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 PDF

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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
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WIPO (PCT)
Prior art keywords
polyethylene glycol
process according
molecular weight
poorly soluble
pharmaceutical
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PCT/IB2002/003015
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French (fr)
Inventor
Bakulesh Mafatlal Khamar
Piyush Shantilal Kariya
Sunil Vandse
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Bakulesh Mafatlal Khamar
Piyush Shantilal Kariya
Sunil Vandse
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Application filed by Bakulesh Mafatlal Khamar, Piyush Shantilal Kariya, Sunil Vandse filed Critical Bakulesh Mafatlal Khamar
Publication of WO2003013481A1 publication Critical patent/WO2003013481A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167Amides, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/192Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic 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
    • A61K31/403Heterocyclic 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
    • A61K31/404Indoles, e.g. pindolol
    • A61K31/405Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/60Salicylic acid; Derivatives thereof
    • A61K31/612Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4858Organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4866Organic 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

The present invention relates to a process for solubilizing poorly soluble active pharmaceutical ingredients in a mixture of low molecular and high molecular polyethylene glycol and polyvinyl pyrolidine. The resulting compositions can be encapsulated in a gelatin shell and their capsules provide an effective means for oral delivery of a wide variety of poorly soluble pharmaceutical actives.

Description

/013481
THE PROCESS OF MANUFACTURING PHARMACEUTICAL COMPOSITION WITH INCREASED CONTENT OF POORLY SOLUBLE PHARMACEUTICAL INGREDIENTS
Technical Field
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.
According to present invention use of two or polyethelene glycol of different molecular weight along with a dispersing agent like vinyl pyrolidone. The resulting solution are clear and remains clear even after encapsulation in a soft gelatin capsule for its self life and beyond.
BACKGROUND OF THE I ENTION
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, llexφle 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.
However, despite these advantages of liquid compositions, it is not always possible to prepare a liquid composition of the desired pharmaceutical active. Many pharmaceutical actives are poorly soluble and therefore require relatively large volumes of solvent for dissolution. Also, the choice of solvents available for use in liquid compositions is limited by safety, compatibility, stability, and economic concerns. Furthermore, the 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
effective amount of active. It would thus be difficult, if^ot impossible, to encapsulate such large volumes into only one or two gelatin capsules and yet have them be of a reasonable size for easy swallowing.
One approach to overcoming these solubility problem's has been to incorporate water, water-miscible co-solvents, and surfactants into the compositions. See, U.S. Pat. No. 4,794,117, to Corbiere, issued Dec. 27, 1988 which discloses the solubiliazation of hydrophobic pharmaceuticals in aqueous solutions of polyethylene glycol at controlled pH; U.S. Pat. No. 4,690,823, to Lohner at εil, issued Sep. 1, 1987 which discloses the solubilization of ibuprofen in a mixture of polyethylene glycol and a surfactant; U.S. Pat. No. 3,784,684, to Bossert et Ά\.,' issued Jan. 8, 1974 which discloses the solubilization of a pharmaceutical active in a mixture of polyethylene glycol and an alcohol having 2-8 carbons and l-3 hydroxy groups; It is desirable to have poorly soluble dtugs like acetaminophen solubilised into a clear solution in as high concentration as possible. It typically involves use of organic solvenls.
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 pharmaceutical1 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.
PCT Application No. W088/02625, to Yu et al., published Apr. 21, 1988 which discloses the solubilization of an ionized or partly-ionized pharmaceutical active in a mixture of water.
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.
In many instances it may not be possible or desirable to incorporate, water-miscible co-solvents, or sutfactants into a pharmaceutical composition. For example, water- miscible co-solvents, such as ethanol, have the disadvantage of being relatively volatile, thereby resulting in concentration changes in the actives over time. Also, these co-solvents may not be compatible with Ihe desited pharmaceutical actives. A more important disadvantage of volatile waler-tniscible co-solvents is that they ate incompatible with soft gelatin capsules. Even though it may be possible to prepare soft gelatin capsules containing these solvents, over time the capsules gradually soften and deform, and develop leaks as these solvents dissolve the soft gelatin shell Thus, it would be highly desirable to develop a solubilization process water-miscible co- solvents are used, it would be highly desirable to develop a process in which the water-miscible solvents are ultimately removed from the final compositions.
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.
