WO2003013481A1 - The process of manufacturing pharmaceutical composition with increased content of poorly soluble pharmaceutical ingredients - Google Patents
The process of manufacturing pharmaceutical composition with increased content of poorly soluble pharmaceutical ingredients Download PDFInfo
- Publication number
- WO2003013481A1 WO2003013481A1 PCT/IB2002/003015 IB0203015W WO03013481A1 WO 2003013481 A1 WO2003013481 A1 WO 2003013481A1 IB 0203015 W IB0203015 W IB 0203015W WO 03013481 A1 WO03013481 A1 WO 03013481A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polyethylene glycol
- process according
- molecular weight
- poorly soluble
- pharmaceutical
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Definitions
- the present invention lelates to process foi manufacturing pharmaceutical composition witli increased content of poorly soluble active pharmaceutical ingredients. Poorly soluble active pharmaceutical ingredients needs larger amount of inactives to prepare a clear liquid prepaiation for encapsulation into a soft gelatin capsule. This necessitates increase in size of a capsule and/or increase in numbei of capsules to be consumed for a therapeutic effect.
- the present invention relates to improving the content of poorly soluble active phaimaceutical ingredients in a clear liquid solution.
- Liquid, and especially concentrated liquid pharmaceutical compositions offer many 'advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Liquids provide a rapid onset of pharrnacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Concentrated liquid compositions are ideally suited for encapsulation within a soft gelatin shell, to provide a portable and easy-to-swallow soft, llex ⁇ le capsule. Encapsulation would also permit the accurate and uniform delivery of a unit dose of a pharmaceutical active, an advantage which becomes especially important when telatively small amounts of an active are to be delivered. Additionally, soft gelatin capsules are aesthetically appealed (especially when filled with a transparent liquid) and can be manufactured in a wide variety of sizes, shapes, and colors.
- liquid compositions of the desired pharmaceutical active.
- Many pharmaceutical actives are poorly soluble and therefore require relatively large volumes of solvent for dissolution.
- choice of solvents available for use in liquid compositions is limited by safety, compatibility, stability, and economic concerns.
- use of large volumes of solvents for solubilizing pharmaceutical actives is undesirable because (he resulting solutions would be so dilute as to require unpractically large dosages for delivering a therapeutically /013481
- US patent 5484606 describes the process for reducing the precipitation of difficult to solublize pharmaceutical actives. It used propylene glycol to achieve this purpose along with polyethylene glycol and polyvinyl pyrolidine to achieve this.
- US patent 5505961 deals with gelatin capsules containing a highly concentrated acetaminophen solution. The invention, involves use of alkali metal acetate to improve solubility of acetaminophen in a solution -containing polyethylene glycol, polypropylene glycon and water.
- US patent 5510389 deals with concentrated acetaminophen solution compositions.
- Use of propylene glycol along with polyethylene glycol and polyvinyl pyrolidine improves solubility.
- Patent no. 5071643 is for solvent system enhancing the solubility of pharmaceuticals for encapsulation. It involves use of gelling agents like sodium stearate, sodium palmitate and calcium acetate to improve solubility of pharmaceutical ingredients into polyethylene glycol.
- US patent 6287594 discloses oral liquid compositions with improved Bioavai lability. They are designed to provide drugs with minimal gastric irritability wherein ratio of active drug to polymer based dispersing agent is from about 3:1 to 1:50 w/w. The resulting solution is found to be hazy. Polyvinyl pyrolidone is dispersing agent described. The purpose of invention is not to provide a clear solution.
- US patent 6383515 provides a medicament in concentration of 49% to 70 % wherein solvent system comprises of low molecular weight polymer and organic acid. It involves heating as a part of process. The process may, may not result in a clear solution as disclosed in examples.
- US patent 63 ' 87400 discloses a process for improving concentration of a pharmaceutically active ingredient relative to fill composition. It comprises of two step addition process. In step one a suspension o part of a drug is made in polyethelene glycol with a molecular weight of 200 daltons to 100,000 daltons and solubilizing it subsequently with hydroxide ion. In step two remaining drug is added and resulting suspension is solubilized by adding remaining part of hydroxide ion. The ratio of a drug to fill material by weight is 1:2 and/or 5:9. /013481
- US patent 5919, 481 discloses till material for soft gelatin capsule which is translucent, semisolid in nature. It uses poly alkylene .glycol with average molecular weight of about 600 or less along with cellulose ether.
