WO2006129160A2 - Stable aqueous oral solution of risperidone - Google Patents

Stable aqueous oral solution of risperidone Download PDF

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Publication number
WO2006129160A2
WO2006129160A2 PCT/IB2006/001391 IB2006001391W WO2006129160A2 WO 2006129160 A2 WO2006129160 A2 WO 2006129160A2 IB 2006001391 W IB2006001391 W IB 2006001391W WO 2006129160 A2 WO2006129160 A2 WO 2006129160A2
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Prior art keywords
acid
risperidone
oral solution
solution
antioxidant
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PCT/IB2006/001391
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French (fr)
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WO2006129160A3 (en
Inventor
Subhashini Radhakrishnan
Ashish Gogia
Sivakumaran Meenakshisunderam
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Aurobindo Pharma Limited
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Publication of WO2006129160A2 publication Critical patent/WO2006129160A2/en
Publication of WO2006129160A3 publication Critical patent/WO2006129160A3/en

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Classifications

    • 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
    • A61K9/08—Solutions
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof

Definitions

  • the present invention relates to stable aqueous solutions of antipsychotic drug. More particularly, the present invention relates to stable aqueous solutions of risperidone, wherein the composition is free of buffering agents.
  • the present invention also relates to preparation of stable aqueous solutions of risperidone, wherein the composition is free of buffering agents.
  • Risperidone is chemically known as 3-[2-[4-(6-fluoro-l.,2-benzisoxazol-3- yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4- one.
  • Risperidone is an antipsychotic agent belonging to a new chemical class, the benzisoxazole derivatives.
  • Risperidone and its pharmaceutically acceptable acid addition salts are disclosed for the first time in US patent No. 4,804,663.
  • Tablet, orally disintegrating tablet and oral solution formulations of risperidone are commercially available in different countries and are currently marketed under the tradename RISPERDALTM in the US.
  • US patent No. 4,804,663 discloses an unbuffered oral solution containing - benzisoxazolyl derivative as an antipsychotic ingredient, rhethylparaben, propylparaben, tartaric acid, sodium saccharin, raspberry and gooseberry essence, the polyhydric alcohols sorbitol and glycerol and a relatively small amount water ( ⁇ 30% v/v). It is disclosed in US 5,616,587, that the above oral solution exhibited an unsatisfactory physicochemical stability and the instability was found to be caused due to sorbitol, which accelerated the decomposition of risperidone upon storage at elevated temperatures as disclosed in US Patent No. 5,453,425.
  • US patent Nos. 5,616,587 and 5,453,425 describe essentially sorbitol free aqueous solution, suitable for oral and parenteral administration, comprising water, risperidone or a pharmaceutically acceptable acid addition salt thereof, characterized in that said solution comprises a buffer to maintain the pH in the range of 2 to 6. Further it is disclosed that the pH of the composition is maintained by a buffer system, which comprise mixtures of appropriate amounts of an acid such as phosphoric, succinic, tartaric, lactic, or citric acid, and a base, in particular, sodium hydroxide or disodium hydrogen phosphate. Ideally, the buffer has sufficient capacity to remain in the intended pH range upon dilution with a neutral, a slightly acidic or a slightly basic beverage.
  • WO 2004/017975 describes aqueous solution, which includes water; a therapeutically effective amount of risperidone; one or more polyhydric alcohols; and one or more buffering agents configured to maintain the pH in the range of about 2 to about 6. It is further disclosed that the advantages of polyhydric alcohols as most widely used sweeteners or bitter taste-masking agents in oral liquid dosage forms.
  • the main objective of the present invention is to provide stable oral solutions of risperidone.
  • Yet another objective of the present invention is to provide new, stable oral solutions of risperidone free of buffering agents.
  • the present invention provides essentially buffer free stable oral solution composition comprising risperidone and benzoic acid or sorbic acid as preservatives.
  • the essentially buffer free stable oral solution composition further comprises one or more pharmaceutically acceptable excipients.
  • the amount of preservative may range from about 0.01 to about 6.0 mg/ml of the composition, preferably, from 0.01 to 5.0 mg/ml of the composition.
  • pharmaceutically acceptable excipient comprises an antioxidant.
  • the antioxidant may • be selected from acetylcysteine, alpha tocopherol acetate, d-alpha tocopherol, dl- alpha tocopherol, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), cysteine, cysteine hydrochloride, propyl gallate, ascorbic acid, isoascorbic acid, thioglycerol, citric acid, tartaric acid, edetic acid (EDTA) and its salts, hydroxyquinoline sulphate, phosphoric acid and sodium citrate.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxy toluene
  • cysteine cysteine hydrochloride
  • propyl gallate ascorbic acid
  • isoascorbic acid isoascorbic acid
  • thioglycerol citric acid, tartaric acid, edetic acid (EDTA
  • pharmaceutically acceptable excipient comprises pH adjusting agents such as amino acids selected from the group consisting of glutamic acid, aspartic acid, cysteine hydrochloride and the like or inorganic acid such as hydrochloric acid.
  • the stable oral solutions of risperidone are free of ion content such as sodium, potassium and the like.
  • the pH of the essentially buffer free stable oral solution is in the range of 2.0 to 6.0.
  • the essentially buffer free compositions of risperidone may further comprise bulk / intense sweeteners such as glucose, glycerol, fructose, sucrose, lactose, maltose, sorbitol, xylitol, maltitol, erythritol, aspartame, prosweet and the like.
  • the oral solutions of the present invention are characterized by an unchanged concentration of risperidone during storage over prolonged period of time.
  • a manufacturing process for the preparation of stable oral solution of risperidone comprising i) dissolving the preservative in hot purified water, ii) allowing the solution to cool and dissolving risperidone to the resulting solution iii) optionally adding an antioxidant and if necessary adjusting the pH of the solution with acid and iv) make up the volume with purified water to obtain stable oral solution of risperidone.
  • the manufacturing process for preparing Risperidone oral solution comprises the steps of : i) 70% of total volume of water was taken and heated to not less than 90 0 C, ii) benzoic acid was added to the. hot water and stirred until it dissolved completely and the solution was cooled to 30 0 C, iii) risperidone was added to the solution of step (ii) and stirred well, iv) the pH of the solution was adjusted to 3 with O.lNhydrochloric acid, v) the volume was made up with purified water and mixed well and the solution was filtered and filled into the containers.
  • Risperidone oral solution described in the following examples are prepared using the process similar to the one described in example 1.
  • Risperidone oral solution 1 mg/niL was subjected to accelerated stability at different temperature and humidity conditions (8O 0 C and 40°C/75% RH) for one month and two months.
  • the stability data is given in table 1 below .

Abstract

The present invention relates to stable aqueous solutions of antipsychotic drug. More particularly, the present invention relates to stable aqueous solutions of risperidone, wherein the composition is free of buffering agents. The present invention also relates to preparation of stable aqueous solutions of risperidone, wherein the composition is free of buffering agents.

Description

STABLE AQUEOUS SOLUTIONS OF AN ANTIPSYCHOTIC AGENT
Field of the invention
The present invention relates to stable aqueous solutions of antipsychotic drug. More particularly, the present invention relates to stable aqueous solutions of risperidone, wherein the composition is free of buffering agents.
The present invention also relates to preparation of stable aqueous solutions of risperidone, wherein the composition is free of buffering agents.
Background of the invention
Risperidone is chemically known as 3-[2-[4-(6-fluoro-l.,2-benzisoxazol-3- yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4- one. Risperidone is an antipsychotic agent belonging to a new chemical class, the benzisoxazole derivatives. Risperidone and its pharmaceutically acceptable acid addition salts are disclosed for the first time in US patent No. 4,804,663.
Tablet, orally disintegrating tablet and oral solution formulations of risperidone are commercially available in different countries and are currently marketed under the tradename RISPERDAL™ in the US.
US patent No. 4,804,663 discloses an unbuffered oral solution containing - benzisoxazolyl derivative as an antipsychotic ingredient, rhethylparaben, propylparaben, tartaric acid, sodium saccharin, raspberry and gooseberry essence, the polyhydric alcohols sorbitol and glycerol and a relatively small amount water (<30% v/v). It is disclosed in US 5,616,587, that the above oral solution exhibited an unsatisfactory physicochemical stability and the instability was found to be caused due to sorbitol, which accelerated the decomposition of risperidone upon storage at elevated temperatures as disclosed in US Patent No. 5,453,425.
To overcome the problems associated with the use of polyhydric alcohols, US patent Nos. 5,616,587 and 5,453,425 describe essentially sorbitol free aqueous solution, suitable for oral and parenteral administration, comprising water, risperidone or a pharmaceutically acceptable acid addition salt thereof, characterized in that said solution comprises a buffer to maintain the pH in the range of 2 to 6. Further it is disclosed that the pH of the composition is maintained by a buffer system, which comprise mixtures of appropriate amounts of an acid such as phosphoric, succinic, tartaric, lactic, or citric acid, and a base, in particular, sodium hydroxide or disodium hydrogen phosphate. Ideally, the buffer has sufficient capacity to remain in the intended pH range upon dilution with a neutral, a slightly acidic or a slightly basic beverage.
WO 2004/017975 describes aqueous solution, which includes water; a therapeutically effective amount of risperidone; one or more polyhydric alcohols; and one or more buffering agents configured to maintain the pH in the range of about 2 to about 6. It is further disclosed that the advantages of polyhydric alcohols as most widely used sweeteners or bitter taste-masking agents in oral liquid dosage forms.
Apart from the above-referred literature describing the oral solution of risperidone, there are no other references, which disclose an oral solution of risperidone. The above prior art references discloses oral solutions of risperidone wherein parabens are used as preservatives as disclosed in US 4,804,663, buffer system is added to maintain the stability of the solution as disclosed in US 5,616,587; 5,453,425 and WO 2004/017975. The inventors of the present invention found that the stability of risperidone oral solutions can be maintained during storage using benzoic acid as the preservative without using buffering agent.
Objective of the present invention
The main objective of the present invention is to provide stable oral solutions of risperidone.
