WO2015089530A1

WO2015089530A1 - Extended-release oral dosage form containing morphine and naloxone

Info

Publication number: WO2015089530A1
Application number: PCT/AT2014/000220
Authority: WO
Inventors: Thomas Frisch; Elisabeth KÜHBERGER; Doris Lechner; Christof WACHTER; Harald Wagner
Original assignee: G.L. PHARMA GmbH
Priority date: 2013-12-20
Filing date: 2014-12-09
Publication date: 2015-06-25

Abstract

Disclosed is an extended-release oral dosage form comprising morphine or a physiologically acceptable salt thereof and naloxone or a physiologically acceptable salt thereof for oral opioid substitution therapy. The dosage form contains 0.5 to 2 mg naloxone per 100 mg morphine.

Description

Oral prolonged release dosage form containing morphine and naloxone

The invention relates to a sustained-release oral dosage form comprising morphine or a physiologically acceptable salt thereof and naloxone or a physiologically acceptable salt thereof for oral replacement therapy in opioid-dependent patients.

Drug dependence, especially dependence on opioids, such as heroin, is a chronic psychiatric disorder that can be associated with multiple psychiatric, physical and also infectious co-morbidities. The substitution treatment of opioid-dependent patients is carried out with prescriptive and regulatory-compliant drugs with the primary goal of stabilizing patients and thus significantly improving the health and social situation of patients. Abstinence is not the primary treatment goal due to the high morbidity associated with it.

Common substitution agents are, for example, ^' methadone, morphine and buprenorphine, in which methadone therapy in particular is not well tolerated by some of the patients and because of its metabolism via CYP3A4 methadone has a higher interaction potential than, for example, morphine. Furthermore, the partial agonist buprenorphine is due to its low intrinsic activity for only a portion of the opioid addicts as a substitute means overall is (Haltmeyer et al (2009), Consensus Statement "Sub ^¬ stitutionsgestüt zte treatment of opioid addicts" Suchtmed. 11: 281-297), so there is a need for innovative alternatives that are well tolerated. In addition, it is extremely important to prevent an abusive parenteral, in particular intravenous administration of said oral substitution preparations and thus further damage largely.

Slow-release morphine is an ideal substitution agent because it is the active ingredient of the addictive agent - usually heroin, which is rapidly deacetylated to morphine in the organism - and must be administered only once daily due to the delayed release of the drug.

The risk of substitution therapy is generally the non-prescription intake of substitution products. In intravenous administration, about one-third to one-fifth of the oral dose is sufficient to achieve the desired effect. An abusive parenteral administration of the retarded morphine by the patient can be largely avoided if the opioid antagonist naloxone is added to the retarded morphine in such a way that it can not be separated from the agonist. When taken orally, the opioid antagonist is virtually ineffective due to its pronounced first-pass metabolism in the liver and the resulting low bioavailability, and the opioid exhibits its full effect, whereas abusive parenteral administration suppresses the action of the opiate by the opioid antagonist and the desired effect of the opioid is absent.

Several combined administration forms of morphine and naloxone, which find use in drug-replacement therapy, are already known from the prior art. Both EP 1810678 AI and EP 1976524 Bl disclose combination preparations of morphine and naloxone for the treatment of drug dependence. The ones described in these documents. However, exact dosage of morphine and naloxone is not recommended in order to prevent oral withdrawal episodes which occur when the dose of naloxone is too high and the opioid effect is sufficient if used improperly Press down, which in turn requires a sufficient amount of naloxone. The ratio morphine to naloxone, so must be chosen exactly. In doing so, a large number of influence factors must be taken into account. For example, it must be taken into account that naloxone has a much more potent pharmacological activity than morphine. In general, naloxone given intravenously can completely antagonize the effect of 25 mg of heroin (Goodman &Gilraan's, The Pharmacological Basis of Therapeutics, 2 ^t ed ed 2011: 511).