- the US patent 5141961 discloses a process for solubilizing difficulty soluble pharmaceutical 1 actives. It uses polyet elene glycol, polyvinyl pyrolidine and monohydric alcohols. The ratio of polyethylene glycol to polyvinyl pyrolidine is about 2.5 to 1. It does not involve use of heat. It does not require use of solvent and surfactants.
- the present invention provides a process by which clear solution of poorly soluble pharmaceutical substances is obtained wherein the amount of pharmaceutical substance is increased compared to conventional pharmaceutical compositions available.
- water-miscible co-solvents or sutfactants into a pharmaceutical composition.
- water- miscible co-solvents such as ethanol
- these co-solvents may not be compatible with Ihe desited pharmaceutical actives.
- volatile waler-tniscible co-solvents are that they ate incompatible with soft gelatin capsules.
- the present invention uses a combination of polyethylene glycol will) diffetent molecular weight with polymer and water.
- Polyethylene glycol(PEG) used as per the present invention is a mixture of PEG with different molecular weights.
- Polymer is any polymer, including polyvinyl pyrolidone.
- the process as per the present invention does not ' use any alkalizing substance, surfactant to increase content of poorly soluble pharmaceutical ingredients as a clear liquid solution for encapsulation in a soft gelatin capsule.
- the invention herein provides for a process whereby the concentration of pharmaceutically active ingredients is improved in clear solution which can be used for encapsulation in a soft gelatin capsule. This permits the use of reduced overall fill volumes or alternatively, higher concentrations, of the active ingiedient per dosage unit or form.
- the process according to the present invention inci eases the achievable concentration of pharmaceutically active ingredient in a clear liquid solution which can be used for encapsulation of soft gelatin capsule comprises use of two or more polyethelene glycol with different molecular weight and polyvinyl pyrolidone.
- compositions suitable for use invention including but not limited to acetaminophen, acetylsalicylic acid, ibuprofen, fenbrprofen, flurbiprofen; indomethacin, naproxen, and mixture thereof.
- Polyethelene glycols which can be used in accordance with present invention include those having molecular weight range from about 200 daltons to about 100000 daltons.
- Preferable two polyethelene glycol as per present invention are those having average molecular weight of 400 daltons and 1000 daltons.
- Polyvinyl pyrolidone is used in present invention can also have a wide ranging molecular weight most preferred poly vinyl pyrolidone has molecular weight of about 30,000(k 30) 3/013481
- the heating is required to achieve a clear liquid solution.
- Pleating should not exceed 90°c. It is preferable done between 60°c to 80°c.
- the invention provides clear liquid solution with increased content of active pharmaceutical ingredient comprising: a. from about 15% to about 40% of at least one poorly soluble pharmaceutical active; b. from about 40% to about 60% of a polyethylene glycol; c. from about 4% to about 8% of a polyvinyl pyrolidine; and d. from about 5% to about 10%o water, wherein the ratio of poltethylene glycol to polyvinyl pyrolidine is from 4:1 to 15:1 .
- the pharmaceutical composition and soft gelatin capsule made as per present invention are stable for more than two years undei standard, stability conditions and self life
- the polyethylene glycols useftil herein are those which are liquids at room temperature or have a melting point slightly there above.
- Preferred are the polyethylene glycols having a moleculai weight range from about 300 to about 1000 More preferred are the polyethylene glycols having a molecular weight lange from about 400 to about 1000. Most preferred is a polyethylene glycol having a molecular weight of about 600 and 1000.
- Tf only a low molecular weight.
- PEG the poorly soluble drug aie either become turbid or precipitate.
- I a high molecular weight PEG, with poorly soluble drugs are not formed a clear liquid.
- a mixture of low and high molecular height PEG are bettei, therefore, mixtures of two or more polyethylene glycols of different average molecular weight range can also be employed in the present invention.
- the process for preparing the highly concentraled liquid compositions of the present invention comprises adding from about 40% to about 60% polyethylene glycol.
- PVP polyvinylpyrrolidone
- soluble forms of polyvinylpyrrolidone are preferred for use in the present invention.
- Preferred are soluble polyvinylpyrrolidones having an average molecular weight in the range from about 2900 to about 1 ,100,000; more preferred are those having an average molecular weight in the range from about 9000 to about 45,000; and most preferred are those having an average molecular weight of about 30,000 (k-30).
