WO2009109990A2 - Pharmaceutical composition of pramipexole - Google Patents
Pharmaceutical composition of pramipexole Download PDFInfo
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- WO2009109990A2 WO2009109990A2 PCT/IN2009/000056 IN2009000056W WO2009109990A2 WO 2009109990 A2 WO2009109990 A2 WO 2009109990A2 IN 2009000056 W IN2009000056 W IN 2009000056W WO 2009109990 A2 WO2009109990 A2 WO 2009109990A2
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- pramipexole
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising pramipexole or its pharmaceutically acceptable salts or its hydrates or solvates thereof.
- Pramipexole (S)-2-amino-4, 5, 6, 7 - tetrahydro-6-(propylamino) benzole, is a non ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D 2 subfamily of dopamine receptors. It is indicated in the treatment of signs and symptoms of idiopathic Parkinson's disease.
- United States patent application number 20070129329 discloses a stabilized pharmaceutical composition of pramipexole comprising one or more dextrin.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a mixture of pramipexole or its pharmaceutically acceptable salts or its hydrates or solvates thereof, sugar alcohol (s) and a pharmaceutically acceptable carrier medium substantially free of polyvinyl pyrrolidone.
- the term 'labeled amount' as used herein, refers to the amount of therapeutically active ingredient present in a pharmaceutical product.
- a unit dose of the therapeutically active ingredient is present in the pharmaceutical product, it is often termed as a unit dosage form.
- Detailed monographs, often called label, of the marketed dosage form contain its description, pharmacology, clinical studies, indication, contraindications, warnings, precautions, adverse events, dosage and administration and other details of the marketed product.
- the dosage form may be available in various doses, specified in the label, for example, pramipexole tablets are available as 0.125, 0.25, 0.5, 1.0 and 1.5 mg of pramipexole dihydrochloride monohydrate. These various doses in the tablets are herein referred to as the 'labeled amount' of pramipexole dihydrochloride monohydrate.
- the dosage form should be chemically 'stable' and retain the labeled amount of the iheiapeuiieall) active ingredient upon storage and the impurities in the pharmaceutical product should remain low.
- a 'stable' pharmaceutical composition comprising a mixture of pramipexole or its pharmaceutically acceptable salts or hydrates or solvates thereof, sugar alcohol (s) and a pharmaceutically acceptable carrier medium substantially free of polyvinyl pyrrolidone.
- compositions when stored in high density polyethylene containers at a temperature of about 40 0 C + 2 0 C and relative humidity of about 75 % + 5 % for a period of three months, showed the content of pramipexole dihydrochloride monohydrate ranging from about 95 % to about 105 % by weight of the labeled amount of pramipexole dihydrochloride monohydrate and the total impurities (known and unknown) were less than I % of the labeled amount of pram ⁇ pe ⁇ le d ⁇ h) di udil ⁇ J ⁇ .
- these impurities were separated by High performance liquid chromatography (HPLC) and quantified by measuring the absorption in the ultraviolet region.
- HPLC High performance liquid chromatography
- any other suitable analytical method may also be employed to determine the pramipexole content and to quantify the known and unknown impurities.
- composition of the present invention comprises a mixture of pramipexole or its pharmaceutically acceptable salts or its- hydrates or solvates thereof, sugar alcohol (s) and a pharmaceutically acceptable carrier medium substantially free of polyvinyl pyrrolidone.
- mixture' as used herein means pramipexole or its pharmaceutically acceptable salts or its hydrates or solvates thereof is intimately blended or is in physical contact with the pharmaceutically acceptable carrier medium.
- the pharmaceutical composition of the present invention is considered to be stable ' when the ⁇ hu ⁇ iiciceuiieul composition upon storage in suitable containers with or without desiccants at a temperature of about 40° C ⁇ 2° C and a relative humidity of about 75 % ⁇ 5 %, shows the pramipexole dihydrochloride monohydrate content in the range of about 95 % to about 105 % of the labeled amount and total impurities are less than about 1 % by weight of pramipexole dihydrochloride monohydrate.
- the composition of the present invention comprises pramipexole or its pharmaceutically acceptable salts or its hydrates or solvates thereof.
