IE990301A1 - Tilidene salts - Google Patents
Tilidene saltsInfo
- Publication number
- IE990301A1 IE990301A1 IE19990301A IE990301A IE990301A1 IE 990301 A1 IE990301 A1 IE 990301A1 IE 19990301 A IE19990301 A IE 19990301A IE 990301 A IE990301 A IE 990301A IE 990301 A1 IE990301 A1 IE 990301A1
- Authority
- IE
- Ireland
- Prior art keywords
- tilidine
- salicylate
- acetylsalicylate
- pharmaceutical composition
- preparation
- Prior art date
Links
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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
- A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
-
- 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
- A61K31/60—Salicylic acid; Derivatives thereof
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to novel salt adducts of tilidine [(+-)-ethyl-trans-2-dimethylamino)-1-phenyl-3-cyclohexene-1-carboxylate], processes for their preparation and their use in pharmaceutical products. The novel salts claimed are tilidine acetylsalicylate and tilidine salicylate, formed by reacting tilidine hydrochloride hemihydrate with acetylsalicylic or salicylic acid, respectively.
Description
THUS COPI AS
LQDQED
Introduction
The invention relates to novel salts of Tilidine, processes for their preparation and their use in pharmaceutical products.
(±)-Ethyl-taz«s-2-(dimethylamino)-1 -phenyl-3-cyclohexene-1 -carboxylate (Tilidine) is a pharmaceutically active substance with strong analgesic properties.
Trans-Tilidine Base (I) is known to be a compound with a very low melting point (Pharm. Ind. 40(6), 657-664 [1978]; Cienc. Ind. Farm. 8(1). 4-11 [1976]). This creates problems for the manufacture of final pharmaceutical products.
Therefore, Tilidine is generally used in pharmaceuticals in the form of Hydrochloride Hemihydrate, a more stable compound than Tilidine base itself. As the Hydrochloride Hemihydrate is very soluble in water it is suitable for the preparation of solutions which can be administered for fast pain relief. Certain types of soft capsules can also be manufactured using Tilidine Hydrochloride
Hemihydrate as an active ingredient. However, the Hydrochloride Hemihydrate is not suitable for “solid formulations” required for the production of tablets. Furthermore it seems to be unsuitable for the manufacture of Tilidine containing products with a retard profile.
OPEN TO PUBLIC INSPECTION UNDER
SECTION 28 AND RULE 23
JNLNOJ^^.OF
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-2Salts other than Tilidine Hydrochloride Hemihydrate are described in WO-A94/10129. The compound disclosed is Tilidine Dihydrogen Orthophosphate, which is said to be stable and therefore suitable for the preparation of solid pharmaceutical formulations such as tablets or dragees. However, the process for the preparation of Tilidine Dihydrogen Orthophosphate appears to be critical and complicated.
There is therefore a need for a new chemical entity based on Tilidine which is stable, easily producible in high quality and good yields and which can be formulated to provide a range of different delivery routes.
This invention is directed towards providing such a new entity.
Statements of Invention
According to the invention there is provided an acid base salt adduct of Tilidine formed by reacting Tilidine with acetylsalicylic acid or salicylic acid as their corresponding salts.
Preferably the Tilidine is introduced in the form of Tilidine Hydrochloride /
Hemihydrate.
One aspect of the invention provides Tilidine Acetylsalicylate.
Yet another aspect of the invention provides Tilidine Salicylate.
In one embodiment the invention provides a process for the preparation of Tilidine Acetylsalicylate comprising:reacting Tilidine Hydrochloride Hemihydrate with an Acetylsalicylic Acid salt and isolating the desired salt.
-3In another embodiment the invention provides a process for the preparation of Tilidine Salicylate comprising:reacting Tilidine Hydrochloride Hemihydrate with a Salicylic Acid salt and isolating the desired salt.
The reaction is preferably carried out in the presence of a base such as an amine base for example ammonia, triethylamine, Hunigs base or hydroxides such as alkali hydroxides.
Most preferably the reaction is carried out in an appropriate solvent, typically MIBK, MEK, acetone, THF, or «-butanol. However other solvents may be used.
Preferably the reaction temperature is from 0 to 80°C, most preferably from 0 to 30°C.
The invention further provides a pharmaceutical composition containing Tilidine Acetylsalicylate as an active ingredient.
The invention further provides a pharmaceutical composition containing Tilidine Salicylate as an active ingredient.
The composition may be in a solid form. Typically the composition is in the form of a tablet, dragee, capsule, suppository, granulate or plaster.
The composition may be used as a retard formulation for sustained release or for dual action applications.
The invention will be more clearly understood from the following description thereof given by way of example only.
-4Description of the Invention
It has been found that Tilidine Acetylsalicylate and Tilidine Salicylate can be obtained via a simple process. The salts are very stable, show unusual solubility and pH properties and are suitable for solid formulations. Furthermore Tilidine Acetylsalicylate and Tilidine Salicylate can be used in plasters for percutaneous applications in the form of a transdermal patch and for dual action applications.
