WO2000078290A2 - Pharmaceutical composition comprising a salt of paroxetine - Google Patents
Pharmaceutical composition comprising a salt of paroxetine Download PDFInfo
- Publication number
- WO2000078290A2 WO2000078290A2 PCT/EP2000/005638 EP0005638W WO0078290A2 WO 2000078290 A2 WO2000078290 A2 WO 2000078290A2 EP 0005638 W EP0005638 W EP 0005638W WO 0078290 A2 WO0078290 A2 WO 0078290A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition according
- diluent
- paroxetine
- water
- composition
- Prior art date
Links
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 title claims abstract description 39
- 229960002296 paroxetine Drugs 0.000 title claims abstract description 37
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 150000003839 salts Chemical class 0.000 title claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
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Classifications
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K9/2009—Inorganic compounds
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to novel pharmaceutical compositions comprising certain paroxetine salts and their use in treating and or preventing medical disorders.
- the present invention relates to salts of paroxetine which are more soluble than paroxetine hydrochloride hemihydrate, which salt is currrently used in commercial presentations of paroxetine.
- An example of a more soluble salt is paroxetine methanesulfonate.
- Paroxetine methanesulfonate and pharmaceutical compositions thereof are disclosed in the published PCT application WO 98/56787 (Synthon).
- the Synthon application discloses pharmaceutical compositions that comprise a carrier or diluent, but the application is silent as to the kind of carrier or diluent which is suitable or that which maximizes the advantages of paroxetine methanesulfonate.
- salts of paroxetine which are more water-soluble than the hydrochloride hemihydrate salt (for example the methanesulfonate salt) can be advantageously formulated with a water-soluble or hydrophilic diluent.
- compositions comprising a salt of paroxetine which is more water-soluble than paroxetine hydrochloride hemihydrate and a pharmaceutically acceptable carrier wherein the carrier comprises a water-soluble and/or hydrophilic diluent, excluding the following tablet compositions consisting of:
- the salt of paroxetine is at least two times, preferably at least 10 times, and more preferably at least 100 times more soluble than paroxetine hydrochloride hemihydrate in water at 20°C.
- Examples of such salts of paroxetine include glutamate, succinate, propionate, gluconate, 4-hydroxybutyrate, aspartate, formate, benzenesulfonate, toluenesulfonate or methanesulfonate.
- a particular example of a more water-soluble salt is paroxetine methanesulfonate.
- the aqueous solubility of a water-soluble diluent at 20°C is at least 0.005 mg/ml, preferably at least 0.01 mg/ml and more preferably at least O. lmg/ml, for example 0.2 mg/ml.
- Suitable water-soluble diluents include water-soluble carbohydrate diluents such as sugar or starch diluents and mixtures thereof.
- Suitable hydrophilic diluents include carbohydrate hydrophilic diluents such as cellulose diluents.
- Carbohydrate diluents suitable for use in the present invention include compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, fructose, microcrystalline cellulose (such as different grades of Avicel, Emcocel, and Nivacel, e.g.
- silicified microcrystalline cellulose which is a mixture of colloidal silicon dioxide and microcrystalline cellulose such as Pro solv SMCC99
- pregelatinised starch powdered cellulose, lactose, maltodextrin, mannitol, sorbitol, sucrose, sugar spheres, lactitol, maltitol or xylitol or mixtures thereof.
- the diluents of the present invention may be present in an amount ranging from 1 to 99% , preferably 10 to 95% , more preferably 20 to 95% , and most preferably from 40 to 95% , for example 80 to 90% w/w of the composition.
- the diluent of the present invention may be present in admixture with an additional diluent, such as calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, or dibasic calcium phosphate or a mixture thereof.
- an additional diluent such as calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, or dibasic calcium phosphate or a mixture thereof.
- diluent admixture comprises at least 20% by weight (e.g. 30% , 40%, 50%, 60% , 70% , 80% , or 90% by weight) of the water-soluble and/or hydrophilic diluent.
- the water-soluble and/or hydrophilic diluent is present as the sole diluent.
- compositions of the present invention may also include a binder, a disintegrant, a lubricant, a glidant, a surfactant, a colouring agent, and a flavouring agent.