As per the present invention it is possible to obtain a stable clear liquid 'solution of acetaminophen using PEG and PVP alone, wherein the concentration of acetaminophen is mpre than 30%. /013481
It is not possible to make a clear solution of acetaminophen to a concentration more than 27% without using hydroxide, alkalizing substance, surfactant or propylene glycol.
It is therefore an object of the present invention to provide a process for solubilizing poorly soluble pharmaceutical actives. Another object of the present invention is to provide a solubilization process which does not require hydroxide, alkalizing agent, or surfactants. A further object of the present invention is to provide pharmaceutical compositions containing increased poorly soluble pharmaceutical actives.
These and other objects of this invention will become apparent in light of the following disclosure.
SUMMARY OF THE INVENTION
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.
Thus there is disclosed process of increasing concentration of pharmaceutically cative ingredient in a clear liquid solution comprising the steps of a. Mixing polyethylene glycol of different molecular weights in the range of about 40% to about 60% of the total weight. b. Addition of water while stirring to step a.
-c Addition of dispersing agents like polyvinyl pyrrolidine while stiπing in a range of about 4% to about 8% to the liquid obtained
Figure imgf000005_0001
d. Addition of pootly soluble active pharmaceutical ingredients while stirring to the liquid obtained from step c. ■ e. Heating of a resultant mixtute obtained from step d while stirring at temperature not exceeding 90 °C.
Pharmaceutical active ingredients 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
DETAILED DESCRIPTION OF THE INVENTION
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 is used, 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. To get clear concentrated liquid preparation, 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.
An essential component of the present compositions is polyvinylpyrrolidone ("PVP"), which is a polymer of N-vinyl-2-pyrrolidone
The 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). Moreover, 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.
With the use of PVP in combination with PEGs there is a definite increase the solubility of poorly soluble drugs. If heating is given to the mixture of poorly soluble drugs along with PVP and PEG, the solubility of poorly soluble drugs can be further increased.
EXAMPLE I
Ingredients Quantity per capsule Quantity for a batch of
(mg) 0 2 Lac capsule (Kg)
1. Acetaminophen 325 00 6.500
2. Pseudoephedrine hydrochloride 32.25 0.645
3. Chlorpheniramine Maleate 2.15 0.043
4. Polyethylene glycol 400 510.60 10.212
5. Polyethylene glycol 1000 30.00 0.600
6. Purified water 75.00 1.500
7. Poly vinyl pyrolidine 55.00
1.100
Total Weight 1030 mg 20.600 Kg
Process :
Take 10.212 Kg of polyethylene glycol 400 (PEG 400) and filter through 80 mesh stainless steel sieve in to a stainless steel jacketed tank with impeller type stirrer. Take 1.500 Kg purified water and add to the PEG 400 after filtering through 80 mesh stainless steel sieve. To the mixture of PEG 400 and purified water, slowly add 0.600 Kg of polyethylene glycol 1000 with stiiring The resultant mixture is subjected to heating up to 70 °C and mix for 10 minutes. Take 1 .100 Kg Poly vinyl pyrolidine and pass through 40 mesh stainless steel sieve and add slowly to the above mixture with constant stirring till clear liquid obtains. Take 6.500 Kg of Acetaminophen, 0.645 Kg of Pseudoephedrine hydrochloride and 0 043 Kg of Chlorpheniramine Maleate and separately pass through a 60 mesh stainless steel sieve with the help of mechanical vibratory shifter. Add Acetaminophen, Pseudoephedrine hydrochloride and Chlorpheniramine Maleate one after another to the clear liquid obtained above with constant stirring. After addition of all the ingredients, heat the mixture slowly up to a maximum of 90 °C with constant stirring till clear liquid obtained. Filler the clear liquid through 200 mesh stainless steel sieve and allow the' liquid to cool up to 25 °C. 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%.