According to the literature (WO-A-94/10129) Tilidine salts are difficult to crystallise. Surprisingly therefore we have found that Tilidine Acetylsalicylate and Tilidine Salicylate can be crystallised as l:l-adducts by reacting Tilidine Hydrochloride Hemihydrate and salts of Acetylsalicylic Acid or Salicylic Acid, for example in organic or organic/aqueous or aqueous media. Tilidine Acetylsalicylate and Tilidine Salicylate can be isolated as a white to off-white, odourless powder in high yield. Both salts show a pH value of 5-6 (~1% aqueous solution) which is, compared to the Hydrochloride Hemihydrate and Dihydrogen Orthophosphate, more basic, almost in the neutral range. It was found that the Acetylsalicylate and the Salicylate are very stable over a long period of time. Furthermore the Acetylsalicylate and the Salicylate are non-hygroscopic in contrast to known Tilidine salts such as Tilidine Hydrochloride Hemihydrate and /
Dihydrogen Orthophosphate.
As Tilidine Acetylsalicylate and Tilidine Salicylate are very stable and nonhygroscopic they are very suitable for the manufacture of granulates which are readily convertible into tablets, dragees or pills. A delayed action of the active compound Tilidine may be obtained by incorporation in a suitable retard formulation.
Due to poor water solubility the compounds may be used for the manufacture of plasters/patches for percutaneous applications with a delayed and slow release of the active ingredients.
-5In preparing such compositions any of the various adjuvant' or excipient materials customarily employed in the art may be used. These adjuvants or excipients include, for example, inert substances such as water, gelatine, lactose, vegetable oil as well as many of the other compatible materials conventionally used in the preparation of medicaments.
As Tilidine Acetylsalicylate and Tilidine Salicylate are combinations of two active compounds either may be used for dual action applications.
Tilidine is known to be a highly potent analgesic which is used for the treatment of severe pain. Salicylic acid and Acetylsalicylic acid can be used as a mild analgesic with an additional antipyretic and antiphlogistic profile. Moreover in particular Acetylsalicylic acid is known for its antithrombotic activity. Therefore it can be anticipated that the salts Tilidine Acetylsalicylate and Tilidine Salicylate respectively show an advanced pharmacological profile over Tilidine Hydrochloride Hemihydrate. The salts are therefore useful if a tandem therapy is required in the sense of additional antipyretic, antithrombotic or antiphlogistic effectiveness.
The process for the preparation of Tilidine Acetylsalicylate and Tilidine Salicylate is extremely simple and efficient. The product is isolated in a simple procedure at high yields, greater than 50% and at a very high level of purity, greater than 99%.
-6Reaction Scheme
Tilidine Acetylsalicylate
Tilidine Salicylate
R', R2 and R3 are hydrogen or Ci-C4 alkyl groups. In addition to the ammonium acetylsalicylates and salicylates the corresponding earth alkali salts may also be utilised in the process. Preferred salts, in these cases, are sodium or potassium analogues.
-7Example 1
Preparation of Tilidine Acetylsalicylate
.2g (0.056 mol) of Acetylsalicylic Acid were dissolved in 100-150 ml of a suitable organic solvent such as methanol, ethanol, acetone, THF or mixtures thereof. The solution was treated with one equivalent of base. The base may typically be triethylamine, Hiinigs base or ammonia. The mixture was agitated and 18.lg (0.056 mol) of Tilidine Hydrochloride Hemihydrate were added. Agitation was continued for 0.5-2 hours, preferably at room temperature. The byproduct formed was removed by filtration. The solvent was removed from the mother liquor by distillation, preferably under vacuum conditions providing the crude product in almost quantitative yield. The product may be purified by crystallisation from a suitable solvent such as ether, petroleum ether or mixtures thereof. Typically a yield of >50% of the purified material is obtained.
FT-IR (KBr): v[cml] = 2978, 1727, 1588, 1485, 1458, 1371, 1321, 1237, 1200, 1146, 729, 704.
Stability
Tilidine Acetylsalicylate was found to be stable when stored over a long period of time under standard conditions. No critical change in purity was observed and no significant amounts of degradation product was detected.
Example 2
Preparation of Tilidine Salicylate
Aqueous ammonia was added to 43.4g (0.31 mol) of Salicylic Acid until complete dissolution was obtained. The excess of ammonia can then be removed under vacuum. lOOg (0.31 mol) of Tilidine Hydrochloride Hemihydrate were dissolved in 200-250 ml of water and mixed with the previously prepared ammonium salicylate. The mixture was stirred at room temperature for 0.5-1 hour. The
-8product was extracted from the aqueous phase-with a suitable solvent such as MIBK or CHClj. After removing the organic solvent the product was crystallised from the obtained oil by treatment with MIBK/Petroleum Ether.
A typical yield of 90g corresponding approximately to 70% is obtained with a melting point of 99.7°C.