- the pharmaceutically acceptable acid salts of pramipexole include, but are not limited to, acid addition salts of inorganic acids or organic acids such as hydrobromide, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic and formic acid and the like.
- the pramipexole is used as the dihydrochloride salt, more preferably pramipexole is used as dihydrochloride monohydrate.
- the amount of pramipexole dihydrochloride monohydrate ranges from about 0.05 mg to about 2.0 mg per tablet. More preferably, the amount of pramipexole dihydrochloride monohydrate ranges from about 0.09 mg to about 1 .8 mg per tablet.
- T he composition of the present invention comprises a pharmaceutically acceptable carrier medium substantially free of polyvinyl pyn olidone Although it may be possible to prepare a stable pharmaceutical composition with trace amount of polyvinyl pyrrolidone, preferably the composition is completely devoid of polyvinyl pyrrolidone
- the pharmaceutical composition comprises sugar alcohol (s) as one of the fillers or diluents
- sugar alcohols may be in any stereoisomers or geometric isomers or/and optical isomers forms They may be straight chain or cyclic in nature
- the straight chain sugar alcohols may be ti ihyd ⁇ c to hexafn d ⁇ c sugar alcohol
- Examples of the straight chain sugai alcohols that ma ⁇ be used in (he composition of the present invention include, but are not limited to, hexitols such as sorbitol, mannitol, glycerol, alhtol, talitol, glucitol, iditol and dulcitol, pentitols such as xylitol, adonitol (also called ⁇ bitol) and arabitol, teti itols such as eryth ⁇ tol and threitol, and t ⁇ ols such
- fillers or diluents that may be used in the pharmaceutically acceptable carrier medium substantially free of polyvinyl pyrrolidone, include, but are not limited to, starch and its derivatives like corn staich, pi egelatmized staicli and the like, cal ⁇ um phosphate dibasic, calcium phosphalc u ibasic, m ⁇ uuu ) -.idlli ⁇ iL cellulose, silicified microcrystalline cellulose, powdered cellulose, lactose, dextrose, dextrin, sugar compressible and the like and mixture thereof
- the amount of fillers that may be used in the pharmaceutical composition of the present invention ranges from about 5 % to about 90 % by weight of the composition, preferably 15 % to about 30 % by weight of the composition
- binders examples include, but are not limited to, methyl cellulose, hydioxypropyl cellulose gelatin, tragacanth sodium alginate and the like and mixture thereof
- the amount of bindei that may be used ranges from about 0 % to about 10 % by weight of the composition
- purified water is used as the sole granulating agent
- lubricants/ glidants examples include, but are not limited to, silicon dioxide, colloidal silicon dioxide, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, zinc stearate, talc and the like or mixture thereof
- the amount of lub ⁇ cants/glidants that may be used in the pharmaceutical composition of the present invention ranges from about 0 1 % to about 5 %, preferably about 2 % by weight of the composition
- the pharmaceutical composition consists essentially of a mixtuie oi p ⁇ am ⁇ pe ⁇ ole oi its phdi maceutiuillv dn.cpt.ible salts oi its lnduks oi ->oU ak -> ll ⁇ ol it ti di * ⁇ it derivatives sugai alcohol (s) and a pharmaceutically acceptable carrier medium
- the pharmaceutically acceptable carrier medium is substantially free of polyvinyl pyrrolidone
- the composition is completely devoid of polyvinyl pyrrolidone
- compositions prepared according to Example 1 , 2, 5 were packed and sealed in high density polyethylene containeis with desiccant and were stored at a temperature of about 40 0 C ⁇ 2 0 C and relative humidity of about 75 % ⁇ 5 % for three months
- the compositions were analyzed for the pramipexole content by High performance liquid chromatography (HPLC) Related substances were separated by HPLC and quantified by measuring the absorption in the Ultraviolet region The details of the results are given in table 2 Table 2
- composition according to comparative examples 1-5 of pramipexole were packed and sealed in black-lined high density polyethylene containers without desiccant and weie st ⁇ ied at a lempeidlun. ⁇ i about 40 'C -- 2 L and relative humidity of about 75 % ⁇ 5 % for three months
- HPLC high performance liquid chromatography
- compositions of comparative examples 6-9 were prepared using the ingredients listed in table no 7 and the composition of comparative example 10 was prepared using the ingredients given in table no 8
- the tablets wei e prepared according to the procedure described in comparative examples 1 -5 except use of butylated hydroxy I anisole and butylated hydroxyl toluene dissolved in mixture of isopropyl alcohol and water instead of purified water alone
- composition according to comparative examples 6-9 of pramipexole were packed and sealed in black lined high density polyethylene containers without desiccant and were stored at a temperature of about 40 0 C ⁇ 2° C and relative humidity of about 75 % ⁇ 5 % for a period of three months
- the composition of the comparative example 10 was packed and sealed in white high density polyethylene bottles and was stored at a temperature of about 40 ⁇ C ⁇ 2 0 C and relative humidity of about 75 % ⁇ 5 % for three months
- the compositions were analyzed foi the pramipexole dihydrochlo ⁇ de monohydrate content by HPLC techniques Related substances were separated by HPLC and quantified by measuring the absorption in the UV region The details of the results are given in table 9
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Abstract
A pharmaceutical composition comprising pramipexole or its pharmaceutically acceptable salts or its hydrates or solvates thereof, sugar alcohol (s) and a pharmaceutically acceptable carrier medium substantially free of polyvinyl pyrrolidone.