EXAMPLE π 3/013481
Ingredients Quantity per capsule Quantity for a batch of
(mg) 0.2 .ac capsule (Kg)
1. Acetaminophen 325.00 6.500
2. Pseudoephedrine hydrochloriiddee 32.25 0.645 iromide 10.75 0.215
4. Doxylamine Succinate 6.72 0.1344
5. Polyethylene glycol 400 51 5.28 10.306
6. Polyethylene glycol 1000 30.00 ' 0.600
7. Purified water 75.00 ' 1.500
8. Poly vinyl pyrolidine 55.00 ,
1.100
Total Weight 1050 mg 21 000 Kg
Process :
Take 10.306 Kg of polyethylene glycol 400 (PEG 400) and filter through 80 mesh stainless steel sieve in to a stainless steel jacketed tank with impeller type stirrer. Take 1.500 Kg purified water and add to the PEG 400 aftet .filtering through 80 mesh stainless steel sieve. To the mixture of PEG 400 and purified water, slowly add 0.600 Kg of polyethylene glycol 1000 with stirring. The resultant mixture is subjected to heating up to 70 °C and mix for 10 minutes. Take 1 .100 Kg Poly vinyl pyrolidine and pass through 40 mesh stainless steel sieve and add slowly to the above mixture with constant stirring till clear liquid obtains. Take 6.500 Kg of Acetaminophen, 0.645 Kg of Pseudoephedrine hydrochloride, 0.215 Kg of Dextromethorphan Hydrobromide and 0.1344 Kg of Doxylamine Succinate and separately pass thiough a 60 mesh stainless steel sieve with the help of mechanical vibratory shifter. Add Acetaminophen, Pseudoephedrine hydrochloride, Dextromethorphan Hydrobromide and Doxylamine Succinate one after another to the clear liquid obtained above with constant stirring. After addition of all the ingredients, heat the mixture slowly up to a maximum of 90 °C with constant stirring till clear liquid obtained. Filter the clear liquid through 200 mesh stainless steel sieve and allow the liquid to cool up to 25 °C. After cooling, the liquid is subjected to de aerate 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%.
EXAMPLE TIT
Ingredients Quantity per capsule Quantity for a batch of
(mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 325.00 6.500
2. Pseudoephedrine hydrochloride 32.25 0.645
3. Dextromethorphan Hydrobromide 10.75 0.215
4. Polyethylene glycol 400 512.75 10.240
5. Polyethylene glycol 1000 30.00 0.600
6. Purified water 75.00 1.500 3/013481
7. Poly vinyl pyrolidine 55.00
1.100
Total Weight 1040 mg 20.800 Kg
Process :
Take 10.240 Kg of polyethylene glycol 400 (PEG 400) and filter through 80 mesh stainless steel sieve in to a stainless steel jacketed tank with impeller type stirrer. Take 1.500 Kg purified water and add to the PEG 400 after filtering through 80 mesh stainless steel sieve. To the mixture of PEG 400 and purified water, slowly add 0.600 Kg of polyethylene glycol 1000 with stirring. The resultant mixture is subjected to heating up to 70 °C and mix for 10 minutes. Take 1.100 Kg Poly vinyl pyrolidine and pass through 40 mesh stainless steel sieve and add slowly to the above mixture with constant stirring till clear liquid obtains. Take 6.500 Kg of Acetaminophen, 0.645 Kg of Pseudoephedrine hydrochloride and 0.215 Kg of Dextromethorphan Hydrobromide and separately pass through a 60 mesh stainless steel sieve with the help of mechanical vibratory shifter. Add Acetaminophen, Pseudoephedrine hydiochlorlde and Dextromethorphan Hydrobromide one after another to the clear liquid obtained above with constant stirring. After addition of all the ingredients, heat the mixture slowly up to a maximum of 90 °C with constant stirring till clear liquid obtained. Filter the clear liquid through 200 mesh stainless steel sieve and allow the liquid to cool up to 25 C. 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%.
EXAMPLE IV
Ingredients Quantity per capsule Quantity for a batch of
(mg) 0.2 Lac capsule (Kg)
1 Acetaminophen 325.00 6.500
2. Pseudoephedrine hydrochloride 32.25 0.645
3. Polyethylene glycol 400 512.75 10.255
4. Polyethylene glycol 1000 30.00 0.600
5. Purified water 75.00 1.500
6. Poly vinyl pyrolidine 55 00
1.100
Total Weight 1040 mg 20.600 Kg
Process :
Take 10.255 Kg of polyethylene glycol 400 (PEG 400) and filter through 80 mesh stainless steel sieve in to a stainless steel jacketed tank with impeller type stirrer. Take 1.500 Kg purified water and add to the PEG 400 after, filtering through 80 mesh stainless steel sieve. To the mixture of PEG 400 and puri ied water, slowly add 0.600 Kg of polyethylene glycol 1000 with stirring. The resultant mixture is subjected to heating up to 70 °C and mix for 10 minutes. Take 1. 100 Kg Poly vinyl pyrolidine and 013481
pass through 40 mesh stainless steel sieve and add slowly to the above mixture with constant stirring till clear liquid obtains. Take 6.500 Kg of Acetaminophen, 0 645 Kg of Pseudoephedrine hydrochloride and separately pass through a 60 mesh stainless steel sieve with the help of mechanical vibratory shifter,. Add Acetaminophen, Pseudoephedrine hydrochloride one after anothei to the clear liquid obtained above with constant stirring. After addition of all the ingredients, heat the mixture slowly up to a maximum of 90 °C with constant stirring till clear-liquid obtained. Filter the clear liquid through 200 mesh stajnless steel sieve and allow the liquid to cool up to 25 °C. 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%.
