AU697284B2 - A new composition containing selegiline - Google Patents
A new composition containing selegiline Download PDFInfo
- Publication number
- AU697284B2 AU697284B2 AU40236/95A AU4023695A AU697284B2 AU 697284 B2 AU697284 B2 AU 697284B2 AU 40236/95 A AU40236/95 A AU 40236/95A AU 4023695 A AU4023695 A AU 4023695A AU 697284 B2 AU697284 B2 AU 697284B2
- Authority
- AU
- Australia
- Prior art keywords
- acid
- selegiline
- composition
- pharmaceutically acceptable
- composition according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
4
AUSTRALIA
Patents Act COMPLETE SPECIFICATION
(ORIGINAL)
Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art:
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I C cit tc lift P C
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I. C c rt Name of Applicant: Orion-Yhtyma Oy Actual Inventor(s): Matti Aukusti Halonen Ulla Inkeri Leinonen Seppo Sulevi Lennart Parhl Ilse Maria Piippo Gunilla Margareta Orn Address for Service: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: A NEW COMPOSITION CONTAINING SELEGILINE Our Ref 435160 POF Code: 176352/20383 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -M07589 7 06 2l.
T_ A NEW COMPOSITION CONTAINING SELEGILINE The present application is a divisional from parent Australian application 64300/94 (663995), the entire disclosure of which is incorporated herein by reference.
The invention relates to a new stable composition suitable for oral administration comprising a pharmaceutically acceptable acid addition salt of selegiline e.g. the hydrochloride.
Selegiline N-(1-phenyl isopropyl)-N-methyl-N-propionyl amine) is a MAO-B inhibitor. It has been available for more than ten years as an ariti- Parkinson's disease drug.
The most common composition of selegiline is a tablet having the following main constituents: selegiline hydrochloride, a diluent e.g. lactose and starch, a binder such as polyvinyl pyrrolidone and a lubricant, usually a stearic acid salt e.g. magnesium stearate (EP 146363, WO 90/019289).
Australian Patent No. 71541/87 lists a large number of auxiliary agents useful in a synergic composition of selegiline and amantadine. Among these 20 are mentioned vegetable oils arachis oil, castor oil, olive oil, sesame oil, cotton seed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, mono-, di-, and triglycerides of saturated fatty acids C12 to C18). The only solid composition described contains 0.1 kg of magnesium stearate to 0.75 kg of selegiline hydrochloride.
European Patent No. 294 441 discloses a composition to prevent seasicknes which comprises an active ingredient such as selegiline hydrochloride. The composition may contain an acceptable lubricating agent, S such as stearic acid or a salt thereof, and may contain flavourants which are conventional additives of sweet industry, such as citric acid, tartaric acid and lactic acid. Example 1 describes pastilles weighing 1.3 g and containing mg of selegiline hydrochloride, 7 mg of magnesium stearate and 13 mg tartaric acid.
The invention relates to a new stable solid composition suitable for oral administration comprising a pharmaceutically acceptable acid addition salt of selegiline e.g. selegiline hydrochloride. It was observed during long term stability studies of different formulations of selegiline hydrochloride that tablets containing magnesium stearate are not stable. Under stressed conditions i.e.
heat (60 OC) combined with humidity (relative humidity of 75 the instability increases i.e. the content of selegiline hydrochloride decreases.
i i ii -2- The present invention overcomes the destabilizing effect of stearic acid salts by decreasing the amount of magnesium stearate below a certain level, e.g. by replacing all or a substantial part of the magnesium stearate with another lubricant such as a fatty acid ester, polyethylene glycol, colloidal silicon dioxide or vegetable oil.
The destabilizing effect of stearic acid salts may also be overcome by adding a pharmaceutically acceptable acid to the composition. Such a composition may contain a stearic acid salt or may be void of such salts.
The invention provides a solid composition suitable for oral 1 0 administration tablets, granules or capsules containing granules or powders) of a pharmaceutically acceptable acid addition salt of selegiline which is substantially free of stearic acid salts. By the expression substantially free of steric acid salts it is meant that the total amount of the stearic acid salt present in the composition (calculated as magnesium stearate or equivalent 15 amount of the other stearic acid salt) is not more than 1 part by weight per parts of selegiline hydrochloride (or equivalent amount of the other acid addition salt of selegiline), especially preferably per 25 parts of selegiline hydrochloride.
In one embodiment according to the invention t:e stearic acid salt is replaced with another lubricant. Examples of suitable groups of lubricants are esters of fatty acids and vegetable oils. It is a prerequisite for an effective lubricant that it does not melt during the manufacture of the composition.
