IE930446A1 - Pharmaceutical soft capsules containing lysine clonixinate¹and a process for their preparation - Google Patents
Pharmaceutical soft capsules containing lysine clonixinate¹and a process for their preparationInfo
- Publication number
- IE930446A1 IE930446A1 IE044693A IE930446A IE930446A1 IE 930446 A1 IE930446 A1 IE 930446A1 IE 044693 A IE044693 A IE 044693A IE 930446 A IE930446 A IE 930446A IE 930446 A1 IE930446 A1 IE 930446A1
- Authority
- IE
- Ireland
- Prior art keywords
- filling
- weight
- lysine clonixinate
- polyethylene glycol
- capsules
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
Soft gelatin capsules filled with lysine clonixinate as active substance in a hydrophilic matrix. The capsules according to the invention are distinguished by excellent storage stability, ease of manufacture and rapid activity on oral administration. The hydrophilic matrix comprises polyethylene glycol with an average molecular weight of approximately 200 to 1000 or a mixture thereof with propylene glycol and/or propylene carbonate, 3 to 10% by weight of glycerol and 5 to 15% by weight of water. The soft gelatin capsules can be employed for states of pain and inflammations.
Description
SECTION
UNDER
SECTION 28 AND RULE 23 JNL. No......<7X4.. .OF 5.1'P3
Pharmaceutical soft ft
-1/ 1 iirr cr 57/3^
3///15, j?,· /^ j capsules containing lysine clonixinate and a process for their preparation
The present invention relates to a pharmaceutical composition for oral administration containing as active ingredient the analgesic and anti-inflammatory agent lysine clonixinate. The invention also concerns a process for the preparation of soft capsules that comprise lysine clonixinate. Moreover the invention relates to the use (method of treatment) of lysine clonixinate in capsules for the treatment of pain and inflammatous conditions.
The L-lysine salt of 2-((3-chloro-2-methylphenyl)amino]-3-pyridine carboxylic acid, or lysine clonixinate, is described in patent specifications DE 2.253.134 and US 3.973.027. In both of these specifications there is reference to formulations for oral, parenteral and rectal administration.
Oral administration constitutes a preferred route for administering lysine clonixinate, but tablets are the only type of formulation known in the art and existing in the market. However, it has been observed that the administration of lysine clonixinate in the forms of solid tablets -or of powder filled, hard shell capsules- present the problem of inducing some local erosion in the digestive tract. On the other hand, the time of onset of the therapeutic action following oral administration of the drug is an important consideration: It is highly desirable from the patient's point of view that the drug begin to relieve 30 pain or inflammation as quickly as possible. Therefore, the development of an oral pharmaceutical formulation of lysine clonixinate that provides more rapid therapeutic onset and less discomfort would be interesting.
Soft elastic gelatin capsules are widely used as an
-2alternative to powder-filled hard-shell capsules or tablets for the oral administration of pharmaceuticals, vitamins, dietary supplements and the like. These soft capsules are often preferred by patients since they are easier to swallow than conventional hard capsules or tablets.
With a highly water soluble compound, as lysine clonixinate is, a soft gelatin capsule formulation faces the problem of embrittelement of the shell, with the corresponding leaking of the fill material. The prevention of the oxidation of the lysine clonixinate in a filling in the form of solution or dispersion constitutes an extra problem in this case.
It is an object of the present invention to provide soft gelatin capsules containing an effective unit dosage amount of lysine clonixinate, said capsules being stable during a long time, easy to manufacture with the standard machinery, and providing rapid onset of the therapeutic activity upon oral administration of the capsule, with less harmful side-effects than the lysine clonixinate tablets currently in the market.
An embodiment of the present invention is a pharmaceutical dosage unit form of the type soft gelatin capsule with a filling comprising lysine clonixinate as active ingredient, 25 said filling being based on a hydrophilic matrix comprising polyethylene glycol having an average molecular weight of from about 200 to 1000, or a mixture of the polyethylene glycol with propylene glycol and/or propylene carbonate, glycerol in 3 to 10% by weight, and water in 5 to 15% by weight (all concentration values relate to the filling).