Furthermore, naloxone, after parenteral administration, penetrates the brain much more rapidly than morphine. After intravenous administration, the ratio of the concentration in the brain to that in the blood plasma for naloxone is 2: 1, whereas in the case of morphine the ratio is only 1:10 (Berkowitz et al. (1976), Disposition of naloxone: use of a new radioimmunoassay, J Pharmacol Exp Tner 195: 499-504), This relationship must be considered in the design of the oral dosage form Case of improper parenteral administration to achieve the desired result. In addition, morphine has a lower affinity for the μ-opioid receptor than naloxone, with the result that naloxone also binds much less concentrated than the morphine binds to the μ-opioid receptor and blocks the binding of morphine (Freissmuth et al (1993), Dinding and structure-activity-relation of benzo [f] isoquinolines and norco-deinone-derivatives at μ-opioid receptors in the rat cerebral cortex; Br J Pharmacol 110: 1429-1436). Furthermore, the plasma half-life of naloxone is much lower than that of morphine. Naloxone is thus degraded much faster in the body than morphine.

In order to optimally choose the ratio of morphine to naloxone in an oral dosage form, the above framework conditions should be taken into account as comprehensively as possible and a dose optimization in comparison to already known dosage forms is required. The present invention therefore aims to provide a sustained-release oral dosage form comprising morphine or a physiologically acceptable salt thereof, and naloxone or a physiologically acceptable salt thereof, wherein the amounts of the two active substances are coordinated with each other, that withdrawal symptoms when taken orally can be successfully avoided and abusive administration of the dosage form effective verhin ^¬ changed is. To achieve this object, the sustained-release oral dosage form according to a first aspect of the invention contains 0.5 to 2 mg of naloxone per 100 mg of morphine. Surprisingly, it has been found that the dosage form in the dosage ratio according to the invention safely protects against parenteral abuse. In the dosage according to the invention, naloxone reduces or eliminates the main and secondary effects of morphine in the case of abusive parenteral administration. The degree of reduction / cancellation ultimately depends only on the particular concentration of morphine and naloxone. Since orally taken naloxone does not reach the major blood circulation and therefore the brain in a significant concentration due to the pronounced first pass mechanism in the liver, the substitution effect of morphine is not impaired, ie no withdrawal symptoms are triggered. By combining naloxone with morphine in the optimal dosage ratio according to the invention, a substitution agent is obtained which does not cause any withdrawal reactions when administered orally and nevertheless sufficiently suppresses the action of the opioid in the case of abusive parenteral administration.

Furthermore, it has been observed that the dosage ratio according to the invention allows a wide range of dosage strengths. In particular, dosage strengths between 50 mg of morphine and 400 mg of morphine per dosage form are possible, even the small absolute amount of naloxone 50 mg dose effectively prevents parenteral abuse, and at the same time the large absolute amount of naloxone in the 500 mg dosage in oral administration still no Withdrawal reminders triggers. In addition, the dosage ratio according to the invention allows a cumulation of at least two dosage forms, in particular tablets, to achieve higher total dosage strengths. In contrast, it was in the dosage forms of the prior art often problematic when the patient takes a plurality of low-dose dosage forms at the same time to obtain a correspondingly higher, required for the replacement therapy dose. In particular, when compared to the invention higher naloxone / morphine ratios there was the danger that with the cumulative amount of morphine such a high absolute Naloxonmenge was taken that despite the low bioavailability still sufficient amount of naloxone enters the large bloodstream, so withdrawal symptoms are triggered. Conversely, in comparison to the invention smaller Na ^¬ loxon / morphine ratios there is the danger that the small absolute amount of naloxone, which is in low-dose forms (eg 50 - ^■ 100 mg morphine) contained in abusive parenteral administration not sufficient antagonistic Effect caused.

The administration of the substitution agent according to the invention can be due to the present in retarded form morphine less frequently than non-retarded morphine and the desire of the patient to get new drugs as soon as possible, is mitigated due to the longer-lasting effect of morphine. Furthermore, the risk of overdose can be reduced since the active ingredient is controlled and released into the blood while avoiding concentration peaks.

If morphine and naloxone amounts and ratios are given in the context of the invention, all stated values are based on the morphine hydrochloride trihydrate and the sodium oxone hydrochloride dihydrate. The factor for converting morphine hydrochloride trihydrate into alkaloid base of morphine is 0.759195 and the conversion factor of naloxone hydrochloride dihydrate to the alkaloid base of naloxone is 0.818713. It has proved to be particularly advantageous if the claimed dosage form contains 0.5 to 1 mg of naloxone, preferably 1 mg of naloxone per 100 mg of morphine. With this dosage ratio, the advantageous effects described above can be further optimized.