Yet another objective of the present invention is to provide new, stable oral solutions of risperidone free of buffering agents. Summary of the invention
Accordingly, the present invention provides essentially buffer free stable oral solution composition comprising risperidone and benzoic acid or sorbic acid as preservatives.
In yet another embodiment of the present invention, the essentially buffer free stable oral solution composition further comprises one or more pharmaceutically acceptable excipients.
Detailed description of the invention
The amount of preservative may range from about 0.01 to about 6.0 mg/ml of the composition, preferably, from 0.01 to 5.0 mg/ml of the composition.
In yet another embodiment of the present invention, pharmaceutically acceptable excipient comprises an antioxidant.
The antioxidant may • be selected from acetylcysteine, alpha tocopherol acetate, d-alpha tocopherol, dl- alpha tocopherol, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), cysteine, cysteine hydrochloride, propyl gallate, ascorbic acid, isoascorbic acid, thioglycerol, citric acid, tartaric acid, edetic acid (EDTA) and its salts, hydroxyquinoline sulphate, phosphoric acid and sodium citrate.
In yet another embodiment of the present invention, pharmaceutically acceptable excipient comprises pH adjusting agents such as amino acids selected from the group consisting of glutamic acid, aspartic acid, cysteine hydrochloride and the like or inorganic acid such as hydrochloric acid.
In yet another embodiment of the present invention, the stable oral solutions of risperidone are free of ion content such as sodium, potassium and the like.
In yet another embodiment of the present invention, the pH of the essentially buffer free stable oral solution is in the range of 2.0 to 6.0. In yet another embodiment of the present invention, the essentially buffer free compositions of risperidone may further comprise bulk / intense sweeteners such as glucose, glycerol, fructose, sucrose, lactose, maltose, sorbitol, xylitol, maltitol, erythritol, aspartame, prosweet and the like.
The oral solutions of the present invention are characterized by an unchanged concentration of risperidone during storage over prolonged period of time.
In yet another embodiment of the present invention, there is provided a manufacturing process for the preparation of stable oral solution of risperidone comprising i) dissolving the preservative in hot purified water, ii) allowing the solution to cool and dissolving risperidone to the resulting solution iii) optionally adding an antioxidant and if necessary adjusting the pH of the solution with acid and iv) make up the volume with purified water to obtain stable oral solution of risperidone.
The following example further exemplifies the inventions and is not intended to limit the scope of the inventions. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.
Example 1
Figure imgf000005_0001
The manufacturing process for preparing Risperidone oral solution comprises the steps of : i) 70% of total volume of water was taken and heated to not less than 90 0C, ii) benzoic acid was added to the. hot water and stirred until it dissolved completely and the solution was cooled to 300C, iii) risperidone was added to the solution of step (ii) and stirred well, iv) the pH of the solution was adjusted to 3 with O.lNhydrochloric acid, v) the volume was made up with purified water and mixed well and the solution was filtered and filled into the containers.
Risperidone oral solution described in the following examples are prepared using the process similar to the one described in example 1.
Example 2
Figure imgf000006_0001
Example 3
Figure imgf000006_0002
Example 4
Figure imgf000006_0003
Figure imgf000007_0001
Stability studies
Risperidone oral solution 1 mg/niL was subjected to accelerated stability at different temperature and humidity conditions (8O0C and 40°C/75% RH) for one month and two months. The stability data is given in table 1 below .
Table - 1
Figure imgf000007_0002