- a binder e.g., a binder for aqueous lubricant, a glidant, a surfactant, a colouring agent, and a flavouring agent.
- agents may be utilized in a conventional manner, for example in a manner similar to that already used for marketed paroxetine formulations.
- compositions of the present invention comprise up to 30% by weight of a disintegrant, preferably from 1 to 20% , more preferably from 2-10% and even more preferably from 4-8% by weight of the composition.
- a disintegrant may be selected from alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate, sodium starch glycollate, starch, carmelose sodium, cationic exchange resins, modified starch, sodium glycine carbonate and mixtures thereof.
- Preferred disintegrants include starch, methylcellulose, crospovidone, croscarmellose sodium and sodium starch glycollate and mixtures thereof. Most preferably the disintegrant is sodium starch glycollate.
- compositions of this invention may comprise said salts of paroxetine in non- crystalline form, preferably in crystalline form, including any solvates or hydrates thereof.
- Paroxetine methanesulfonate exists in more than one crystalline form.
- WO98/56787 describes a crystalline form of paroxetine methanesulfonate having ter alia one or more of the following characteristic Infra Red (IR) peaks: 1208, 1169, 1038, 962, 931, 838 and 546 cm “1 .
- IR Infra Red
- Another crystalline form of paroxetine methanesulfonate is disclosed in GB-A-2336364 having inter alia one or more of the following characteristic IR peaks: 1604, 1194, 1045, 946, 830, 601, 554 and 539 cm 1 .
- compositions are usually presented as unit dose compositions containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to lOOmg, for example 10 to 50mg such as 10, 12.5, 15, 20, 25, 30 or 40mg per unit dose. Most preferably unit doses contain 20mg of active ingredient calculated on a free base basis.
- Such a composition is normally taken by a human patient from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400mg of active ingredient calculated on a free base basis.
- a suitable daily dose is from 0.05 to 6mg/kg, more preferably
- unit dose is taken once a day.
- Preferred unit dosage forms include tablets or capsules, especially a modified oval or pentagonal shaped tablet.
- compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
- tablets can be produced by a wet granulation process.
- the active drug substance and excipients are screened and mixed in a high shear mixer granulator.
- the blend is granulated by the addition of a granulating solution
- sprayed into the high shear mixer granulator typically purified water, disintegration agent dissolved/dispersed in purified water, or drug dissolved/dispersed in purified water or a suitable solvent
- wetting agents e.g. surfactants can be added.
- the resulting granules are dried usually with residual moisture of 1-5 % by tray, fluid bed or microwave drying techniques.
- the dried granules are milled to produce a uniform particle size, the granules are blended with extragranular excipients as necessary, typically a lubricant and glidant (e.g. magnesium stearate, silicon dioxide).
- the compression blend can be compressed using a rotary tablet press typically in the range of 100 to lOOOmg.
- the resulting tablets can be coated in a pan coater typically with a 1-5% aqueous film coat.
- tablets can be produced by a direct compression process.
- the active drug substance and excipients are screened and mixed in a suitable blender e.g. a cone, cube or V- blender.
- a suitable blender e.g. a cone, cube or V- blender.
- Other excipients are added as necessary, and further blended.
- the compression blend can be compressed using a rotary tablet press typically in the range of 100 to lOOOmg.
- the resulting tablets can be coated in a pan coater.
- Suitably capsules can be produced by screening and mixing the active drug substance and excipients in a suitable blender e.g. a cone, cube or V- blender. Other excipients are added as necessary, typically a lubricant and glidant, and the mixture blended. The blend is filled into capsules with a fill weight typically ranging from 100- lOOOmg using a standard capsule filling machine.
- a suitable blender e.g. a cone, cube or V- blender.
- Other excipients are added as necessary, typically a lubricant and glidant, and the mixture blended.
- the blend is filled into capsules with a fill weight typically ranging from 100- lOOOmg using a standard capsule filling machine.
- compositions may be used to treat and prevent the following disorders:
- PMDD Pre-Menstrual Dysphoric Disorder
- the Disorders are herein after referred to as "the Disorders”.
- the present invention further provides a method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a composition of the invention to a sufferer in need thereof.