The dosage form according to the invention preferably contains 0.25 to 1 mg, in particular 0.25 to 0.5 mg, preferably 0.5 naloxone and 50 mg morphine. Surprisingly, it has been found that even the very small amount of naloxone contained in this particular dosage form successfully prevents parenteral abuse. The binding ability of naloxone to the μ-opioid receptor is much more pronounced than that of morphine. As a result, even small amounts of naloxone are sufficient to successfully bind the μ-opioid receptor and prevent the binding of morphine.

The dosage form preferably contains 0.5 to 2 mg, in particular 0.5 to 1 mg, preferably 1 mg, naloxone and 100 mg morphine.

The dosage form preferably contains 1 to 4 mg, in particular 1 to 2 mg, preferably 2 mg, naloxone and 200 mg morphine. In another preferred embodiment, the dosage form contains 1.5 to 6 mg, in particular 1.5 to 3 mg, preferably 3 mg, naloxone and 300 mg of morphine. In another preferred embodiment, the dosage form contains _. 2 to 8 mg, in particular 2 to 4 mg, preferably 4 mg, naloxone and 400 mg morphine. Surprisingly, it has been found that the comparatively high-dose naloxone in this particular dosage form does not trigger any withdrawal symptoms, naloxone binds with higher affinity to the μ-opioid receptor than morphine. This usually causes the morphine to have no chance of binding to the receptor in the case of too high a nitrous oxide dose, which results in withdrawal symptoms. In this preferred dosage form, however, the amount of naloxone is low enough.

According to a further aspect of the invention it is provided that the naloxone in the inventive oral form of administration is present in an amount such that it exerts no pharmacological effect relevant for ora ^¬ ler handover. A substance will show a pharmacological effect if it leads to interactions with any cellular component present in the user's body. With regard to the dosage form according to the invention, this therefore means that the naloxone is present in such a small amount that there is no interaction between naloxone and the μ-opioid receptor upon oral administration, and consequently the naloxone does not unfold its antagonistic action.

Drug addicts often try to separate the active substances of the combination preparations offered as part of a substitution therapy in order to obtain the ingredient in question. This is done for example by pulverization of the dosage form and subsequent separation of the ingredients. In order to prevent separation, the oral dosage form according to the invention Particularly preferred form a breaking strength of at least 4.0 N / mm ² , whereby the abuse potential is significantly reduced, since a pulverization of the dosage form is difficult or insufficient possible. As a result, powdering of the administration form is made considerably more difficult by conventional means, such as a mortar and hammer, and the abuse following comminution is decisively restricted or prevented. For a safe parenteral intake namely, a sufficient comminution of the dosage form is necessary. If there is insufficient crushing, the injection involves a large number of dangers or the extraction of the active ingredient before the injection would take too long.

According to the following formula (Pitt et al (2013), Determina ^¬ tion of the tensile strength of elongated tablets; Powder Technol 238. 169-175) can be calculated, the breaking strength (ed) for round, bi-convex tablets.

For this purpose, only parameters such as the force at break (P), the diameter of the tablet (D), the thickness above everything (t) and the thickness of the central cylinder or the web height (W) must be known.

Oblong tablets use the following formula:

D in this case is the diameter or width of the oblong tablet. The preparation according to the invention is administered as a solid oral dosage form, for example as a tablet, tablet or coated tablet. The person skilled in the appropriate dosage forms are known. Depending on the specific form of administration, the preparation according to the invention contains the auxiliaries customary for this purpose, which make it possible to achieve a corresponding breaking strength, which are likewise well known to the person skilled in the art and, as a result, need not be further explained. In addition, it makes sense to package the dosage form in a child-resistant packaging.