Ή-NMR (CDCb, 60 MHz): δ = 1.05 (t, 3H,CH2CH3); 2.25-2.60 (m, 10H, N(CH3)2, CH2CH2); 4.05 (q, 2H,CH2CH3); 4.45 (d^.lH, NCH); 5.95-6.15 (m, 2H, CH=CH), 6.75- 7.85, (m, 10H, aryl-H, NH); 12.0 (s, 1H, OH).
FT-IR (KBr): vfcm1] = 2977, 2476, 1728, 1624, 1587, 1485, 1459, 1371, 1322, 1294, 1237, 1147, 854, 770, 729, 704.
Stability
Tilidine Salicylate was found to be stable when stored over a long period of time under standard conditions. No critical change in purity was observed and no significant amounts of degradation product was detected.
Example 3
Retard Formulation of Tilidine Salicylate
1070g Tilidine Salicylate prepared as in ^xample 2 was added to 70.4g Naloxon Hydrochloride Dihydrate, 740g lactose and 700g hydrated castor oil, slowly stirred and heated up to a temperature of 50-85°C. The mixture was filtered through a filter with a pore size of 2.5mm. After cooling to room temperature, the mixture was further filtered through a filter with a pore size of 1 mm. 273.6g of ammonia methyl acrylate co-polymer, 32 g magesium stearate and 24 g silicon dioxide were added to the mixture. The resultant mixture was then compressed into tablet form. Retard formulations of Tilidine Acetylsalicylate may be prepared using an analogous protocol.
The invention is not limited to the embodiments hereinbefore described which may be varied in detail.
Claims (23)
1. An acid base salt adduct of Tilidine formed by reacting Tilidine with acetylsalicylic acid or salicylic acid as their corresponding salts.
2. An acid base salt adduct as claimed in claim 1 wherein the Tilidine is introduced in the form of Tilidine Hydrochloride Hemihydrate.
3. Tilidine Acetylsalicylate.
4. Tilidine Salicylate.
5. A process for the preparation of Tilidine Acetylsalicylate comprising:15 reacting Tilidine Hydrochloride Hemihydrate with an Acetylsalicylic Acid salt and isolating the desired salt.
6. A process for the preparation of Tilidine Salicylate comprising:20 reacting Tilidine Hydrochloride Hemihydrate with a Salicylic Acid salt and isolating the desired salt.
7. A process as claimed in claim 5 or 6 wherein the reaction is carried out in the presence of a base such as ammonia, Hunigs base or triethylamine.
8. A process as claimed in any of claims 5 to 7 wherein the reaction is carried out in an appropriate solvent.
9. A process as claimed in any of claims 5 to 8 wherein the process carried out at a temperature of from 0 to 80°C. - ιο
10. A process as claimed in claim 9 wherein the process is carried out at a ' temperature of from 0 to 30°C.
11. A process as claimed in any of claims 8 to 10 wherein the solvent is MIBK.
12. A process for the preparation of Tilidine Acetylsalicylate substantially as herein before described with reference to the example.
13. A process for the preparation of Tilidine Salicylate substantially as hereinbefore described with reference to the example.
14. Tilidine Acetylsalicylate whenever prepared by a process as claimed in any of claims 5 or 7 to 12.
15. Tilidine Salicylate whenever prepared by a process as claimed in any of claims 6 to 12 or 13.
16. A pharmaceutical composition containing Tilidine Acetylsalicylate as an active ingredient. /
17. A pharmaceutical composition containing Tilidine Salicylate as an active ingredient.
18. A pharmaceutical composition as claimed in claim 16 or 17 in a liquid form.
19. A pharmaceutical composition as claimed in claim 16 or 17 in a solid form.
20. A pharmaceutical composition as claimed in any of claims 16 to 19 which is formulated to provide a retard formulation. - ll
21. A pharmaceutical composition as claimed in any of claims 16 to 20 which is in a form for percutaneous application.
22. A pharmaceutical composition as claimed in any of claims 16 to 21 which 5 is in the form of a transdermal patch.
23. A pharmaceutical composition substantially as hereinbefore described with reference to the examples.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE1999/0301A IE83591B1 (en) | 1999-04-09 | Tilidene salts |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IEIRELAND14/07/19981998/0564 | |||
IE980564 | 1998-07-14 | ||
IE1999/0301A IE83591B1 (en) | 1999-04-09 | Tilidene salts |
Publications (3)
Publication Number | Publication Date |
---|---|
IE19990301A1 IE19990301A1 (en) | 2000-03-08 |
IE990301A1 true IE990301A1 (en) | 2000-03-08 |
IE83591B1 IE83591B1 (en) | 2004-09-22 |
Family
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Also Published As
Publication number | Publication date |
---|---|
GB9908107D0 (en) | 1999-06-02 |
GB2339570A (en) | 2000-02-02 |
GB2339570B (en) | 2003-04-16 |
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