- the present invention also provides the use of a diluent of the invention in the manufacture of a paroxetine methanesulfonate containing medicament for treating and/or preventing the Disorders.
- paroxetine methanesulfonate formulations each containing 20mg paroxetine free base
- the rates of dissolution of these formulations were compared with a control tablet formulation comprising paroxetine hydrochloride hemihydrate (also containing 20mg paroxetine free base) which salt is used in commercial presentations of paroxetine.
- Example 1 The formulation of Example 1 is essentially identical to the control formulation except for the replacement of paroxetine hydrochloride hemihydrate with paroxetine methanesulfonate. Whilst the methanesulfonate salt of paroxetine is significantly more soluble than the hydrochloride salt, surprisingly the rate of dissolution of Example 1, which comprises dibasic calcium phosphate as the sole diluent, is much slower than the control formulation. This observation of reduced dissolution from a salt with higher aqueous solubility than the standard hydrochloride hemihydrate salt can be explained by the in situ formation of the hydrochloride hemihydrate salt on the dissolving surface of the tablet of Example 1. This hydrochloride hemihydrate salt forms a substantial shield on the tablet surface which then needs to dissolve in turn and the whole dissolution process is slowed.
- Examples 2 to 6 which contain a carbohydrate diluent instead of dibasic calcium phosphate, are faster than the control formulation. Whilst the in situ formation of the hydrochloride hemihydrate salt will occur the presence of the carbohydrate diluent provides an improved dissolution rate.
- paroxetine formulations each containing 20mg paroxetine free base, either as the succinate, propionate or formate ) were prepared using a direct compression process as hereinbefore described and compressed into tablets each weighing 350 mg. The rates of dissolution of these formulations were compared with a control tablet formulation comprising paroxetine hydrochloride hemihydrate (also containing 20mg paroxetine free base) which salt is used in commercial presentations of paroxetine.
- Examples 10, 12 and 14 are essentially identical to the control formulation except for the replacement of paroxetine hydrochloride hemihydrate with paroxetine succinate, propionate or formate. Whilst these salts of paroxetine are all more soluble than the hydrochloride salt, surprisingly the rates of dissolution of these Examples, which comprise dibasic calcium phosphate as the sole diluent, are generally slower than the control formulation. This observation of reduced dissolution from a salt with higher aqueous solubility than the standard hydrochloride hemihydrate salt can be explained by the in situ formation of the hydrochloride hemihydrate salt on the dissolving surface of the tablets of Examples 10, 12 and 14.
- This hydrochloride hemihydrate salt forms a substantial shield on the tablet surface which then needs to dissolve in turn and the whole dissolution process is slowed.
- dissolution rates of Examples 1 1, 13 and 15 which contain a carbohydrate diluent instead of dibasic calcium phosphate, are faster than the control formulation. Whilst the in situ formation of the hydrochloride hemihydrate salt will occur the presence of the carbohydrate diluent provides an improved dissolution rate.
Abstract
Pharmaceutical compositions comprising water soluble salts of paroxetine are described.
Description
Novel Composition
The present invention relates to novel pharmaceutical compositions comprising certain paroxetine salts and their use in treating and or preventing medical disorders.
In particular the present invention relates to salts of paroxetine which are more soluble than paroxetine hydrochloride hemihydrate, which salt is currrently used in commercial presentations of paroxetine. An example of a more soluble salt is paroxetine methanesulfonate.
Paroxetine methanesulfonate and pharmaceutical compositions thereof are disclosed in the published PCT application WO 98/56787 (Synthon). The Synthon application discloses pharmaceutical compositions that comprise a carrier or diluent, but the application is silent as to the kind of carrier or diluent which is suitable or that which maximizes the advantages of paroxetine methanesulfonate.
It has now been discovered that salts of paroxetine which are more water-soluble than the hydrochloride hemihydrate salt (for example the methanesulfonate salt) can be advantageously formulated with a water-soluble or hydrophilic diluent.
Accordingly, in a first aspect of the present invention there is provided a composition comprising a salt of paroxetine which is more water-soluble than paroxetine hydrochloride hemihydrate and a pharmaceutically acceptable carrier wherein the carrier comprises a water-soluble and/or hydrophilic diluent, excluding the following tablet compositions consisting of:
The use of a water-soluble and/or hydrophilic diluent according to the present invention surprisingly enhances the dissolution rate of the paroxetine salts of the present invention.