Furthermore, the oral dosage form according to the invention is preferably in a non-separable tablet form, which prevents the morphine from being separated from the naloxone. For example, the morphine and the naloxone can be present together embedded in a matrix and pressed into a tablet, which considerably increases the separation of the active ingredients from the matrix! and thus the undesired separation of the ingredients is successfully avoided. The naloxone is in particular eingranuliert in the tablet matrix of the dosage form, which further aggravates a separation of the antagonist from the agonist. This makes it impossible for the drug addict because of the visual undecidability to separate the particles from each other. A separation of morphine and naloxone with mechanical and / or visual separation methods or by dissolution of the mixture and subsequent evaporation and / or precipitation of the individual components of the mixture is thus difficult.

In addition to the morphine present in a retarded form according to the invention, it may preferably be provided that the naloxone is also present in a retarded form. The naloxone is released in a controlled manner in the body, and dangerous concentration spikes of the active ingredient in the blood are successfully avoided, thus ensuring, when taken according to the invention, that the opioid - and not the opioid antagonist - exerts its full effect. Common methods for achieving a sustained release of the active ingredient are, for example, the delayed release by means of a retarding polymer matrix.

Preferably, the dosage form for once-a-day intake is formed.

According to the morphine can be administered in all common dosage forms. However, preferred are physiologically acceptable salts such as the morphine hydrochloride trihydrate and the morphine sulfate and its hydrates.

According to the invention, the naloxone can be administered in all conventional dosage forms, but preferably physiologically acceptable salts, such as the naloxone hydrochloride dihydrate are used.

According to a preferred embodiment, the active ingredient naloxone is released largely independent of pH. Is preferred provided that the active ingredient morphine is largely released independent of pH.

Since the preparation according to the invention is a sustained-release preparation, it makes sense that the release of the active ingredient largely takes place regardless of the pH value, since the tablet comes into contact with an acidic environment after swallowing in the stomach and subsequently in the stomach Intestinal tract is located in a slightly alkaline environment. However, the sustained release of active substances must function equally efficiently in both milieus.

Oral dosage forms are commonly coated with a film to mask unpleasant tastes, facilitate swallowing, protect the drugs from external influences, and generally control and modify drug release.

Particularly preferably, the dosage form is coated with a talc-free film in order to preserve the patient unsachgemä ^¬ SSER intravenous administration before granuloma formation and the resulting physical damage.

Misuse of oral substitution agents, which may be crushed or crushed and subsequently dissolved in water and injected, may result in serious injury to health, particularly if the preparations contain talc. Since talc (magnesium silicate) is a mineral that is almost insoluble in water, it can cause severe damage when it enters the bloodstream by injection. An injection into peripheral arteries can lead to occlusion of small blood vessels and capillaries (ischaemia). and subsequently lead to cell death in parts of the distal extremities or organs. The more common mode of injection into peripheral veins can lead to foreign body granulomas in the lungs, liver, kidneys, and retina (Roberts (2002), Pulmonary talc granulomas, pulmonary fibrosis, and pulmonary hypertension resulting from intravenous injection of talc-containing drugs intended for oral use BUMC Proceedings 15: 260-261). These side effects can be successfully avoided by the present invention preferably provided talc-free coating of the claimed oral dosage form.

According to a further aspect of the invention there is provided a kit of oral dosage forms, each containing morphine or a physiologically acceptable salt thereof and naloxone or a physiologically acceptable salt thereof, with mutually different dosages comprising a first oral dosage form containing a first amount of morphine and a second oral dosage form corresponds holding a second quantity of morphine, wherein the second amount of at least twice, preferably at least the Dreifa ^¬ Chen, preferably at least four times, the first quantity. The oral dosage forms of the kit may preferably be used for oral replacement therapy in opioid addicts.

The dosage forms of the kit are preferably those according to the first aspect of the invention which contain 0.5 to 2 mg of naloxone per 100 mg of morphine. These dosage forms preferably contain 0.5 to 1, in particular 1 mg of naloxone per 100 mg of morphine. sur- sighted manner it has been found that compliance with these conditions causes already the small absolute ^'amount naloxone the first oral formulation effectively prevents the parenteral abuse and at the same time the large absolute naloxone amount of the second dosage form for oral administration no withdrawal symptoms triggers. As a result, a wide range of dosage strengths can be covered within the scope of a set. In particular, a dosage range of 50 mg morphine to 1500 mg morphine can be achieved.

According to a preferred development, the set further comprises a third oral dosage form containing a third amount of morphine, wherein the third amount corresponds to at least three times the first amount.

A further preferred embodiment provides that the kit further comprises a fourth oral dosage form containing a fourth amount of morphine, the fourth amount corresponding to at least four times the first amount.

In particular, the set may include a first oral dosage form containing 50 mg of morphine, a second oral Darreichungs ^¬ form containing 100 mg of morphine and a third oral dosage form comprising containing 200 mg morphine.

In particular, the kit may comprise a first oral dosage form containing 50 mg morphine, a second oral dosage form containing 100 mg morphine, a third oral dosage form containing 200 mg morphine and a fourth oral dosage form containing 300 mg morphine. Using the dose strengths contained in these kits, the physician can assemble the individually required dose to the patient. For this purpose, two or more different dosage strengths can be taken in combination. A dose of 650 mg is obtained for example by a set of a combination of a first dosage form containing 50 mg of morphine and two second dosage forms each containing 300 mg of morphine.

Advantageously, the weight is. Ratio of morphine and naloxone in the first and second and optionally third and optionally fourth dosage form chosen the same. This considerably simplifies the preparation of the dosage forms. In production, it is sufficient to make a large amount of a mixture of morphine and naloxone in a given ratio, which can then be processed into dosage forms of different dosage strengths. When recruiting patients for an addiction medication, one key challenge is finding the right dosage. This is called titration. As a rule, the titration is started with a low starting dose, the effect of this dose is monitored, and then the dosage is gradually increased. The pre ^¬ gang titration can be extremely uncomfortable for the patient, as it may initially be too small Do ^¬ sis gets. This leads to a desire for the substance and in further consequence to an increased risk of a crash replacement therapy and a return to unkontrollier ^¬ th drug use. The longer the titration lasts, the greater the associated problems. In this connection, it has been found that the initial dose in the course of titration in a dosage form containing morphine or a physiologically acceptable salt thereof and naloxone or a physiologically acceptable salt thereof can be increased as compared to a corresponding monopreparate containing only morphine Titration can be simplified. Furthermore, in the gradual increase in dosage larger jumps can be made as in a single preparation.

A further aspect of the invention therefore relates to a sustained release oral dosage form comprising morphine or a physiologically acceptable salt thereof and naloxone or a physiologically acceptable salt thereof for oral replacement therapy in opioid dependent, wherein the initial dose in the context of titration is 100 100 mg morphine. The titration preferably takes place in 150 mg steps. The dosage form is preferably a dosage form according to the first aspect of the invention.

Preferably, the dosage form for once-a-day intake is formed.

The invention will be explained in more detail with reference to the following examples, without being limited thereto. Examples 1 to 4:

The tablets according to Examples 1 to 4 are prolonged-release tablets which were prepared as follows (the amounts refer to Example 3):

2 mg of naloxone HCl x 2 H ₂ O are stirred into an aqueous dispersion of 40 mg (based on Lacktrockensubtanz) ethyl acrylate-methyl methacrylate copolymer (Eudragit NE30D), wherein the stirring time does not fall below 30 min.

For this purpose, preference is given to a 30% aqueous ethyl acrylate Methylmethacrylate copolymer dispersion used. But other concentrations can be used.

The granulation solution thus obtained is applied to a mixture of 200 mg of morphine HCl x 3 H ₂ O, 110, 04 mg of Eudragit L100-55 (methacrylic acid ethyl acrylate) and 73.36 mg of Eudragit RSPO (copolymer of ethyl acrylate, methyl methacrylate and a small proportion of methacrylic acid ester with quaternary ammonium groups). This can be done either by wet granulation or fluidized bed process.

The granules thus obtained are dried under moderate conditions (45 ° C). This can be done by means of a drying oven or fluidized bed.

The dried retard granules obtained are sieved after a sufficient standing time, admixed with free fractions 79.8 mg Eudragit L100-55 and 53.2 mg RSPO and mixed for 20 minutes (tumble mixer, suitable loading and RPM), mixed with 1.6 mg magnesium stearate and again 3 mixes min ge ^¬.