The recommended contents of lysine clonixinate per dosage unit is from 20 to 300 mg, preferably 125 mg. The preferred polyethylene glycol has an average molecular weight of about 400.
-3Instead of polyethylene glycol, propylene glycol or propylene carbonate may be utilized.
The capsule filling may if desired contain additional ingredients such as preservatives, flavouring and/or sweetening agents. Lysine clonixinate is kept virtually dissolved in the filling and it is quickly released to the digestive tract when the capsule shell dissolves.
A further embodiment of the invention is a filling comprising lysine clonixinate as active ingredient in a hydrophilic matrix of the type described above.
According to the invention a pharmaceutical dosage unit is provided with lysine clonixinate as active ingredient, comprising a soft gelatine capsule as described above, with a content of lysine clonixinate of 20 mg to 300 mg, preferably 125 mg.
Another embodiment according to the invention is a process for the preparation of soft gelatine capsules with a filling comprising lysine clonixinate as active ingredient comprising the simultaneous or successive steps:
(a) forming the gelatine capsules, and (b) filling the capsules with lysine clonixinate as active ingredient, a hydrophilic matrix comprising polyethylene glycol having an average molecular weight of from about 200 to 1000 or a mixture of said polyethylene glycol with propylene glycol and/or propylene carbonate, glycerol in 3 to 10% by weight, and water in 5 to 15% by weight (all concentration values relate to the filling).
A further embodiment according to the invention is the use (method of treatment) of the above mentioned capsules as analgetics or anti-inflammatory agents.
-4The filling of the present invention may be used with a conventional soft gelatin capsule shell. In one conventional shell formulation, there is included about
-35 parts by weight of gelatin, about 15-48 parts by weight of a plasticiser, such as glycerol or sorbitol, and about 16-40 parts by weight of water. Additionally, the gelatin shell may contain preservatives, such as mixed parabens in minor proportions. In a conventional manner, the gelatin composition is mixed and melted under vacuum conditions. The capsules may be simultaneously formed and filled using conventional methods and apparatus. The gelatin capsules are formed into the desired shape and size so that they can be readily swallowed, usually with the aid of water. The resulting capsule is soluble in water and in gastrointestinal juices.
The interval of average molecular weight (from about 200 to 1000) for the polyethylene glycol used in the filling of the present invention is crucial, because
2Q polyethylene glycols of much lower molecular weight tend to diffuse through the shells of conventional soft gelatin capsules. In turn, the use of polyethylene glycols with higher molecular weight tends to result in a too viscous, unpumpable vehicle, difficult to manufacture by ordinary machinery.
The contents of glycerol (3-10%) and water (5-15%) in the filling corresponding to the dosage units of the
-5present invention are crucial to reduce any undesirable interaction between the polyethylene glycol and the soft gelatin shell. Glycerol and water act as humectants by setting up a sort of equilibrium between 5 the moisture content of the filling and the soft gelatin capsule shell. Similarly, glycerol acts as equilibrium plasticiser so that the polyethylene glycol does not remove excessive amounts of plasticisers from the soft gelatin capsule shell. Thus, water and
1Q glycerol prevent the polyethylene glycol from rendering the soft gelatin capsule hard, brittle, and subject to damage and leaking during handling. Preferred filling compositions according to the present invention are those of Example 1.
The fact that lysine clonixinate is kept in solution in the filling of the capsules, and therefore it is quickly released to the digestive tract when the shell dissolves, gives the capsules of the present invention a higher bioavailability than that of the corresponding tablets known in the art. This feature, which is illustrated by the pharmacokinetic results of Example 2, represents a more rapid therapeutic onset for the patient, and therefore an advantage over the current tablets in the market.
The administration of the dosage unit forms of the present invention has another advantage: When the shell dissolves, lysine clonixinate diffuses very quickly in its environment. Thus, local erosion -and its associated damage or discomfort- is smaller than with the current tablets.