013481
EXAMPLE V
Ingredients Quantity per capsule Quantity for a batch of
(mg) 0.2 Lac capsule (fCg)
1. Acetaminophen 325.00 6.500
2. Pseudoephedrine hydrochloride 32.25 0.645
3. Dextromethorphan Hydrobromide J 0.75 0.215
4. Chlorpheniramine maleate 2.15 0.043
4. Polyethylene glycol 400 519.85 10.397
5. Polyethylene glycol 1000 30.00 0.600
6. Purified water 75.00 1.500
7. Poly vinyl pyrolidine 55.00
1.100
Total Weight 1050 mg 21.000 Kg
Process :
Take 10.397 Kg of polyethylene glycol 400 (PEG 400) and filter through 80 mesh stainless steel sieve in to a stainless steel jacketed tank with impeller type stirrer. Take 1.500 Kg purified water and add to the PEG 400 after filtering through 80 mesh stainless steel sieve. To the mixture of PEG 400 and purified water, slowly add 0.600 Kg of polyethylene glycol 1000 with stirring The resultant mixture is subjected to heating up to 70 °C and mix for 10 minutes. Take 1 .100. Kg Poly vinyl pyrolidine and pass through 40 mesh stainless steel sieve and add slowly to the above mixture with constant stining till clear liquid obtains. Take 6.500 Kg of Acetaminophen, 0.645 Kg of Pseudoephedrine hydrochloride and 0.215 Kg of Dextromethorphan Hydrobromide andθ.043 kg of Chlorpheniramine maleate separately pass through a 60 mesh stainless steel sieve with the help of mechanical vibratory shifter. Add Acetaminophen, Pseudoephedrine hydrochloride and Dextromethorphan llydrobromide and Chloipheniramine maleate one after another to (he clear liquid obtained above with constant stirring. After addition of all the ingredients, heat the mixture slowly up to a maximum of 90 °C with- constant stirring till clear liquid obtained. Filter the cleat- liquid through 200 mesh stainless steel sieve and allow the liquid to cool up to 25 °C. After cooling, the liquid is subjected to de aerate undei 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%.
Propylene glycol may be used in above process. FTowever its amount should not increase more than 2%. Otherwise solution looses its clarity.
As per present invention substitution of polyvinyl pyrolidone by surfactants like Tween-80, Tween 40, ITydrogenated castor oil derivatives like cremaphoi RΪ-1-40, Cremaphor EL results in loss of clarity of a solution.
Following examples demonstrates the limitation of present process in obtaining concentrated clear liquid pharmaceutical composition of poorly soluble 013481
pharmaceutical active ingredients. All of below mentioned compositions are eilher no clear or loose their clarity during there self life
EXAMPLE 1
Ingredients Quantity per capsule Quantity for a batch of
(mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 400.00 8.000
2. Polyethylene glycol 400 530.00 J 0.600
3. Polyethylene glycol 1000 30.00 0.600
4.PVP(k 30) 55 1 .100
6. Purified water 75.00 1.500
Total Weight 1090-mg 21.800 Kg
EXAMPLE π
Ingredients Quantity per capsule- Quantity for a batch of
(mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 400.00 8.000
2. Polyethylene glycol 400 530.00 10.600
3. Polyethylene glycol 1000 35.00 0.700
4.PVP(k 30 -i- k90) 57.5 + 27 5 1.100
6. Purified water 75.00 1.500
Total Weight 1125 mg 21.8 Kg
EXAMPLE TO
Ingredients Quantity per capsule Quantity for a batch of (mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 400.00 8.000
2. Polyethylene glycol 400 530.00 10.600
3. Polyethylene glycol 1000 30.00 0.600 4.PVP(k 90) 55 1.100 '
6. Purified water 80.00 1.600
Total Weight 1095 mg 21.900 Kg 3/013481
EXAMPLE IV Ingredients Quantity per capsule Quantity for a batch of
(mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 450.00 9.000
2. Polyethylene glycol 400 550.00 1 1.000
3. Polyethylene glycol 1000 30.00 0.600 4.PVP(k 90) 60 1.200
5. Purified water 85.00 1 .700
Total Weight 1 175 mg 23.500 Kg
EXAMPLE V
Ingredients Quantity per capsule Quantity for a batch of
(mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 400.00 8.000
2. Polyethylene glycol 400(495) 45% 10.600
3. Polyethylene glycol 1000(66) 6% 0.600
4.PVP(k 30) 55 1.100
5. Purified water 75.00 1.500
Total Weight 1 100 mg 21 .8 Kg
EXAMPLE VI
Ingredients Quantity per capsule Quantity for a batch of (mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 400.00 8.000
2. Polyethylene glycol 400(522) 47.5% 10.600
3. Polyethylene glycol 1000(29.2) 2.7% 0.600 4.PVP( 30) 55 1.100
5. Purified water 75.00 1 .500
EXAMPLE VII Ingredients Quantity per capsule Quantity for a batch of (mg) 0.2 Lac capsule (Kg) 1. Acetaminophen 400 00
2. Polyethylene glycol 400(495) 45% , n°?!
3. Polyethylene glycol l 450(44) 4% , „ 4.PVP(k 30) 55 °-600
5. Purified water 75 00 H00'
1.500
EXAMPLE Vffl
Ingredients Quantity per capsule Quantity for a batch of
(mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 400 00 8.000
2. Polyethylene glycol 400 520 10.400
3. Polyethylene glycol 1000 30 0.600 4.PVP(k 30) 90 ' 1.800
5. Purified water 75.00 1.500
6. Potassium Acetate 6 0.J 20
Total Weight 1 121 mg 22.420Kg
/013481
EXAMPLE DC
Ingredients Quantity per capsule Quantity for a batch of
(mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 450.00 8.000
2. Polyethylene glycol 400 400 10.600
3. Polyethylene glycol 200 120
4. Polyethylene glycol 1450 44 0.600
5.PVP(k 30) 90 1.100
6. Purified water 75.00 1.500
Total Weight 1 179 mg 21.8Kg
EXAMPLE XI
Ingredients Quantity per capsule Quantity for a batch (
(mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 400.00 8.000
2. Polyethylene glycol 400 483 00 0.966
3. Polyethylene glycol 1500 29.00 0.580
4. PVP(k 90) 63 1.260 .
5. Purified water 175.00 3.500
Total Weight 1217mg [ 4.306Kg
3/013481
EXAMPLE Xπ
Ingredients Quantity per capsule Quantity for a batch of
(mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 500.00 10.000
2. Polyethylene glycol 400 483.00 0.966
3. Polyethylene glycol 1500 29.00 0.580
4. PVP(k 90) 63 1.260
5. Purified water 175.00 3.500'
Total Weight 1250mg 16.306Kg
EXAMPLE XITI
Ingredients Quantity per capsule Quantity for a batch of (mg) 0.2 Lac capsule (Kg)
1. Acetaminophen 400.00 10.000
2. Polyethylene glycol 400 483.00 0.966
3. Polyethylene glycol 1500 29.00 0.580
4. PVP(k 90) 63 1.260
5. Purified water 175.00 3.500
Total Weight 1250mg 16.306Kg

Claims

O 03/013481We Claim
1. The process of manufacturing pharmaceutical composition with increased content of poorly soluble pharmaceutical ingredients in a clear liquid solution comprising the steps of: a. Preparing a solvent system comprising of at least two from polyethylene glycol of different molecular weights in the range of about 40% to about 60% of the total weight, water, and dispersing agents like polyvinyl pyirolidme in a tange of about 4% to about 8%. b. Addition of poorly soluble active pharmaceutical ingredients while stirring to the liquid obtained from step a. c. Heating of a resultant mixture obtained from step b while stirring at temperature not exceeding 90 °C.
2. The process according to claim 1 wherein the pharmaceutically active ingredient ranges from about 15% to about 40%.
3. The process according to claim 2 wherein the pharmaceutical active ingredient ranges from about 25% to about 33%.
4. The process according to claim 1 wherein at least one of the polyethylene glycol have average molecular weight below 600.
5. The process according to claim 1 wherein one of the polyethylene glycol have average molecular weight is 400.
6. The process according to claim J wherein at least another polyethylene glycol should have molecular weight of 800 or above.
7. The process according to claim 4 wherein at least another polyethylene glycol should have molecular weight of 1000 or above.