Accordingly, the fatty acid is preferably a saturated carboxylic acid of from 6 to 24 carbon atoms, most preferably 12 to 20 carbon atoms. The ester may be a 25 mono-, di- or tri-ester of 1 to 10 carbon atoms, preferably of 2 to 4 carbon atoms. Preferred fatty acid esters which may be used as lubricants include triglycerids of saturated fatty acids or their mixtures e.g. glyceryl tristearates, glyceryl tripalmitates, glyceryl trimyristates, glyceryl tribehenates (sold under the trade name Compritol) and glyceryl palmito-stearic acid ester. Instead of fatty acid esters it is also possible to use high melting fatty acids, for example stearic acid. Long chained polyethylene glycols are most preferred (e.g those ones sold under trade name Macrogol 6000 or 20000). Suitable vegetable oils include solid oils such as cotton seed oil (sold under the trade names Sterotex or Lubritab) and castor seed oil (sold under trade name Cutina HR).
In another embodiment according to the invention the instability of the I oral compositions containing stearic acid salts is avoided by adding one or i 4
I
-3more acids to such compositions. It is preferable to use pharmaceutically acceptable acids which are easily formulated into a solid oral composition, however, liquid acids may also be used. The acid may be organic or inorganic, although organic acids are preferred. Acids having pKa value below 5.88, preferably below 5 and most preferably below 3 are suitable.
Accordinly, preferred acids are di- or tri-basic organic acids, having up to carbon atoms, preferably up to 6 carbon atoms, for example tartaric acid, maleic acid, malic acid, fumaric acid and citric acid.
In a further embodiment according to the invention the two earlier 1 0 embodiments are combined i.e. stearic acid salts are replaced with a fatty acid or vegetable oil and a pharmaceutically acceptable acid is added to the oral composition.
*c C :1 44fl .4.4 4* C *a 4 4444 4..42 e g..
In addition to the active ingredients (a pharmaceutically acceptable acid addition salt of selegiline and possible other active ingredients) and the lubricant, the composition according to the invention may comprise other common additives such as a binder and a pharmaceutically acceptable diluent. There may also be other common excipients present, for example disintegrants, glidants, colours, flavours and sweeteners. Selegiline hydrochloride is preferably present in ,n amount of 2.5 mg to 100 mg per unit dosage. The amount of the other components may vary depending on their type and relative proportions. Accordingly, for compositions wherein selegiline hydrochloride is the only active ingredient, the amount of the lubricant may be about from 0.1 to 60 weight percent, the amount of the binder may vary about from 0 to 20 weight percent and the amount of the diluent is usually about from 1 to 95 weight percent. If a pharmaceutically acceptable acid and stearic acid salt are both present, the pharmaceutically acceptable acid is present in an amount which is at least equivalent to the amount of the stearic acid salt present, and preferably in excess.
The composition according to the invention may be prepared by conventional methods, e.g. the tablets may. be manufactured using the direct compression method in which the ingredients are sieved and mixed in a suitable blender until homogenous and tabletted. It is also possible to capsulate the powder blend in gelatine capsules. The granulation method can also be used. The powders are sieved, mixed in a suitable mixer/granulator, moistened with a liquid until granules are formed. The granules are dried, suitable ingredients are added and the granules are tabletted or capsulated.
The following examples illurate how the compositions according to the -7
V,.
L1- I--L -r..iiwr -4invention may be prepared. However, it should be understood that a person having average skill in the art will be capable of modifying the compositions in several different ways.
Compatibility tests The chemical compatibility of selegiline hydrochloride with different lubricants and fumaric acid was tested by mixing the raw materials pressing tablets weighing about 500 mg, stressing one part of the tablets (one week at 60 °C and 75 relative humidity) and analysing the selegiline hydrochloride content of stressed and unstressed tablets. The results are given in the Table 1.
Table 1 Compatibility of different excipients with selegiline hydrochloride Excipient Content of selegiline hydrochloride unstressed stressed Magnesium stearate 95 88 Compritol 98 96 ,":Lubritab 98 97 Fumaric acid 100 98 I t44X Preparation of the compositions i Tables 2, 3 and 4 show different compositions of selegiline 1 5 hydrochloride according to the invention: In table 2 magnesium strearate is replaced with glyceryl tribehenate (Compritol) and in table 3 with cotton seed oil (Sterotex). In table 4 a pharmaceutically acceptable acid (citric acid) is added keeping the amount of magnesium stearate at the same level as that of the conventional oral compositions.
The compositions were prepared as follows: Selegiline hydrochloride, lactose (or mannitol and maize starch, respectively) and polyvidone were sieved and mixed in a granulator. The powder blend was moistened and granulated with ethanol. The granules were dried and sieved. Microcrystalline cellulose, citric acid (when used) and the lubricant (Compritol, Sterotex and *I F C- ~1.
71 magnesium stearate, respectively) were sieved and mixed with the granules.