Description
PHARMACEUTICAL COMPOSITION OF PRAMIPEXOLE
The present invention relates to a pharmaceutical composition comprising pramipexole or its pharmaceutically acceptable salts or its hydrates or solvates thereof.'
BACKGROUND OF THE INVENTION
Pramipexole, (S)-2-amino-4, 5, 6, 7 - tetrahydro-6-(propylamino) benzole, is a non ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors. It is indicated in the treatment of signs and symptoms of idiopathic Parkinson's disease.
United States Patent number 4,886,812 ('812 patent) claims the markush class of compounds covering pramipexole. However, the patent does not teach or suggest the use of specific excipients to prepare stable pramipexole composition.
Pramipexole. is available in five strengths (0.125, 0.25, 0.50. 1.00 and 1.50 mg per tablet), marketed under the brand name of Mirapex® having mannitol, corn starch, colloidal silicon dioxide, povidone and magnesium stearate as the pharmaceutical excipients. We have found that compositions prepared according to the ingredients of Mirapex8' (Physician Desk Reference, Edition 54, page no 2467), when stored at a temperature of about 40" C ± 2 0C and relative humidity of about 75 % + 5 % for the period of three months showed a drop in the content of pramipexole dihydrochloride monohydrate, to below 95 % of the labeled amount.
United States patent application number 20060051417 ('417 patent application) discloses an extended release tablet formulation comprising pramipexole or its pharmaceutically acceptable salt in a matrix comprising of pregelatinised starch and an anionic polymer.
United States patent application number 20070129329 ('329 patent application) discloses a stabilized pharmaceutical composition of pramipexole comprising one or more dextrin.
SUMMARY OF INVENTION
The present invention provides a pharmaceutical composition comprising a mixture of pramipexole or its pharmaceutically acceptable salts or its hydrates or solvates thereof, sugar alcohol (s) and a pharmaceutically acceptable carrier medium substantially free of polyvinyl pyrrolidone.
DETAILED DESCRIPTION OF THE INVENTION
The term 'labeled amount' as used herein, refers to the amount of therapeutically active ingredient present in a pharmaceutical product. When a unit dose of the therapeutically active ingredient is present in the pharmaceutical product, it is often termed as a unit dosage form. Detailed monographs, often called label, of the
marketed dosage form contain its description, pharmacology, clinical studies, indication, contraindications, warnings, precautions, adverse events, dosage and administration and other details of the marketed product. The dosage form may be available in various doses, specified in the label, for example, pramipexole tablets are available as 0.125, 0.25, 0.5, 1.0 and 1.5 mg of pramipexole dihydrochloride monohydrate. These various doses in the tablets are herein referred to as the 'labeled amount' of pramipexole dihydrochloride monohydrate.