The press-ready mixture obtained is pressed into tablets with a suitable stamping tool and sufficient, adequate pressing force.

The resulting tablets are then coated with 15 mg optical coating (eg finished film from Colorcon containing HPMC, lactose, T1O ₂ , indigo carmine, triacetin, quinoline yellow).

The release profiles of the compositions of Examples 1 to 4 were determined as follows. Morphine values:

Naloxone values:

The release profiles of morphine and naloxone are shown in FIGS. 1 and 2. 1 shows the release of active ingredient morphine HCl trihydrate from morphine-Naloxone retard tablets according to Examples 1 to 4.

FIG. 2 shows the release of active ingredient of naloxone HCl dihydrate from morphine-naloxone-retard tablets according to Examples 1 to 4. Examples 5 to 8:

The preparation of Examples 5 to 8 was carried out analogously to Examples 1 to. The release profiles of the compositions of Examples 5 to 8 were determined as follows: morphine values:

Time% release

"Morphine" "Morphine" "Morphine" "Morphine"

Morphine Naloxone Morphine Naloxone Morphine Naloxone Morphine Naloxone

(h) 200 + 1mg 200 + 2mg 200 + 0mg 200 + 4mg

VCH 146/3 VCH 144/13 VCH 147/13 VCH 145/13

12mm round (WR16) 12mm round (WR16) 12mm round (WR16) 12mm round (WR16)

11 = = 6 n = = 6 n = = 6 n = = 6

_% VK (%)% VK (%)% VK (%)% VK (%)

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

^" EI 18.5 4.2 _" 20_, 0, _ 5.0 19.2 2.8 20.3 2.9

30.5 2.3 1 30.5 2, 1 32.5 2, 1

: · 1.4 47.0 1.3 "43" _, 4 _ 2, 1 48.5 1.4

53.2 0.9 56.6 1.4 2.0 58.9 1.3

~ 8 59.4 0.9 63.5 1.6 57.4 2.0 66.5 1, 1

10 64,3 0,9 69,0 1,5 n2:. 2, 1 72.3 1.4 vT ^™ 68.4 1, 1 73.8 2.2 66.7 2.0 77.2 U

:? '■ 0, 7 77.2 1.5 70.5 1.8 ^" 80.6 1.5

16 5 1.2 80.9 1.2 74.0 1, 7 84.2 2.4

20 80.9 1.2 85.8 1.2 79.4 1.9 89.9 2, 7

^"" T ₈₅ J " ^~ 1, 1 89.7 1.6 84.0 1.8 93.4 1.9

Naloxone values:

The release profiles of morphine and naloxone are shown in FIGS. 3 and 4.

Fig. 3, the release of morphine HCl trihydrate from morphine, naloxone retard shows tablets at constant amount of morphine (200 mg) and different Na ^¬ Loxon amount (1 mg, 2 mg, 0 mg and 4 mg naloxone).

In Fig. 4, the release of naloxone HCl dihydrate from morphine, naloxone retard tablets at constant amount of morphine (200 mg) and different Na ^¬ Loxon amount (1 mg, 2 mg, 0 mg and 4 mg naloxone) is shown.

The release profiles were determined by means hereinafter be ^¬ prescribed, so-called "pH-change method". Dissolution conditions for "pH change method

Method: Paddle model without

Sinker at 50 rpm

Temperature: 37 ° C ± 0.5 ° C

Test pattern: 1 FT / vessel

Discharge tents: 1, 2, 4, 6, 8, 10, 12, 14,

16, 20, 24 hours

Test medium 1st + 2nd hour 375 ml 0.1 M HCl

Removal of the 1st + 2nd hour: approx. 6 ml by hand in test tubes (6 ml by fold filter, discard first 4 ml, rest is sample solution)

Test medium after 2 nd hour: addition of 125 ml 0.2 M

Na ₃ P0 ₄ -sol. - pH 6.8 m. Adjust 2 M HCl or 2 M NaOH

Removal after 2, until 24th hour: autom. 1 ml in HPLC

vials

The samples are measured by HPLC against an exter ^¬ NEN standard.