The powder was tabletted using 6 mm (diameter) punches.
Table 2 A composition containing Compritol.
Ingredient weight, mg j1!1 a Selegiline hydrochloride Lactose Polyvidon (Kollidon 30) Ethanol Microcrystalline cellulose 57.0 q.s.
29.0 Compritol t *r t 54 S Cf
IC
IA
C
I.
Sto 44- When tablets containing 5 mg Compritol were stressed under the above given conditions the content of selegiline hydrochloride decreased only less than three percent (which is within the limits of the reproducibility of the analysis method) whereas it decreased more than 17 percent when similar conventional tablets containing 2 mg of magnesium stearate were stressed.
Table 3. A composition containing Sterotex.
4 4 St.
Ingredient Selegiline hydrochloride Mannitol Maize starch Polyvidone Ethanol Microcrystalline cellulose Sterotex 40.0 40.0 q.s.
28.0 weight, mg When tablets containing 5 mg Sterotex were stresses under the above given conditions the content of selegiline hydrochloride decreased only less than three percent (within reproducibility limits) whereas it decreased more
I
r i" j: .i -6than 14 percent when similar conventional tablets containing 2 mg of magnesium stearate were stressed.
Table 4. A composition containing citric acid.
Ingredient Selegiline hydrochloride Lactose Polyvidon (Kollidon 30) Ethanol Microcrystalline cellulose Magnesium stearate Citric acid monohydrate weight, mg 5.0 57.0 7.0 q.s.
29.0
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*4 a a, a a a~ a 1* j
Claims (8)
1. A solid composition suitable for oral administration comprising a pharmaceutically acceptable acid addition salt of selegiline and a lubricant, wherein the lubricant comprises a stearic acid salt, the total amount of stearic acid salt present being more than 1 part by weight per 10 parts of the selegiline hydrochloride or equivalent amount of other acid addition salt of selegiline, and the composition further comprises a pharmaceutically acceptable acid having a pKa value below 5.88 with the proviso that the lubricant is not magnesium stearate when the acid is tartaric acid. V
2. A composition according to claim 1 wherein the pharmaceutically \acceptable acid has a pKa value below 3.
3. A composition according to claim 1 wherein the acid is a di- or tri-basic organic acid of up to 10 carbon atoms.
4. A composition according to claim 1 wherein the acid is citric acid.
5. A composition according to any one of claims 1 to 3 wherein the «I pharmaceutically acceptable acid addition salt of selegiline is selegiline hydrochloride.
6. A composition according to any one of claims 1 to 5 wherein the solid S 20 composition is a tablet.
7. A composition according to any one of claims 1 to 6 wherein selegiline is the only active ingredient.
8. A composition according to claim 1 substantially as hereinbefore described with reference to the composition of table 4. DATED: 25 August, 1998 PHILLIPS ORMONDE FITZPATRICK Attorneys for: ORION-YHTYMA OY :\WINWORDWICHELLESPECIESW0236-95,DOC -t I_, ii d% ABSTRACT A solid composition suitable for oral administration, including a pharmaceutically acceptable acid addition salt of selegiline, a lubricant, and a pharmaceutically acceptable acid, with the proviso that the lubricant is not magnesium stearate when the acid is tartaric acid. V Vi C 'C' II i\ Nc :\W[NWORDWENDY\TPINDIV643DOC
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9301112 | 1993-04-02 | ||
SE19939301112A SE9301112D0 (en) | 1993-04-02 | 1993-04-02 | A NEW COMPOSITION |
AU64300/94A AU663995C (en) | 1993-04-02 | 1994-03-31 | A new composition containing selegiline |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU64300/94A Division AU663995C (en) | 1993-04-02 | 1994-03-31 | A new composition containing selegiline |
Publications (2)
Publication Number | Publication Date |
---|---|
AU4023695A AU4023695A (en) | 1996-02-15 |
AU697284B2 true AU697284B2 (en) | 1998-10-01 |
Family
ID=25634290
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU40236/95A Ceased AU697284B2 (en) | 1993-04-02 | 1995-12-06 | A new composition containing selegiline |
AU78418/98A Abandoned AU7841898A (en) | 1993-04-02 | 1998-07-27 | A new composition containing selegiline |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU78418/98A Abandoned AU7841898A (en) | 1993-04-02 | 1998-07-27 | A new composition containing selegiline |
Country Status (1)
Country | Link |
---|---|
AU (2) | AU697284B2 (en) |
-
1995
- 1995-12-06 AU AU40236/95A patent/AU697284B2/en not_active Ceased
-
1998
- 1998-07-27 AU AU78418/98A patent/AU7841898A/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
AU7841898A (en) | 1998-10-01 |
AU4023695A (en) | 1996-02-15 |
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Legal Events
Date | Code | Title | Description |
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MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |