° of C, by by the 250mL dissolution medium

B and 20mL dissolution medium A add from Jie in the container in stage 1

The remainder of matter and producing.Stages 2 medium should have approximately 6.8 pH.

Probe temperature: about 37.0 ± 0.5 ° of C

Sinker: the basket sinker (0.46 " x0.80 ") 40 orders, the 316-SS wire cloth

Extract volume: about 10mL

Spectrum time point: approximately 1,2,3,4,6,9 and 11 hour

Medium displacement: nothing

Sampling: automatization

Filter type/size: embedded 10-μ m polyethylene full flow filter

Embodiment 8: controlled release opioid preparation compositions

According to the method for embodiment 6, prepare following preparation:

Table 13: the improvement release microparticles preparation that uses the quaternary amine ylmethyl acrylate copolymer of the RS/RL ratio with 90/10

Preparation has the various preparations of the quaternary amine ylmethyl acrylate RS/RL polymer of different % coating levels (for example 25%, 35%, 45%, 50% and 55%).Figure 19 (a) and 20 (a) provide respectively the representative stripping characteristic spectrum of morphine sulfate and oxycodone hydrochloride.

Table 14. is used the tablet formulation of morphine/oxycodone enteric coating/improvement release microparticles.

Preparation has the various tablet formulations of different % enteric coating levels (for example, 10%, 15%, 20%, 25%, 30% and 40%).Figure 21 and 22 provides respectively the representative stripping characteristic spectrum of morphine sulfate and oxycodone hydrochloride.

The various % of embodiment 9. improve the stripping test that discharges coating level and enteric coating level

Utilize two batches of (～3kg) morphine sulfate/oxycodones of RS/RL polymer ratio coating (weight ratio 3:2) core granule of 90/10 (the 1st batch, in Table 13) and 80/20 (the 2nd batch).By every batch of different coating levels of use (25%, 35%, 45%, 50% and 55%) coating, and in the coating process collected specimens.The 1st batch and the 2nd batch to different coating levels is carried out stripping test (Figure 19 and 20).

In addition, the coating granule (50%RS/RL coating level) that makes to obtain from the 1st batch carries out the enteric coating of different % coating levels (10%, 15%, 25%, 30% and 40%) to produce enteric coated tablet and to carry out stripping test (Figure 21 and 22).

Also analyze the stripping of the function as tablet hardness (low, in or high) of enteric coated tablet batch (using 10% and 15% enteric coating) to determine the resistance (Figure 23 and 24) of tablet to various compacting levels.

Being summarised in table 15 of stripping test provides.

Table 15. stripping test experiments

Figure 19 and 20 is illustrated in the stripping characteristic spectrum that acquisition pays close attention to, and the improvement of different % coating levels discharges the versatility of core spheroidal particle.FR stripping characteristic spectrum allows the specific interior medicine dynamics blood plasma level of targeting and determines external and associated in body.

Figure 21 and 22 also is illustrated in the stripping characteristic spectrum that acquisition pays close attention to, and the improvement of the enteric coating of different % enteric coating levels discharges the versatility of core spheroidal particle.Again, FR stripping characteristic spectrum allows the specific interior medicine dynamics blood plasma level of targeting and determines external and associated in body.

Figure 23 and 24 illustrates the impact of compression stress on the tablet that comprises the enteric coating spheroidal particle, and the improvement that described enteric coating spheroidal particle comprises morphine sulfate and oxycodone hydrochloride discharges the coating granule.Common known high compression forces can significantly reduce the stripping of tablet, particularly known while being the coating polymer of fragility when adopting, as with quaternary amine ylmethyl acrylate copolymer A type and Type B.Figure 23 and 24 confirms that low or high compression forces does not affect the stripping of tablet.This result is unexpected, and confirms the elasticity of preparation/coating to compression stress.

Embodiment 10. controlled release opioid preparation compositions

According to the method for embodiment 6, prepare following preparation:

Table 16: with/without the tablet formulation of the improvement release microparticles (RS/RL) of enteric coating (Eudragit L100-55 C type).

The representative stripping characteristic spectrum of the morphine sulfate of the preparation that Figure 25-27 provide respectively table 16 to provide and oxycodone hydrochloride.These illustrate in obtaining the stripping characteristic spectrum of paying close attention to, and the improvement of different % coating levels discharges the versatility of core spheroidal particle.The enteric coating spheroidal particle preparation that allows to realize FR stripping characteristic spectrum also is provided.

****

Certainly, be to be understood that aforementioned content only relates to some disclosed embodiment of the present invention, and wherein can carry out many modifications or change and not deviate from the spirit and scope of the present invention as shown in appended claims.

Claims (45)

1. a pharmaceutical preparation that is used for the treatment of people's pain, it comprises one or more opioid components, wherein:

(a) described one or more opioid components comprise one or more release characteristic spectrums;

(b) at least one described opioid component is to comprise opioid controlled release opioid component, and wherein said opioid is oxycodone or its salt;

Wherein said pharmaceutical preparation provides about 4.5-after the repeat administration time (T of the plasma concentration to maximum oxycodone or its salt of approximately 8 hours _max).

2. the pharmaceutical preparation of claim 1, wherein said controlled release opioid component also comprises one or more and is selected from the extra opioid in following group: morphine, codeine, hydromorphone, hydrocodone, dihydrocodeine, paramorphan (dihydromorphine), oxymorphone, their mixture and their salt.

3. the pharmaceutical preparation of claim 1, wherein when the oxycodone of the accumulated dose that comprises about 2mg or its salt, the approximately 0-that described preparation provides the about 23.0nghr/mL of about 14.7nghr/mL-after single-dose is the area under curve (AUC of 24 hours approximately ₂₄).

4. the pharmaceutical preparation of claim 3, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 2mg, and has the AUC with 2mg ₂₄proportional AUC ₂₄.

5. the pharmaceutical preparation of claim 1, wherein, when the oxycodone of the accumulated dose that comprises about 2mg or its salt, described preparation provides the average maximum oxycodone of the about 3ng/mL of about 1-or the plasma concentration (C of its salt in limit after repeat administration _max).

6. the pharmaceutical preparation of claim 5, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 2mg, and has the C with 2mg _maxproportional C _max.

7. the pharmaceutical preparation of claim 1, wherein when the oxycodone of the accumulated dose that comprises about 5mg or its salt, the approximately 0-that described preparation provides the about 62.8nghr/mL of about 40.2nghr/mL-after single-dose is the area under curve (AUC of 24 hours approximately ₂₄).

8. the pharmaceutical preparation of claim 7, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 5mg, and has the AUC with 5mg ₂₄proportional AUC ₂₄.

9. the pharmaceutical preparation of claim 1, wherein, when the oxycodone of the accumulated dose that comprises about 5mg or its salt, described preparation provides the average maximum oxycodone of the about 7ng/mL of about 3-or the plasma concentration (C of its salt in limit after repeat administration _max).

10. the pharmaceutical preparation of claim 9, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 5mg, and has the C with 5mg _maxproportional C _max.

11. the pharmaceutical preparation of claim 1, wherein when the oxycodone of the accumulated dose that comprises about 10mg or its salt, the approximately 0-that described preparation provides the about 125.9nghr/mL of about 80.5nghr/mL-after single-dose is the area under curve (AUC of 24 hours approximately ₂₄).

12. the pharmaceutical preparation of claim 11, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 10mg, and has the AUC with 10mg ₂₄proportional AUC ₂₄.

13. the pharmaceutical preparation of claim 1, wherein, when the oxycodone of the accumulated dose that comprises about 10mg or its salt, described preparation provides the average maximum oxycodone of the about 15ng/mL of about 5-or the plasma concentration (C of its salt in limit after repeat administration _max).

14. the pharmaceutical preparation of claim 13, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 10mg, and has the C with 10mg _maxproportional C _max.

15. the pharmaceutical preparation of claim 1, wherein when the oxycodone of the accumulated dose that comprises about 20mg or its salt, the approximately 0-that described preparation provides the about 259.3nghr/mL of about 166.0nghr/mL-after single-dose is the area under curve (AUC of 24 hours approximately ₂₄).

16. the pharmaceutical preparation of claim 15, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 20mg, and has the AUC with 20mg ₂₄proportional AUC ₂₄.

17. the pharmaceutical preparation of claim 1, wherein, when the oxycodone of the accumulated dose that comprises about 20mg or its salt, described preparation provides the average maximum oxycodone of the about 30ng/mL of about 10-or the plasma concentration (C of its salt in limit after repeat administration _max).

18. the pharmaceutical preparation of claim 17, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 20mg, and has the C with 20mg _maxproportional C _max.

19. the pharmaceutical preparation of claim 1, wherein when the oxycodone of the accumulated dose that comprises about 40mg or its salt, the approximately 0-that described preparation provides the about 528.9nghr/mL of about 338.5nghr/mL-after single-dose is the area under curve (AUC of 24 hours approximately ₂₄).

20. the pharmaceutical preparation of claim 19, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 40mg, and has the AUC with 40mg ₂₄proportional AUC ₂₄.

21. the pharmaceutical preparation of claim 1, wherein, when the oxycodone of the accumulated dose that comprises about 40mg or its salt, described preparation provides the average maximum oxycodone of the about 55ng/mL of about 25-or the plasma concentration (C of its salt in limit after repeat administration _max).

22. the pharmaceutical preparation of claim 21, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 40mg, and has the C with 40mg _maxproportional C _max.