- mixtures of two or more soluble polyvinylpyrrolidones of different average molecular weight can be employed. /013481
- the process disclosed in the present invention for prepat ing the highly concentrated liquid compositions of the instant invention comprises adding from about 4% to about 8% of a soluble polyvinylpyrrolidone.
- the liquid After cooling, the liquid is subjected to de aerale under a vacuum pressure between 630 mm hg to 670 mm Hg. This liquid is ready for encapsulation in a soft gelatine shell. All blending and mixing operations are carried out at relative humidity from 25% to 35%.
- the liquid After cooling, the liquid is subjected to de aerate under a vacuum pressure between 630 mm hg to 670 mm Fig. This liquid is ready for encapsulation in a soft gelatine shell. All blending and mixing operations are carried out at relative humidity from 25% to 35%.
- the liquid After cooling, the liquid is subjected to de aerate undei a vacuum pressure between 630 mm hg to 670 mm ITg. This liquid is ready for encapsulation in a soft gelatine shell. All blending and mixing operations are carried out at relative humidity from 25% to 35%.
- Propylene glycol may be used in above process. FTowever its amount should not increase more than 2%. Otherwise solution looses its clarity.
- compositions are eilher no clear or loose their clarity during there self life
- EXAMPLE VII Ingredients Quantity per capsule Quantity for a batch of (mg) 0.2 Lac capsule (Kg) 1. Acetaminophen 400 00
- Polyethylene glycol 400 400 10.600
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IN750MU2001 | 2001-08-03 | ||
IN750/MUM/2001 | 2001-08-03 |
Publications (1)
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WO2003013481A1 true WO2003013481A1 (en) | 2003-02-20 |
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PCT/IB2002/003015 WO2003013481A1 (en) | 2001-08-03 | 2002-08-03 | The process of manufacturing pharmaceutical composition with increased content of poorly soluble pharmaceutical ingredients |
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Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006133519A1 (en) * | 2005-06-17 | 2006-12-21 | Australian Nuclear Science And Technology Organisation | Particles comprising a releasable dopant therein |
WO2006133518A1 (en) * | 2005-06-17 | 2006-12-21 | Australian Nuclear Science And Technology Organisation | Particles having hydrophobic material therein |
US20120183608A1 (en) * | 2011-01-14 | 2012-07-19 | Enspire Group LLC | Highly concentrated liquid acetaminophen solutions |
US8791154B2 (en) | 2011-05-19 | 2014-07-29 | Alcon Research, Ltd. | High concentration olopatadine ophthalmic composition |
US8901113B2 (en) | 2009-09-30 | 2014-12-02 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse |
US8969416B2 (en) | 2012-03-29 | 2015-03-03 | Enspire Group LLC | Polyvinylpyrrolidone-containing acetaminophen liquid formulations |
US9101636B2 (en) | 2012-11-30 | 2015-08-11 | Acura Pharmaceuticals, Inc. | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
US9492443B2 (en) | 2003-11-26 | 2016-11-15 | Acura Pharmaceuticals, Inc. | Abuse deterrent compositions and methods of making same |
US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US9707184B2 (en) | 2014-07-17 | 2017-07-18 | Pharmaceutical Manufacturing Research Services, Inc. | Immediate release abuse deterrent liquid fill dosage form |
US10172797B2 (en) | 2013-12-17 | 2019-01-08 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US10195153B2 (en) | 2013-08-12 | 2019-02-05 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
US10959958B2 (en) | 2014-10-20 | 2021-03-30 | Pharmaceutical Manufacturing Research Services, Inc. | Extended release abuse deterrent liquid fill dosage form |
US11103581B2 (en) | 2015-08-31 | 2021-08-31 | Acura Pharmaceuticals, Inc. | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
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EP0679395A1 (en) * | 1994-04-26 | 1995-11-02 | Bayer S.p.A. | Pharmaceutical compositions containing a ketoprofen solution in a soft gelatine capsule and method to produce them |
EP0719549A1 (en) * | 1994-12-29 | 1996-07-03 | McNEIL-PPC, INC. | Soft gelatine pharmaceutical dosage form containing a translucent gel |
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Patent Citations (5)