Suitably the salt of paroxetine is at least two times, preferably at least 10 times, and more preferably at least 100 times more soluble than paroxetine hydrochloride hemihydrate in water at 20°C. Examples of such salts of paroxetine include glutamate, succinate, propionate, gluconate, 4-hydroxybutyrate, aspartate, formate, benzenesulfonate, toluenesulfonate or methanesulfonate. A particular example of a more water-soluble salt is paroxetine methanesulfonate.
Suitably the aqueous solubility of a water-soluble diluent at 20°C is at least 0.005 mg/ml, preferably at least 0.01 mg/ml and more preferably at least O. lmg/ml, for example 0.2 mg/ml. Suitable water-soluble diluents include water-soluble carbohydrate diluents such as sugar or starch diluents and mixtures thereof.
Suitable hydrophilic diluents include carbohydrate hydrophilic diluents such as cellulose diluents.
Carbohydrate diluents suitable for use in the present invention include compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, fructose, microcrystalline cellulose (such as different grades of Avicel, Emcocel, and Nivacel, e.g. Avicel PH101, Avicel PH 102, Emcocel 50M, Emcocel 90M, Vivacel 101, Nivacel 102), silicified microcrystalline cellulose (which is a mixture of colloidal silicon dioxide and microcrystalline cellulose such as Pro solv SMCC99), pregelatinised starch, powdered cellulose, lactose, maltodextrin, mannitol, sorbitol, sucrose, sugar spheres, lactitol, maltitol or xylitol or mixtures thereof.
Suitably the diluents of the present invention may be present in an amount ranging from 1 to 99% , preferably 10 to 95% , more preferably 20 to 95% , and most preferably from 40 to 95% , for example 80 to 90% w/w of the composition.
If desired the diluent of the present invention may be present in admixture with an additional diluent, such as calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, or dibasic calcium phosphate or a mixture thereof. Suitably such diluent admixture comprises at least 20% by weight (e.g. 30% , 40%, 50%, 60% , 70% , 80% , or 90% by weight) of the water-soluble and/or hydrophilic diluent. Preferably the water-soluble and/or hydrophilic diluent is present as the sole diluent.
Suitably compositions of the present invention may also include a binder, a disintegrant, a lubricant, a glidant, a surfactant, a colouring agent, and a flavouring agent. These agents may be utilized in a conventional manner, for example in a manner similar to that already used for marketed paroxetine formulations.
Examples of such excipients are described in the Handbook of Pharmaceutical Excipients (Second Edition, 1994, edited by A. Wade and P. Weller, published by the American Pharmaceutical Association and the Pharmaceutical Press).
Suitably the compositions of the present invention comprise up to 30% by weight of a disintegrant, preferably from 1 to 20% , more preferably from 2-10% and even more preferably from 4-8% by weight of the composition.
Suitable disintegrants may be selected from alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate, sodium starch glycollate, starch, carmelose sodium, cationic exchange resins, modified starch, sodium glycine carbonate and mixtures thereof. Preferred disintegrants include starch, methylcellulose, crospovidone, croscarmellose sodium and sodium starch glycollate and mixtures thereof. Most preferably the disintegrant is sodium starch glycollate.
The compositions of this invention may comprise said salts of paroxetine in non- crystalline form, preferably in crystalline form, including any solvates or hydrates thereof.
Paroxetine methanesulfonate exists in more than one crystalline form. For example WO98/56787 describes a crystalline form of paroxetine methanesulfonate having ter alia one or more of the following characteristic Infra Red (IR) peaks: 1208, 1169, 1038, 962, 931, 838 and 546 cm"1. Another crystalline form of paroxetine methanesulfonate is disclosed in GB-A-2336364 having inter alia one or more of the following characteristic IR peaks: 1604, 1194, 1045, 946, 830, 601, 554 and 539 cm 1.