Capsules of the present invention have been easily prepared with standard machinery and have proved stable
-6for more than a year under high humidity conditions, as illustrated in the accompanying Example 3.
EXAMPLE 1
Preparation of soft gelatin capsules of lysine clonixinate
Two fill materials having the compositions per capsule shown in Table 1 were prepared. The fill materials were thoroughly mixed under nitrogen atmosphere, and they were encapsulated in conventional soft gelatin shells. The fill materials proved to be nondilatant and compatible with conventional soft gelatin capsule manufacturing processes, such as those disclosed, for example, in US 2.288.327 and US 2.318.718. Besides, the gelled fill materials were temperature stable and did not remove excessive amounts of water or plasticisers from the soft elastic gelatin shell.
TABLE 1
Typical capsule filling compositions (in mg/capsule)
Ingredients Filling A Filling B lysine clonixinate 125 125 polyethylene glycol 400 344 293 anhydrous glycerol 35 31 water 56 50
-7EXAMPLE 2
Pharmacokinetics comparative test between soft gelatin capsules and tablets of lysine clonixinate
A conventional pharmacokinetics comparative study was 5 carried out with 28 healthy fasting human volunteers.
Fourteen of them received a single 125 mg dose of commercially available lysine clonixinate tablets, whereas the other 14 received the same dose in the form of soft gelatin capsules with the filling composition A
1q of Table 1. The obtained pharmacokinetic results are those shown in Table 2.
TABLE 2 Pharmacokinetic parameters of two pharmaceutical forms Parameter Gelatine Capsules Tablets (h) 0.17 0.29 tmax <h> 0.5 1.0 AUC (pg/h/ml) 10.36 10.09cmax 4.8 5.6
Notes: t^ = half life; tmax = time at which Cmax is 20 attained; AUC = Area Under Curve; Cmax = maximum
Concentration.
-8EXAMPLE 3
Stability test of soft gelatin capsules of lysine clonixinate
The stability of the two typical soft gelatin capsules 5 prepared according to Example 1 were studied over a period of 36 months, in conditions of 20-258C and 5070% relative humidity. It was observed that the capsules were stable, without signs of embrittelement, and that the active ingredient was not altered, e.g. by oxidation.
Claims (10)
1. A pharmaceutical dosage unit form of the type soft gelatin capsule with a filling comprising lysine clonixinate as active ingredient, said filling being based on a hydrophilic matrix 5 comprising polyethylene glycol having an average molecular weight of from about 200 to 1000, or a mixture of the polyethylene glycol with propylene glycol and/or propylen carbonate, glycerol in 3 to 10% by weight, and water in 5 to 15% by weight. 10
2. The soft gelatine capsule of claim 1 wherein the polyethylene glycol has an average molecular weight of about 400.
3. The soft gelatine capsule of claim 1 comprising a contents of lysine clonixinate from 20 to 300 mg. 15
4. The soft gelatine capsule of claim 3 comprising a contents of lysine clonixinate of 125 mg.
5. A process for the preparation of a soft gelatin capsule with a filling comprising lysine clonixinate, comprising the simultaneous or successive steps of (a) forming the gelatine 20 capsules, and (b) filling the capsules with lysine clonixinate as active ingredient, a hydrophylic matrix comprising polyethylene glycol having an average molecular weight of from about 2 00 to 1000, or a mixture of said polyethylene glycol with propylene glycol and/or propylene carbonate, glycerol in 3 25 to 10% by weight, and water in 5 to 15% by weight.
6. Use of a soft gelatine capsule as claimed in claim 1 as analgetic and/or anti-inflammatory agent. -10IE 930446
7. A pharmaceutical dosage unit form according to claim 1, substantially as hereinbefore described and exemplified.
8. A process for the preparation of a soft gelatin capsule according to claim 1, substantially as hereinbefore described and 5 exemplified.
9. A soft gelatin capsule according to claim 1, whenever prepared by a process claimed in claim 5 or 8.
10. Use according to claim 6, substantially as hereinbefore described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4219702A DE4219702A1 (en) | 1992-06-16 | 1992-06-16 | Pharmaceutical soft capsules containing lysine clonixinate and a process for the production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE930446A1 true IE930446A1 (en) | 1993-12-29 |
Family
ID=6461132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE044693A IE930446A1 (en) | 1992-06-16 | 1993-06-15 | Pharmaceutical soft capsules containing lysine clonixinate¹and a process for their preparation |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0574822A1 (en) |
| JP (1) | JPH0665078A (en) |
| KR (1) | KR940000108A (en) |
| CN (1) | CN1037934C (en) |
| AU (1) | AU656078B2 (en) |
| CA (1) | CA2098410A1 (en) |
| DE (1) | DE4219702A1 (en) |
| FI (1) | FI932768A (en) |
| IE (1) | IE930446A1 (en) |
| IL (1) | IL105870A (en) |
| MX (1) | MX9303582A (en) |
| NO (1) | NO932097L (en) |
| ZA (1) | ZA934222B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19849848A1 (en) * | 1998-10-29 | 2000-05-04 | Lohmann Therapie Syst Lts | Oral application, spontaneous disintegration with liquid and dosage form and process for its preparation |
| KR20030042935A (en) * | 2001-11-26 | 2003-06-02 | 알앤피코리아 주식회사 | Clonixin lysinate formulation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3337570A (en) * | 1965-10-23 | 1967-08-22 | Schering Corp | Substituted nicotinic acids and method for the manufacture thereof |
| US4144332A (en) * | 1976-01-05 | 1979-03-13 | The Regents Of The University Of Michigan | Process for alleviating proliferative skin diseases |
| DE4037554A1 (en) * | 1990-11-26 | 1992-05-27 | Roemmers Sa | MEDICAMENT FOR TOPICAL APPLICATION |
-
1992
- 1992-06-16 DE DE4219702A patent/DE4219702A1/en not_active Withdrawn
-
1993
- 1993-06-01 IL IL10587093A patent/IL105870A/en not_active IP Right Cessation
- 1993-06-03 AU AU40009/93A patent/AU656078B2/en not_active Ceased
- 1993-06-09 EP EP93109279A patent/EP0574822A1/en not_active Ceased
- 1993-06-09 NO NO932097A patent/NO932097L/en unknown
- 1993-06-10 KR KR1019930010541A patent/KR940000108A/en not_active Application Discontinuation
- 1993-06-11 JP JP5166129A patent/JPH0665078A/en active Pending
- 1993-06-15 MX MX9303582A patent/MX9303582A/en not_active Application Discontinuation
- 1993-06-15 ZA ZA934222A patent/ZA934222B/en unknown
- 1993-06-15 CA CA002098410A patent/CA2098410A1/en not_active Abandoned
- 1993-06-15 IE IE044693A patent/IE930446A1/en not_active IP Right Cessation
- 1993-06-16 CN CN93107267A patent/CN1037934C/en not_active Expired - Fee Related
- 1993-06-16 FI FI932768A patent/FI932768A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO932097L (en) | 1993-12-17 |
| FI932768A (en) | 1993-12-17 |
| EP0574822A1 (en) | 1993-12-22 |
| FI932768A0 (en) | 1993-06-16 |
| IL105870A (en) | 1996-12-05 |
| CN1037934C (en) | 1998-04-08 |
| IL105870A0 (en) | 1993-10-20 |
| ZA934222B (en) | 1994-01-17 |
| CN1083702A (en) | 1994-03-16 |
| MX9303582A (en) | 1994-04-29 |
| AU656078B2 (en) | 1995-01-19 |
| KR940000108A (en) | 1994-01-03 |
| AU4000993A (en) | 1993-12-23 |
| DE4219702A1 (en) | 1993-12-23 |
| JPH0665078A (en) | 1994-03-08 |
| CA2098410A1 (en) | 1993-12-17 |
| NO932097D0 (en) | 1993-06-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM9A | Patent lapsed through non-payment of renewal fee |