The dosage form should be chemically 'stable' and retain the labeled amount of the iheiapeuiieall) active ingredient upon storage and the impurities in the pharmaceutical product should remain low. We have found a 'stable' pharmaceutical composition comprising a mixture of pramipexole or its pharmaceutically acceptable salts or hydrates or solvates thereof, sugar alcohol (s) and a pharmaceutically acceptable carrier medium substantially free of polyvinyl pyrrolidone. These compositions when stored in high density polyethylene containers at a temperature of about 400 C + 20 C and relative humidity of about 75 % + 5 % for a period of three months, showed the content of pramipexole dihydrochloride monohydrate ranging from about 95 % to about 105 % by weight of the labeled amount of pramipexole dihydrochloride monohydrate and the total impurities (known and unknown) were less than I % of the labeled amount of pramιpe\υle dιh) di udilυπJι. iiionoh) Ji ai^ Particularly the content of the known impurities, i.e, impurity A (I), impurity B (II) and Impurity C (III) respectively did not increase when the pharmaceutical composition of the present invention was stored at a temperature of about 400C ± 2° C and relative humidity of about 75 % ± 5 % for about three months. On the contrary, we found a marginal increase in content of impurity A, impurity B and impurity C in compositions containing polyvinyl pyrrolidone. Particularly the unknown impurities increased to greater extent in the presence of polyvinyl pyrrolidone compared to compositions of the present invention.
The known impurities, as described above were identified by chemical structures I, Il and III and were termed as impurity A, impurity B and impurity C respectively. Their structures are given as follows:
II
III
According to one embodiment of the present invention, these impurities were separated by High performance liquid chromatography (HPLC) and quantified by measuring the absorption in the ultraviolet region. Although HPLC was preferred, any other suitable analytical method may also be employed to determine the pramipexole content and to quantify the known and unknown impurities.
Accordingly, the composition of the present invention comprises a mixture of pramipexole or its pharmaceutically acceptable salts or its- hydrates or solvates thereof, sugar alcohol (s) and a pharmaceutically acceptable carrier medium substantially free of polyvinyl pyrrolidone.
The term 'mixture' as used herein means pramipexole or its pharmaceutically acceptable salts or its hydrates or solvates thereof is intimately blended or is in physical contact with the pharmaceutically acceptable carrier medium.
The pharmaceutical composition of the present invention is considered to be stable' when the μhuπiiciceuiieul composition upon storage in suitable containers with or without desiccants at a temperature of about 40° C ± 2° C and a relative humidity of about 75 % ± 5 %, shows the pramipexole dihydrochloride monohydrate content in the range of about 95 % to about 105 % of the labeled amount and total impurities are less than about 1 % by weight of pramipexole dihydrochloride monohydrate.
The composition of the present invention comprises pramipexole or its pharmaceutically acceptable salts or its hydrates or solvates thereof. The pharmaceutically acceptable acid salts of pramipexole. include, but are not limited to, acid addition salts of inorganic acids or organic acids such as hydrobromide, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic and formic acid and the like. In preferred embodiment of the present invention, the pramipexole is used as the dihydrochloride salt, more preferably pramipexole is used as dihydrochloride monohydrate.
In this embodiment, the amount of pramipexole dihydrochloride monohydrate ranges from about 0.05 mg to about 2.0 mg per tablet. More preferably, the amount of pramipexole dihydrochloride monohydrate ranges from about 0.09 mg to about 1 .8 mg per tablet.