Suitably the compositions are usually presented as unit dose compositions containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to lOOmg, for example 10 to 50mg such as 10, 12.5, 15, 20, 25, 30 or 40mg per unit dose. Most preferably unit doses contain 20mg of active ingredient calculated on a free base basis. Such a composition is normally taken by a human patient from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400mg of active ingredient calculated on a free base basis. Thus a suitable daily dose is from 0.05 to 6mg/kg, more preferably
0.14 to 0.86 mg/kg. Most preferably the unit dose is taken once a day.
Preferred unit dosage forms include tablets or capsules, especially a modified oval or pentagonal shaped tablet.
The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
For example tablets can be produced by a wet granulation process. Suitably the active drug substance and excipients are screened and mixed in a high shear mixer granulator. The blend is granulated by the addition of a granulating solution
(typically purified water, disintegration agent dissolved/dispersed in purified water, or drug dissolved/dispersed in purified water or a suitable solvent) sprayed into the high shear mixer granulator. If desired wetting agents e.g. surfactants can be added. The resulting granules are dried usually with residual moisture of 1-5 % by tray, fluid bed or microwave drying techniques. The dried granules are milled to produce a uniform particle size, the granules are blended with extragranular excipients as necessary, typically a lubricant and glidant (e.g. magnesium stearate, silicon dioxide). The compression blend can be compressed using a rotary tablet press typically in the range of 100 to lOOOmg. The resulting tablets can be coated in a pan coater typically with a 1-5% aqueous film coat.
Alternatively tablets can be produced by a direct compression process. Suitably the active drug substance and excipients are screened and mixed in a suitable blender e.g. a cone, cube or V- blender. Other excipients are added as necessary, and further blended. The compression blend can be compressed using a rotary tablet press typically in the range of 100 to lOOOmg. The resulting tablets can be coated in a pan coater.
Suitably capsules can be produced by screening and mixing the active drug substance and excipients in a suitable blender e.g. a cone, cube or V- blender. Other excipients are added as necessary, typically a lubricant and glidant, and the mixture blended. The
blend is filled into capsules with a fill weight typically ranging from 100- lOOOmg using a standard capsule filling machine.
The compositions may be used to treat and prevent the following disorders:
Alcoholism Anxiety
Depression Obsessive Compulsive Disorder
Panic Disorder Chronic Pain
Obesity Senile Dementia Migraine Bulimia
Anorexia Social Phobia
Pre-Menstrual Dysphoric Disorder (PMDD) Adolescent Depression
General Anxiety Disorder Smoking Cessation
These disorders are herein after referred to as "the Disorders".
The present invention further provides a method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a composition of the invention to a sufferer in need thereof.
The present invention also provides the use of a diluent of the invention in the manufacture of a paroxetine methanesulfonate containing medicament for treating and/or preventing the Disorders.
The following Examples illustrate the present invention.
Examples 1 to 9
The following nine paroxetine methanesulfonate formulations (each containing 20mg paroxetine free base) were prepared using a direct compression process as hereinbefore described and compressed into tablets each weighing 350 mg. The rates of dissolution of these formulations were compared with a control tablet formulation comprising paroxetine hydrochloride hemihydrate (also containing 20mg paroxetine free base) which salt is used in commercial presentations of paroxetine.
NA not applicable
S slower than control formulation
F faster than control formulation
The formulation of Example 1 is essentially identical to the control formulation except for the replacement of paroxetine hydrochloride hemihydrate with paroxetine methanesulfonate. Whilst the methanesulfonate salt of paroxetine is significantly more soluble than the hydrochloride salt, surprisingly the rate of dissolution of Example 1, which comprises dibasic calcium phosphate as the sole diluent, is much slower than the control formulation. This observation of reduced dissolution from a salt with higher aqueous solubility than the standard hydrochloride hemihydrate salt can be explained by the in situ formation of the hydrochloride hemihydrate salt on the dissolving surface of the tablet of Example 1. This hydrochloride hemihydrate salt
forms a substantial shield on the tablet surface which then needs to dissolve in turn and the whole dissolution process is slowed.
By contrast the dissolution rates of Examples 2 to 6, which contain a carbohydrate diluent instead of dibasic calcium phosphate, are faster than the control formulation. Whilst the in situ formation of the hydrochloride hemihydrate salt will occur the presence of the carbohydrate diluent provides an improved dissolution rate.