Claims

Claims:

1. A sustained-release oral dosage form comprising morphine or a physiologically acceptable salt thereof and naloxone or a physiologically acceptable salt thereof for oral replacement therapy in opioid dependent, characterized in that the dosage form contains 0.5 to 2 mg naloxone per 100 mg morphine.

2. Oral dosage form according to claim 1, characterized in that the dosage form contains 0.5 to 1 mg, preferably 1 mg, naloxone per 100 mg of morphine.

3. Oral dosage form according to claim 1 or 2, characterized in that the dosage form contains 0.25 to 1 mg, in particular 0.25 to 0.5 mg, preferably 0.5 mg, naloxone and 50 mg of morphine.

4. oral dosage form according to any one of claims 1 or 2, characterized in that the dosage form contains 0.5 to 2 mg, in particular 0.5 to 1 mg, preferably 1 mg, naloxone and 100 mg of morphine.

5. oral dosage form according to one of claims 1 or 2, characterized in that the dosage form 1 to

4 mg, in particular 1 to 2 mg, preferably 2 mg, naloxone and 200 mg morphine contains.

6. oral dosage form according to any one of claims 1 or 2, characterized in that the dosage form contains 1.5 to 6 mg, in particular 1.5 to 3 mg, preferably 3 mg, Na ^¬ loxone and 300 mg of morphine.

7. oral dosage form according to any one of claims 1 or 2, characterized in that the dosage form contains 2 to 8 mg, in particular 2 to 4 mg, preferably 4 mg, naloxone and 400 mg of morphine.

8. Oral dosage form according to one of claims 1 to

7, characterized in that the naloxone is present in an amount such that it does not develop a relevant pharmacological effect when given orally.

9. Oral dosage form according to one of claims 1 to

8, characterized in that the dosage form has a breaking strength of at least 4.0 N / mm ² .

10. Oral dosage form, according to one of claims 1 to

9, characterized in that the dosage form is in a non-separable tablet form.

11. oral dosage form according to one of claims 1 to 10, characterized in that the naloxone is present in a retarded form.

12. Oral dosage form according to one of claims 1 to

11, characterized in that the morphine is used as morphine hydrochloride trihydrate.

13. Oral dosage form according to one of claims 1 to

12, characterized in that the naloxone is used as naloxone hydrochloride dihydrate.

14. Oral dosage form according to one of claims 1 to

13, characterized in that the active ingredient naloxone is released largely independent of pH.

15. Oral dosage form according to one of claims 1 to

14, characterized in that the active ingredient morphine is released largely independent of pH.

16. Oral dosage form according to one of claims 1 to

15, characterized in that the dosage form is coated with a talcum-free film.

17. Set of oral dosage forms according to one of claims 1 to 16 with mutually different dosages comprising a first oral dosage form containing a first amount of morphine and a second oral dosage form containing a second amount of morphine, the second amount at least twice, preferably at least three times, preferably at least four times, corresponds to the first amount.

The kit of claim 17 further comprising a third oral dosage form containing a third amount of morphine, wherein the third amount is at least three times the first amount.

19. A kit according to claim 17 or 18 further comprising a fourth oral dosage form containing a fourth amount

Morphine, wherein the fourth amount corresponds to at least four times the first amount.

20. Set according to one of claims 17 to 19 in mutually different dosages comprising a first oral dosage form containing 50 mg of morphine, a second oral dosage form containing 100 mg of morphine and a third oral dosage form containing 200 mg of morphine.

21. A kit according to any one of claims 17 to 20 in mutually different dosages comprising a first oral dosage form containing 50 mg of morphine, a second oral dosage form containing 100 mg of morphine, a third oral dosage form containing 200 mg of morphine and a fourth oral dosage form containing 300 mg of morphine ,

22. Set according to one of claims 17 to 21, character- ized in that the wt. Ratio of morphine and naloxone in the first and second and optionally third and optionally fourth dosage form is the same.

23. The oral dosage form with sustained release comprehensively morphine or a physiologically acceptable salt because of ^¬ and naloxone or a physiologically acceptable salt thereof for oral replacement therapy in opioid-dependent, wherein the initial dose is 100 mg morphine as part of the titration ^.

24. Oral dosage form according to claim 23, characterized in that the oral dosage form is designed according to one of claims 1 to 16.