8. Polyethylene glycol with molecular weight lower than 600 as claimed in claim 4 should be 85% or above of total polyethylene glycol.
9. The process according to claim 8 wherein polyethylene glycol with molecular weight lower than 600 should be 88%) or above of total polyethylene glycol.
10. The process according to claim 8 wherein polyethylene glycol with molecular weight lower than 600 should be 92% or above of total polyethylene glycol.
1 1 . The process according to claim 1 wherein polyethylene glycol with high molecular weight should be 15% or less of total polyethylene glycol.
12. The process according to claim 1 1 wherein polyethylene glycol with high molecular weight should be at least 3% of total polyethylene glycol.
13. The process according to claim 1 1 wherein polyethylene glycol with high molecular weight should be at least 5% of total polyethylene glycol.
14. The process according to claim 1 wherein the ratio of polyethylene glycol to polyvinyl pyrolidine is about 4:1 to 15: L.
15. The process according to claim 14 wherein the ratio of polyethylene glycol to polyvinyl pyrolidine is about 4: 1 or above.
16. The process according to claim 14 wherein the ratio of polyethylene glycol to polyvinyl pyrolidine is about 5:1 or above.
17. The process according to claim 14 wherein the ratio of polyethylene glycol to polyvinyl pyrolidine is about 6:1 or above.
18. A process according to claim 1 wherein poorly soluble active pharmaceutical ingredients is selected from the group consisting of acetaminophen, acetylsalicylic acid, ibuprofen, fenbrprofen, flurbiprofen, indomethacin, naproxen, and mixture thereof.
19. A process according to claim 18. wherein the poorly soluble active pharmaceutical ingredient is acetaminophen. /013481
20. A process according to claim 1 which further comprises combining in step (b) form about 0.5% to 20%o of a second pharmaceutical active ingredient selecte'd from the group consisting of dextromethorphan hydrobromide, doxyllamine succinate, pseudoephedrine hydrochloride, chlorpheniramine maleate, guaifenesin, tripolidine hydrochloride, diphenhydramine hydrochloride, and mixture thereof.
21. A process of manufacturipg pharmaceutical composition with increased content of poorly soluble pharmaceutical ingredients in a clear liquid solution comprising the steps of: . a. Preparing a solvent system comprising of at least two from polyethylene glycol of different molecular weights in the range of about 40% to about 60% of the total weight, water, and dispersing agents like polyvinyl pyrrolidine in a range of about 4% to about 8%. b. Addition of poorly soluble active pharmaceutical ingredients while stirring to the liquid obtained from step a. c. Heating of a resultant mixture , obtained from step b while stirring at temperature not exceeding 90 °C. d. Encapsulating the clear liquid composition in a soft gelatin shell.
22. A process according to claim 21 wherein poorly soluble active pharmaceutical ingredients is selected from the group consisting of acetaminophen, acetylsalicylic acid, ibuprofen, fenbrprofen, flu rbi pro fen, indomethacin, naproxen, and mixture thereof.
23. A process according to claim 21 which further comprises combining in step (b) form about 0.5% to 20% of a second pharmaceutical active ingredient selected from the group consisting of dextromethorphan hydrobromide, doxyllamine succinate, pseudoephedrine hydrochloride, chlorpheniramine 'maleate, guaifenesin, tripolidine hydrochloride, diphenhydramine hydrochloride, and mixtuie thereof.
24. A concentrated clear liquid , pharmaceutical composition prepared in accordance with the process of claim I .
25. A concentrated clear liquid , pharmaceutical composition prepared in accordance with the process of claim 18.
26. A concentrated clear liquid , pharmaceutical composition prepared in accordance with the process of claim 20.
27. A soft gelatin capsule prepared in accordance with the process of claim 21.
28. A soft gelatin capsule prepared in accordance with the process of claim 22.
29. A soft gelatin capsule prepared in accordance with the process of claim 23.
30. A concentrated clear liquid, pharmaceutical composition which is 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% water, wherein the ratio of poltethylene glycol to polyvinyl pyrolidine is from 4:1 to 15:1.
PCT/IB2002/003015 2001-08-03 2002-08-03 The process of manufacturing pharmaceutical composition with increased content of poorly soluble pharmaceutical ingredients WO2003013481A1 (en)

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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
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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
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US8969416B2 (en) 2012-03-29 2015-03-03 Enspire Group LLC Polyvinylpyrrolidone-containing acetaminophen liquid formulations
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