The results for Examples 1 and 7 indicate that the rate of dissolution for paroxetine methanesulfonate formulations containing dibasic calcium phosphate can be increased by raising the level of disintegrant present. However it is preferable also to use a carbohydrate diluent as evidenced by the results for Examples 8 and 9 which dissolution rates are also faster than the control formulation.
In summary, these results demonstrate that a highly water soluble salt of paroxetine (such as the methanesulfonate salt) can be advantageously formulated with a water- soluble and/or hydrophilic diluent (such as a carbohydrate diluent).
Examples 10 to 15
The following three pairs of paroxetine formulations (each containing 20mg paroxetine free base, either as the succinate, propionate or formate ) were prepared using a direct compression process as hereinbefore described and compressed into tablets each weighing 350 mg. The rates of dissolution of these formulations were compared with a control tablet formulation comprising paroxetine hydrochloride hemihydrate (also containing 20mg paroxetine free base) which salt is used in commercial presentations of paroxetine.
NA not applicable
S slower than control formulation
F faster than control formulation
The formulations of Examples 10, 12 and 14 are essentially identical to the control formulation except for the replacement of paroxetine hydrochloride hemihydrate with paroxetine succinate, propionate or formate. Whilst these salts of paroxetine are all more soluble than the hydrochloride salt, surprisingly the rates of dissolution of these Examples, which comprise dibasic calcium phosphate as the sole diluent, are generally slower than the control formulation. This observation of reduced dissolution from a salt with higher aqueous solubility than the standard hydrochloride hemihydrate salt can be explained by the in situ formation of the hydrochloride hemihydrate salt on the dissolving surface of the tablets of Examples 10, 12 and 14. This hydrochloride hemihydrate salt forms a substantial shield on the tablet surface which then needs to dissolve in turn and the whole dissolution process is slowed.
By contrast the dissolution rates of Examples 1 1, 13 and 15, which contain a carbohydrate diluent instead of dibasic calcium phosphate, are faster than the control formulation. Whilst the in situ formation of the hydrochloride hemihydrate salt will occur the presence of the carbohydrate diluent provides an improved dissolution rate.
In summary, these results demonstrate that alternative water soluble salts of paroxetine (such as the succinate, propionate or formate salt) can be advantageously formulated with a water-soluble and/or hydrophilic diluent (such as a carbohydrate diluent).
Claims
1. A pharmaceutical composition comprising a salt of paroxetine which is more water-soluble than paroxetine hydrochloride hemihydrate and a pharmaceutically acceptable carrier wherein the carrier comprises a water-soluble and/or hydrophilic diluent, excluding the following tablet compositions consisting of:
2. A composition according to claim 1 in which the salt of paroxetine is selected from glutamate, succinate, propionate, gluconate, 4-hydroxybutyrate, aspartate, formate, benzenesulfonate, toluenesulfonate or methanesulfonate.
3. A composition according to claim 1 or 2 in which the salt of paroxetine is paroxetine methanesulfonate.
4. A composition according to any one of claims 1 to 3 wherein the diluent has a water solubility at 20°C of at least 0.005 mg/ml.
5. A composition according to claim 4 wherein the diluent has a water solubility at 20°C of at least 0.01 mg/ml.
A composition according to claim 5 wherein the diluent has a water solubility at 20°C of at least 0.1 mg/ml.
. A composition according to any one of claims 1 to 3 wherein the water soluble and/or hydrophilic diluent is a carbohydrate diluent.
8. A composition according to claim 7 wherein the carbohydrate diluent is selected from compressible sugar, confectioner's sugar, a dextrate, dextrin, dextrose, fructose, microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinised starch, powdered cellulose, lactose, maltodextrin, mannitol, sorbitol, sucrose, sugar spheres, lactitol, maltitol, or xylitol or a mixture thereof.
9. A composition according to claim 8 wherein the carbohydrate diluent is selected from lactose, microcrystalline cellulose or mannitol or a mixture thereof.
10. A composition according to any one of claims 1 to 9 wherein the diluent is present in an amount ranging from 1 to 99% w/w of the composition.
11. A composition according to claim 10 wherein the diluent is present in an amount ranging from 20 to 95% w/w of the composition.
12. A composition according to claim 11 wherein the diluent is present in an amount ranging from 40 to 95% w/w of the composition.