Claims

We claim :
1. An essentially buffer free stable oral solution composition comprising risperidone and benzoic acid or sorbic acid as preservative.
2. The oral solution as claimed in claim 1, further comprise one or more pharmaceutically acceptable excipients such as antioxidant, pH adjusting agent and sweeteners.
3. The oral solution as claimed in claim 2, wherein the pH adjusting agent is selected from the group consisting of glutamic acid, aspartic acid or hydrochloric acid.
4. The oral solution as claimed in claim 2, wherein excipient sweetener is selected from the group consisting of glucose, glycerol, fructose, sucrose, lactose, maltose, sorbitol, xylitol, maltitol, erythritol, aspartame or prosweet.
5. The oral solution as claimed in claim 2, wherein the antioxidant is selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, cysteine, cysteine hydrochloride, propyl gallate ascorbic acid, isoascorbic acid, thioglycerol citric acid, tartaric acid or EDTA.
6. The oral solution as claimed in claim 1, wherein the pH is in the range of 2.0 to 6.0.
7. A process for the preparation of stable oral solution of risperidone comprising the steps of i) dissolving the preservative in hot purified water, ii) allowing the solution to cool and dissolving risperidone to the resulting solution, iii) optionally adding an antioxidant and if necessary adjusting the pH of the solution with acid and iv) make up the volume with purified water to obtain stable oral solution of risperidone.
PCT/IB2006/001391 2005-06-01 2006-05-29 Stable aqueous oral solution of risperidone WO2006129160A2 (en)

Applications Claiming Priority (2)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008260708A (en) * 2007-04-11 2008-10-30 Ohkura Pharmaceutical Co Ltd Oral jelly-like pharmaceutical composition containing benzisoxazole derivative
US20100189818A1 (en) * 2009-01-20 2010-07-29 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
US10098861B1 (en) 2017-10-24 2018-10-16 Syneurx International (Taiwan) Corp. Pharmaceutical composition comprising sodium benzoate compound and clozapine, and uses thereof
US10336679B2 (en) 2016-10-24 2019-07-02 Syneurx International (Taiwan) Corp. Polymorphic forms of sodium benzoate and uses thereof
US11369579B2 (en) 2016-10-24 2022-06-28 Syneurx International (Taiwan) Corp. Polymorphic forms of sodium benzoate and uses thereof
CN114994198A (en) * 2022-05-20 2022-09-02 上海市精神卫生中心（上海市心理咨询培训中心） Method for simultaneously and quantitatively detecting 78 neuropsychiatric drugs by liquid chromatography-mass spectrometry
US11731928B2 (en) 2016-06-13 2023-08-22 Syneurx International (Taiwan) Corp. Co-crystals of sodium benzoate and uses thereof
US11739046B2 (en) 2016-06-13 2023-08-29 Syneurx International (Taiwan) Corp. Co-crystals of lithium benzoate and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4804663A (en) * 1985-03-27 1989-02-14 Janssen Pharmaceutica N.V. 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
WO1996001652A1 (en) * 1994-07-11 1996-01-25 Janssen Pharmaceutica N.V. Aqueous risperidone formulations
WO2004017975A1 (en) * 2002-08-23 2004-03-04 Ranbaxy Laboratories Limited Stable aqueous solutions of risperidone and methods for their preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4804663A (en) * 1985-03-27 1989-02-14 Janssen Pharmaceutica N.V. 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
WO1996001652A1 (en) * 1994-07-11 1996-01-25 Janssen Pharmaceutica N.V. Aqueous risperidone formulations
WO2004017975A1 (en) * 2002-08-23 2004-03-04 Ranbaxy Laboratories Limited Stable aqueous solutions of risperidone and methods for their preparation

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008260708A (en) * 2007-04-11 2008-10-30 Ohkura Pharmaceutical Co Ltd Oral jelly-like pharmaceutical composition containing benzisoxazole derivative
US10149845B2 (en) 2009-01-20 2018-12-11 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
US9649304B2 (en) * 2009-01-20 2017-05-16 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
US9675604B2 (en) 2009-01-20 2017-06-13 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
US10039730B2 (en) 2009-01-20 2018-08-07 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
US20100189818A1 (en) * 2009-01-20 2010-07-29 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
US11529342B2 (en) 2009-01-20 2022-12-20 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
US11731928B2 (en) 2016-06-13 2023-08-22 Syneurx International (Taiwan) Corp. Co-crystals of sodium benzoate and uses thereof
US11739046B2 (en) 2016-06-13 2023-08-29 Syneurx International (Taiwan) Corp. Co-crystals of lithium benzoate and uses thereof
US10336679B2 (en) 2016-10-24 2019-07-02 Syneurx International (Taiwan) Corp. Polymorphic forms of sodium benzoate and uses thereof
US11369579B2 (en) 2016-10-24 2022-06-28 Syneurx International (Taiwan) Corp. Polymorphic forms of sodium benzoate and uses thereof
US10098861B1 (en) 2017-10-24 2018-10-16 Syneurx International (Taiwan) Corp. Pharmaceutical composition comprising sodium benzoate compound and clozapine, and uses thereof
CN114994198A (en) * 2022-05-20 2022-09-02 上海市精神卫生中心（上海市心理咨询培训中心） Method for simultaneously and quantitatively detecting 78 neuropsychiatric drugs by liquid chromatography-mass spectrometry

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