T he composition of the present invention comprises a pharmaceutically acceptable carrier medium substantially free of polyvinyl pyn olidone Although it may be possible to prepare a stable pharmaceutical composition with trace amount of polyvinyl pyrrolidone, preferably the composition is completely devoid of polyvinyl pyrrolidone
According to the present invention, the pharmaceutical composition comprises sugar alcohol (s) as one of the fillers or diluents The sugar alcohols that are used may be in any stereoisomers or geometric isomers or/and optical isomers forms They may be straight chain or cyclic in nature The straight chain sugar alcohols may be ti ihydπc to hexafn dπc sugar alcohol Examples of the straight chain sugai alcohols that ma\ be used in (he composition of the present invention include, but are not limited to, hexitols such as sorbitol, mannitol, glycerol, alhtol, talitol, glucitol, iditol and dulcitol, pentitols such as xylitol, adonitol (also called πbitol) and arabitol, teti itols such as erythπtol and threitol, and tπols such as glycerol Examples of cyclic sugar alcohol that may be used include, but are not limited to, inositol and the like
In one embodiment of the piesent invention, mannitol is used as the sugar alcohol The amount of mannitol used in the composition may range from about 60 % to about 90 %, preferably from about 70 % to about 80 % and most prefeiably about 75 % by weight of composition It is advantageous to use a sugai alcohoi paiticulai ly ioi the low dose drugs like pramipexole dihydrochloπde monohydrate for uniform distribution of the drug In one preferred embodiment, the mannitol having a mean particle size ranging from about 5 microns to about 70 microns, preferably from about 10 microns to about 50 microns, most preferably from about 15 microns to about 30 microns is used
Other examples of fillers or diluents that may be used in the pharmaceutically acceptable carrier medium substantially free of polyvinyl pyrrolidone, include, but are not limited to, starch and its derivatives like corn staich, pi egelatmized staicli and the like, calαum phosphate dibasic, calcium phosphalc u ibasic, mιuuu ) -.idlliιiL cellulose, silicified microcrystalline cellulose, powdered cellulose, lactose, dextrose, dextrin, sugar compressible and the like and mixture thereof The amount of fillers that may be used in the pharmaceutical composition of the present invention ranges from about 5 % to about 90 % by weight of the composition, preferably 15 % to about 30 % by weight of the composition
Examples of the binders that may be used include, but are not limited to, methyl cellulose, hydioxypropyl cellulose gelatin, tragacanth sodium alginate and the like and mixture thereof The amount of bindei that may be used ranges from about 0 % to about 10 % by weight of the composition In one piefeπed embodiment of the present invention, purified water is used as the sole granulating agent
Examples of lubricants/ glidants that may be used include, but are not limited to, silicon dioxide, colloidal silicon dioxide, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, zinc stearate, talc and the
like or mixture thereof The amount of lubπcants/glidants that may be used in the pharmaceutical composition of the present invention, ranges from about 0 1 % to about 5 %, preferably about 2 % by weight of the composition
In one embodiment of the present invention the pharmaceutical composition comprises one or more antioxidants Examples of the antioxidants that may be used in the phai maceutical composition includes but TI C not limited to, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, fumaπc acid, malic acid, alpha tocopherol, ascorbic acid palmitate, propyl gallate, sodium ascorbate, sodium metabisulfite and the like and mixture thereof Preferably antioxidants used in the composition of the present invention are butylated hydroxytoluene and/or butylated hydroxyanisole The amount of antioxidant used may range fiom about 0 % to about 1 % by weight of the composition
In one preferred embodiment of the present invention, the pharmaceutical composition consists essentially of a mixtuie oi pι amιpe\ole oi its phdi maceutiuillv dn.cpt.ible salts oi its lnduks oi ->oU ak -> llκκ ol it ti di *\ it derivatives sugai alcohol (s) and a pharmaceutically acceptable carrier medium In this embodiment, the pharmaceutically acceptable carrier medium is substantially free of polyvinyl pyrrolidone Although it may be possible to prepare a stable pharmaceutical composition with trace amounts of polyvinyl pyrrolidone preferably the composition is completely devoid of polyvinyl pyrrolidone
T he composition of the present invention may be prepared in the form of powders, granules, capsules sachets and tablets using conventional methods, involving mixing, granulation, drying blending and compression Preferably, it is recommended that the mixing of the drug with excipients be designed according to known methods in the art that result in a uniform mixing of the drug with the excipients For example mixing ot the drug with excipients in geometric proportions may be preferred or for instance when granulating, wet granulation may be preferred over dry granulation or direct compression into tablets When water is used in the granulation fluid, the granules are preferably dried to moisture content not more than about 4 % by weight of the dried granules
1 he examples that follow are provided as illustrations only and do not limit the scope of the present invention
Examples 1-5
Compositions of examples 1 -5 of the present invention were prepared using the ingredients listed in table no 1 Pramipexole dihydrochloπde monohydrate manmtol corn starch and prege!ntini7cd stai ch w ere sifted thi oιι»h 40 # mesh Manmtol (Part B) was first loaded to the rotating mixture granulator followed by Pramipexole dihydiochloπde monohydrate, remaining portion of manmtol (Part A), corn starch and a portion of pregelatinised starch The ingredients were dry mixed for about 5 minutes The mixture was then granulated with water The wet mass was screened and the granules were dried and milled The moisture content of the dried granules was about 3 0 % by weight of the dried granules Remaining portion of pregelatinized starch was added to dried, milled granules and the blend was lubricated with colloidal silicon dioxide and magnesium stearate This mixture was then compressed into tablets
Table I
The compositions prepared according to Example 1 , 2, 5 were packed and sealed in high density polyethylene containeis with desiccant and were stored at a temperature of about 400C ± 20 C and relative humidity of about 75 % ± 5 % for three months The compositions were analyzed for the pramipexole content by High performance liquid chromatography (HPLC) Related substances were separated by HPLC and quantified by measuring the absorption in the Ultraviolet region The details of the results are given in table 2
Table 2
ND- Not detected
Examples 6-9
Compositions of examples 6 to example 9 of the present invention were prepared using the ingredients listed in table no 3 The tablets were prepared according to the procedure described in examples 1 -5 except the addition of butylated hydroxy! anisole and butylated hydroxyl toluene dissolved in a mixture of isopropyl alcohol and water
Table 3
Composition prepared according to examples 6-9 were packed and sealed in black lined high density polyethylene containers with desiccant and was in stored at a temperature ot about 40υC ± 2° C and relative humidity of about 75 % ± 5 % for three months The compositions were analyzed for the pi amipexole dihydrochloπde monohydrate content By HPLC techniques Related substances were separated by HPLC and quantified by measuring the absorption in the UV region The details of the results are given in table 4
Table 4
ND - Not detected
Comparative Examples 1-5
Composition according to Comparative examples 1 -5 were prepared using the ingredients listed in i able no D Pi amipexole dihydrochloπde monohydrate, manmtol, corn starch and pregelatmized starch were sifted through 40 number mesh Manmtol (Part B) was first loaded to the rotating mixture granulator followed by pramipexole dihydrochloπde monohydrate, remaining portion of manmtol (Part A), corn starch and a portion of pregelatinised starch The ingredients were dry mixed for about 5 minutes The mixture was granulated with water The wet mass was screened and the granules were dried till the moisture content was about 3 0 % by weight of the dried granules The dried granules were milled Remaining portion of pregelatmized starch was added to dried granules and the blend was lubricated with colloidal silicon diox ide and magnesium stearate This mixture was then compressed into tablets
Table 5
Table 6
ND - Not detected
Comparative Examples 6-10
Compositions of comparative examples 6-9 were prepared using the ingredients listed in table no 7 and the composition of comparative example 10 was prepared using the ingredients given in table no 8 The tablets wei e prepared according to the procedure described in comparative examples 1 -5 except use of butylated hydroxy I anisole and butylated hydroxyl toluene dissolved in mixture of isopropyl alcohol and water instead of purified water alone
Comparative Example 10 Table 8
The composition according to comparative examples 6-9 of pramipexole were packed and sealed in black lined high density polyethylene containers without desiccant and were stored at a temperature of about 400C ± 2° C and relative humidity of about 75 % ± 5 % for a period of three months The composition of the comparative example 10 was packed and sealed in white high density polyethylene bottles and was stored at a temperature of about 40ϋC ± 20 C and relative humidity of about 75 % ± 5 % for three months The compositions were analyzed
foi the pramipexole dihydrochloπde monohydrate content by HPLC techniques Related substances were separated by HPLC and quantified by measuring the absorption in the UV region The details of the results are given in table 9
Table 9
As seen from example 1 -9 of the present invention in comparison to prior art composition comprising polyvinyl pyrrohdone it was found that when the compositions were packed and sealed in high density polyethylene containei s with desiccants and stored at a temperature of about 40° C ± 2° C and relative humidity of about 75 % ± 5 % for a period ot three months, the compositions showed the content of pramipexole dihvdrochloπde monohydrate within the range of about 95 % to about 105 % of the labeled amount and the total impurity did not exceed 1 % by weight of pramipexole dihydrochloπde monohydrate
Claims
1. A pharmaceutical composition comprising a mixture of pramipexole or its pharmaceutically acceptable salts or its hydrates or solvates thereof, sugar alcohol (s) and a pharmaceutically acceptable carrier medium substantially free of polyvinyl pyrrolidone.