13. A composition according to claim 12 wherein the diluent is present in an amount ranging from 80 to 90% w/w of the composition.
14. A composition according to any one of claims 1 to 13 further comprising an additional diluent selected from calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate or dibasic calcium phosphate or a mixture thereof.
5. A composition according to claim 14 which does not contain dicalcium phosphate in combination with microcrystalline cellulose.
16. A composition according to claim 14 which does not contain dicalcium phosphate.
17. A composition according to any one of claims 14 to 16 wherein the diluent admixture comprises at least 20 % by weight thereof of the water-soluble and/ or hydrophilic diluent.
18. A composition according to any one of claims 14 to 16 wherein the diluent admixture comprises at least 40 % by weight thereof of the water-soluble and/ or hydrophilic diluent.
19. A composition according to any one of claims 14 to 16 wherein the diluent admixture comprises at least 60 % by weight thereof of the water-soluble and/ or hydrophilic diluent.
20. A composition according to any one of claims 14 to 16 wherein the diluent admixture comprises at least 80 % by weight thereof of the water-soluble and/ or hydrophilic diluent.
21. A composition according to any one of claims 1 to 13 wherein the water soluble and/or hydrophilic diluent is present as the sole diluent.
22. A composition according to any one of claims 1 to 21 further comprising a disintegrant.
23. A composition according to claim 22 wherein the disintegrant is selected from starch, methylcellulose, crospovidone, croscarmellose sodium or sodium starch glycollate or a mixture thereof.
4. A composition according to claim 23 wherein the disintegrant is sodium starch glycollate.
25. A composition according to any one of claims 22 to 24 wherein the disintegrant is present in an amount up to 30% w/w of the composition.
26. A composition according to claim 25 wherein the disintegrant is present from
1 to 20%o w/w of the composition.
27. A composition according to claim 26 wherein the disintegrant is present from
2 to 10% w/w of the composition.
28. A composition according to any one of claims 1 to 27 wherein said more water soluble salt of paroxetine is in crystalline form.
29. A composition according to claim 28 wherein paroxetine methanesulfonate is in crystalline form.
30. A composition according to claim 29 wherein the paroxetine methanesulfonate has inter alia the following characteristic IR peaks: 1208, 1169, 1038, 962,
931, 838 and 546 ± 2 cm"1.
31. A composition according to claim 29 wherein the paroxetine methanesulfonate has inter alia the following characteristic IR peaks: 1604, 1194, 1045, 946, 830, 601 , 554 and 539 ± 2 cm"' .
32. A composition according to any one of claims 1 to 31 comprising 1 to 200mg of said more water soluble salt of paroxetine per unit dose, calculated on a free base basis.
3. A composition according to claim 32 comprising 10 to 50mg of said more water soluble salt of paroxetine per unit dose, calculated on a free base basis.
34. A composition according to claim 33 comprising 10, 12.5, 15, 20, 25, 30 or 40mg of said more water soluble salt of paroxetine methanesulfonate per unit dose, calculated on a free base basis.
35. A composition according to any one of claims 32 to 34 wherein said more water soluble salt of paroxetine is paroxetine methanesulfonate.
36. A composition according to any one of claims 1 to 35 adapted for oral administration.
37. A composition according to claim 36 which is a tablet or capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU50787/00A AU5078700A (en) | 1999-06-22 | 2000-06-16 | Novel composition |
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9914601.1 | 1999-06-22 | ||
| GBGB9914601.1A GB9914601D0 (en) | 1999-06-22 | 1999-06-22 | Composition |
| GBGB9914712.6A GB9914712D0 (en) | 1999-06-23 | 1999-06-23 | Composition |
| GB9914712.6 | 1999-06-23 | ||
| GB9927498.7 | 1999-11-19 | ||
| GBGB9927498.7A GB9927498D0 (en) | 1999-11-19 | 1999-11-19 | Composition |
| GB9928693.2 | 1999-12-03 | ||
| GBGB9928693.2A GB9928693D0 (en) | 1999-12-03 | 1999-12-03 | Novel composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000078290A2 true WO2000078290A2 (en) | 2000-12-28 |
| WO2000078290A3 WO2000078290A3 (en) | 2001-05-25 |
Family
ID=27451907
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2000/005638 WO2000078290A2 (en) | 1999-06-22 | 2000-06-16 | Pharmaceutical composition comprising a salt of paroxetine |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU5078700A (en) |
| WO (1) | WO2000078290A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001058449A1 (en) * | 2000-02-11 | 2001-08-16 | Smithkline Beecham Plc | Water dispersible formulation of paroxetine |
| WO2002055062A2 (en) * | 2001-01-11 | 2002-07-18 | Synthon B.V. | Pharmaceutical tablet comprising paroxetine mesylate |
| WO2003020717A1 (en) * | 2001-08-02 | 2003-03-13 | Spurcourt Limited | Paroxetine isethionate salt, process of preparation and use in the treatment of depression |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5371092A (en) * | 1990-11-24 | 1994-12-06 | Beecham Group, P.L.C. | Use of paroxetine for the treatment of senile dementia, bulimia, migraine or anorexia |
| WO1995016448A1 (en) * | 1993-12-15 | 1995-06-22 | Smithkline Beecham Plc | Paroxetine tablets and process to prepare them |
| WO1997003670A1 (en) * | 1995-07-20 | 1997-02-06 | Smithkline Beecham P.L.C. | Paroxetine controlled release compositions |
| WO1998056787A1 (en) * | 1997-06-10 | 1998-12-17 | Synthon B.V. | 4-Phenylpiperidine compounds |
| WO1999040084A1 (en) * | 1998-02-06 | 1999-08-12 | Smithkline Beecham Plc | Salts of paroxetine |
| EP0970955A1 (en) * | 1998-07-02 | 2000-01-12 | Smithkline Beecham Plc | Paroxetine methanesulfonate |
| WO2000008016A1 (en) * | 1998-08-08 | 2000-02-17 | Smithkline Beecham Plc | Paroxetine salts |
-
2000
- 2000-06-16 AU AU50787/00A patent/AU5078700A/en not_active Abandoned
- 2000-06-16 WO PCT/EP2000/005638 patent/WO2000078290A2/en active Application Filing
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5371092A (en) * | 1990-11-24 | 1994-12-06 | Beecham Group, P.L.C. | Use of paroxetine for the treatment of senile dementia, bulimia, migraine or anorexia |
| WO1995016448A1 (en) * | 1993-12-15 | 1995-06-22 | Smithkline Beecham Plc | Paroxetine tablets and process to prepare them |
| WO1997003670A1 (en) * | 1995-07-20 | 1997-02-06 | Smithkline Beecham P.L.C. | Paroxetine controlled release compositions |
| WO1998056787A1 (en) * | 1997-06-10 | 1998-12-17 | Synthon B.V. | 4-Phenylpiperidine compounds |
| WO1999040084A1 (en) * | 1998-02-06 | 1999-08-12 | Smithkline Beecham Plc | Salts of paroxetine |
| EP0970955A1 (en) * | 1998-07-02 | 2000-01-12 | Smithkline Beecham Plc | Paroxetine methanesulfonate |
| WO2000008016A1 (en) * | 1998-08-08 | 2000-02-17 | Smithkline Beecham Plc | Paroxetine salts |
Non-Patent Citations (1)
| Title |
|---|
| SUCKER H ET AL: "PHARMAZEUTISCHE TECHNOLOGIE" , DE,STUTTGART, THIEME VERLAG, PAGE(S) 259-260 XP002060945 page 259 -page 260 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001058449A1 (en) * | 2000-02-11 | 2001-08-16 | Smithkline Beecham Plc | Water dispersible formulation of paroxetine |
| WO2002055062A2 (en) * | 2001-01-11 | 2002-07-18 | Synthon B.V. | Pharmaceutical tablet comprising paroxetine mesylate |
| WO2002055062A3 (en) * | 2001-01-11 | 2003-03-13 | Synthon Bv | Pharmaceutical tablet comprising paroxetine mesylate |
| WO2003020717A1 (en) * | 2001-08-02 | 2003-03-13 | Spurcourt Limited | Paroxetine isethionate salt, process of preparation and use in the treatment of depression |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000078290A3 (en) | 2001-05-25 |
| AU5078700A (en) | 2001-01-09 |
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