23. the pharmaceutical preparation of claim 1, wherein when the oxycodone of the accumulated dose that comprises about 80mg or its salt, the approximately 0-that described preparation provides the about 1356.9nghr/mL of about 868.4nghr/mL-after single-dose is the area under curve (AUC of 24 hours approximately ₂₄).

24. the pharmaceutical preparation of claim 23, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 80mg, and has the AUC with 80mg ₂₄proportional AUC ₂₄.

25. the pharmaceutical preparation of claim 1, wherein, when the oxycodone of the accumulated dose that comprises about 80mg or its salt, described preparation provides the average maximum oxycodone of the about 110ng/mL of about 50-or the plasma concentration (C of its salt in limit after repeat administration _max).

26. the pharmaceutical preparation of claim 25, it is formulated as oxycodone or its salt of the accumulated dose that is different from about 80mg, and has the C with 80mg _maxproportional C _max.

27. the pharmaceutical preparation of claim 1, it comprises the second controlled release opioid component.

28. the pharmaceutical preparation of claim 27, wherein said the second controlled release opioid component comprises the opioid be selected from following group: morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, paramorphan (dihydromorphine), oxymorphone, their mixture and their salt.

29. the pharmaceutical preparation of claim 1, it comprises releases the opioid component.

30. the pharmaceutical preparation of claim 29, the wherein said opioid component of releasing comprises the opioid be selected from following group: morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, paramorphan (dihydromorphine), oxymorphone, their mixture and their salt.

31. the pharmaceutical preparation of claim 30, the wherein said opioid of releasing in the opioid component is morphine or its salt.

32. the pharmaceutical preparation of claim 31, in wherein said preparation, the weight ratio of total morphine or its salt and total oxycodone or its salt is that about 3:2 morphine or its salt are than oxycodone or its salt.

33. the pharmaceutical preparation of claim 1, it comprises the second opioid component and the 3rd opioid component, wherein:

(a) described the second opioid component is for releasing the opioid component, and comprises the opioid with kappa agonist activity; And

(b) described the 3rd opioid component is controlled release opioid component, and comprises the opioid with MU agonist activity.

34. the pharmaceutical preparation of claim 33, the opioid that wherein has the kappa agonist activity is oxycodone or its salt.

35. the pharmaceutical preparation of claim 33, the opioid that wherein has the MU agonist activity is morphine or its salt.

36. the pharmaceutical preparation of claim 1, wherein said controlled release opioid component comprises morphine or its salt.

37. the pharmaceutical preparation of claim 36, the morphine that wherein said controlled release opioid component packet content is about 3:2 weight ratio or its salt and oxycodone or its salt.

38. the pharmaceutical preparation of claim 1, while wherein measuring in USP I type device under about 37 ° of C in water with about 50rpm, the stripping of described preparation discharged about 0-approximately 20% oxycodone or its salt after 2 hours.

39. the pharmaceutical preparation of claim 1, while wherein measuring in USP I type device under about 37 ° of C in water with about 50rpm, the stripping of described preparation discharged about 15-approximately 60% oxycodone or its salt after 4 hours.

40. the pharmaceutical preparation of claim 1, while wherein measuring in USP I type device under about 37 ° of C in water with about 50rpm, the stripping of described preparation discharged about 25-approximately 80% oxycodone or its salt after 6 hours.

41. the pharmaceutical preparation of claim 1, while wherein measuring in USP I type device under about 37 ° of C in water with about 50rpm, the stripping of described preparation discharged about 35-approximately 85% oxycodone or its salt after 8 hours.

42. the pharmaceutical preparation of claim 1, while wherein measuring in USP I type device under about 37 ° of C in water with about 50rpm, the stripping of described preparation discharged about 45-approximately 95% oxycodone or its salt after 10 hours.

43. the pharmaceutical preparation of claim 1, while wherein measuring in USP I type device under about 37 ° of C in water with about 50rpm, the stripping of described preparation discharged about 60-approximately 100% oxycodone or its salt after 12 hours.

44. the controlled release method of one or more compounds with opioid receptor agonist activity that absorb for the people, wherein said method comprises the pharmaceutical preparation that administration comprises one or more components, wherein:

(a) described one or more opioid components comprise one or more release characteristic spectrums;

(b) at least one described opioid component is to comprise opioid controlled release opioid component, and wherein said opioid is oxycodone or its salt;

Wherein said pharmaceutical preparation provides about 4.5-after the repeat administration time (T of the plasma concentration to maximum oxycodone or its salt of approximately 8 hours _max).

45. a method for the treatment of people's pain, described method comprises the pharmaceutical preparation that administration comprises one or more components, wherein:

(a) described one or more opioid components comprise one or more release characteristic spectrums;

(b) at least one described opioid component is to comprise opioid controlled release opioid component, and wherein said opioid is oxycodone or its salt;

Wherein said pharmaceutical preparation provides about 4.5-after the repeat administration time (T of the plasma concentration to maximum oxycodone or its salt of approximately 8 hours _max).

Images