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WO1988002625A1 (en) * | 1986-10-17 | 1988-04-21 | R.P. Scherer Corporation | Solvent system for an ionizable pharmaceutical agent |
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US5141961A (en) * | 1991-06-27 | 1992-08-25 | Richrdson-Vicks Inc. | Process for solubilizing difficulty soluble pharmaceutical actives |
EP0679395A1 (en) * | 1994-04-26 | 1995-11-02 | Bayer S.p.A. | Pharmaceutical compositions containing a ketoprofen solution in a soft gelatine capsule and method to produce them |
EP0719549A1 (en) * | 1994-12-29 | 1996-07-03 | McNEIL-PPC, INC. | Soft gelatine pharmaceutical dosage form containing a translucent gel |
Cited By (29)
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---|---|---|---|---|
US9492443B2 (en) | 2003-11-26 | 2016-11-15 | Acura Pharmaceuticals, Inc. | Abuse deterrent compositions and methods of making same |
WO2006133519A1 (en) * | 2005-06-17 | 2006-12-21 | Australian Nuclear Science And Technology Organisation | Particles comprising a releasable dopant therein |
WO2006133518A1 (en) * | 2005-06-17 | 2006-12-21 | Australian Nuclear Science And Technology Organisation | Particles having hydrophobic material therein |
US9345667B2 (en) | 2005-06-17 | 2016-05-24 | Australian Nuclear Science And Technology Organisation | Particles having hydrophobic material therein |
US9131681B2 (en) | 2005-06-17 | 2015-09-15 | Australian Nuclear Science & Technology Organisation | Particles comprising a releasable dopant therein |
US9017643B2 (en) | 2005-06-17 | 2015-04-28 | Australian Nuclear Science & Technology Organisation | Particles comprising a releasable dopant therein |
US8815291B2 (en) | 2005-06-17 | 2014-08-26 | Austrailian Nuclear Science & Technology Organisation | Particles comprising a releasable dopant therein |
US8901113B2 (en) | 2009-09-30 | 2014-12-02 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse |
US10155044B2 (en) | 2009-09-30 | 2018-12-18 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse |
WO2012096939A3 (en) * | 2011-01-14 | 2012-10-18 | Enspire Group LLC | Highly concentrated liquid acetaminophen solutions |
US8518438B2 (en) | 2011-01-14 | 2013-08-27 | Enspire Group, Llc | Highly concentrated liquid acetaminophen solutions |
US20120183608A1 (en) * | 2011-01-14 | 2012-07-19 | Enspire Group LLC | Highly concentrated liquid acetaminophen solutions |
US9533053B2 (en) | 2011-05-19 | 2017-01-03 | Alcon Research, Ltd. | High concentration olopatadine ophthalmic composition |
US8791154B2 (en) | 2011-05-19 | 2014-07-29 | Alcon Research, Ltd. | High concentration olopatadine ophthalmic composition |
EP2830607A4 (en) * | 2012-03-29 | 2015-10-07 | Enspire Group LLC | Polyvinylpyrrolidone-containing acetaminophen liquid formulations |
US8969416B2 (en) | 2012-03-29 | 2015-03-03 | Enspire Group LLC | Polyvinylpyrrolidone-containing acetaminophen liquid formulations |
US9101636B2 (en) | 2012-11-30 | 2015-08-11 | Acura Pharmaceuticals, Inc. | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
US9320796B2 (en) | 2012-11-30 | 2016-04-26 | Acura Pharmaceuticals, Inc. | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
US10441657B2 (en) | 2012-11-30 | 2019-10-15 | Abuse Deterrent Pharmaceuticals, Llc | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
US11857629B2 (en) | 2012-11-30 | 2024-01-02 | Acura Pharmaceuticals, Inc. | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
US10688184B2 (en) | 2012-11-30 | 2020-06-23 | Acura Pharmaceuticals, Inc. | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
US10639281B2 (en) | 2013-08-12 | 2020-05-05 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
US10195153B2 (en) | 2013-08-12 | 2019-02-05 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
US10172797B2 (en) | 2013-12-17 | 2019-01-08 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US10792254B2 (en) | 2013-12-17 | 2020-10-06 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US9707184B2 (en) | 2014-07-17 | 2017-07-18 | Pharmaceutical Manufacturing Research Services, Inc. | Immediate release abuse deterrent liquid fill dosage form |
US10959958B2 (en) | 2014-10-20 | 2021-03-30 | Pharmaceutical Manufacturing Research Services, Inc. | Extended release abuse deterrent liquid fill dosage form |
US11103581B2 (en) | 2015-08-31 | 2021-08-31 | Acura Pharmaceuticals, Inc. | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
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