5 2. A pharmaceutical composition as claimed in claim 1 wherein the sugar alcohol is mannitol and is present in the amount ranging from about 60 % to about 85 % by weight of the composition.
3. A pharmaceutical composition as claimed in claim 2 wherein the particle size of mannitol ranges from about 15 microns to about 35 microns.
4. A pharmaceutical composition as claimed in claim 1 wherein the composition is in ihe form υf granules.
10 5. A pharmaceutical composition as claimed in claim 4 wherein the moisture content of the granules is not more than about 4 % by weight of the dried granules.
6. A pharmaceutical composition as claimed in claim 1 wherein the pharmaceutically acceptable carrier medium comprises starch or its derivatives.
7. A pharmaceutical composition as claimed in claim 6 wherein the corn starch is present intragranularly and 1 5 pregelatinized starch is present intragranularly and extragranularly.
8. A pharmaceutical composition as claimed in claim 7 wherein the amount of corn starch present intragranularly ranges from about I U % to about 15 % by weight of the composition and the amount ol pregelaiinised starch
* present intragranularly ranges from about 5 % to about 10 % by weight of the composition and the amount of pregelatinised starch present extragranularly ranges from about 1 % to about 5 % by weight of the composition.
20 8. A pharmaceutical composition as claimed in claim 1 wherein the composition comprises one or more antioxidants.
9. A pharmaceutical composition consisting essentially of a mixture of pramipexole or its pharmaceutically acceptable salts or its hydrates or solvates thereof, starch or its derivatives, sugar . alcohol(s) and a pharmaceutically acceptable carrier medium.
25 10. A pharmaceutical composition as claimed in claim 1 wherein said pharmaceutical composition when stored at a temperature of about 40 0C ± 2 0C and relative humidity of about 75 % ± 5 % in high density polyethylene container showed the content of pramipexole dihydrochloride monohydrate in the range of about 95 % to about 105 % of the labeled amount and the total impurities less than about 1 % by weight of pramipexole dihydrochloride monohydrate.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102772403A (en) * | 2011-05-10 | 2012-11-14 | 浙江京新药业股份有限公司 | Preparation method for pramipexole preparation |
| EP3600291A4 (en) * | 2017-03-27 | 2020-12-23 | Chase Therapeutics Corporation | COMPOSITIONS AND METHODS OF TREATMENT OF SYNUCLEINOPATHIA |
| EP3648756A4 (en) * | 2017-07-03 | 2021-03-31 | Chase Therapeutics Corporation | Statin compositions and methods for use in treating synucleinopathies |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004100857A2 (en) * | 2003-05-07 | 2004-11-25 | Akina, Inc. | Highly plastic granules for making fast melting tablets |
| US20070148238A1 (en) * | 2005-06-23 | 2007-06-28 | Spherics, Inc. | Dosage forms for movement disorder treatment |
| US20070196494A1 (en) * | 2006-02-17 | 2007-08-23 | Arnaud Grenier | Low-friability, patient-friendly orally disintegrating formulations |
| WO2007137071A2 (en) * | 2006-05-16 | 2007-11-29 | Knopp Neurosciences, Inc. | Compositions of r(+) and s(-) pramipexole and methods of using the same |
-
2009
- 2009-01-22 WO PCT/IN2009/000056 patent/WO2009109990A2/en active Application Filing
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102772403A (en) * | 2011-05-10 | 2012-11-14 | 浙江京新药业股份有限公司 | Preparation method for pramipexole preparation |
| CN102772403B (en) * | 2011-05-10 | 2015-11-25 | 浙江京新药业股份有限公司 | Pramipexole preparation and preparation method thereof |
| EP3600291A4 (en) * | 2017-03-27 | 2020-12-23 | Chase Therapeutics Corporation | COMPOSITIONS AND METHODS OF TREATMENT OF SYNUCLEINOPATHIA |
| US11547700B2 (en) | 2017-03-27 | 2023-01-10 | Chase Therapeutics Corporation | Compositions and methods for treating synucleinopathies |
| EP3648756A4 (en) * | 2017-07-03 | 2021-03-31 | Chase Therapeutics Corporation | Statin compositions and methods for use in treating synucleinopathies |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009109990A3 (en) | 2009-12-10 |
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