GB2280604A - Tablet formulation of betahistine and selegiline - Google Patents
Tablet formulation of betahistine and selegiline Download PDFInfo
- Publication number
- GB2280604A GB2280604A GB9313739A GB9313739A GB2280604A GB 2280604 A GB2280604 A GB 2280604A GB 9313739 A GB9313739 A GB 9313739A GB 9313739 A GB9313739 A GB 9313739A GB 2280604 A GB2280604 A GB 2280604A
- Authority
- GB
- United Kingdom
- Prior art keywords
- betahistine
- selegiline
- formulation
- active agent
- granulate
- 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.)
- Granted
Links
- UUQMNUMQCIQDMZ-UHFFFAOYSA-N betahistine Chemical compound CNCCC1=CC=CC=N1 UUQMNUMQCIQDMZ-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 229960004536 betahistine Drugs 0.000 title claims abstract description 11
- 229960003946 selegiline Drugs 0.000 title claims abstract description 7
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 title claims abstract description 7
- 239000007916 tablet composition Substances 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 238000009472 formulation Methods 0.000 claims abstract description 14
- 239000013543 active substance Substances 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 239000008187 granular material Substances 0.000 claims description 11
- 239000012736 aqueous medium Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 230000006835 compression Effects 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 3
- 238000005520 cutting process Methods 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000000648 anti-parkinson Effects 0.000 description 2
- 239000000939 antiparkinson agent Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229910021485 fumed silica Inorganic materials 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- IYETZZCWLLUHIJ-UHFFFAOYSA-N methyl-(1-phenylpropan-2-yl)-prop-2-ynylazanium;chloride Chemical compound Cl.C#CCN(C)C(C)CC1=CC=CC=C1 IYETZZCWLLUHIJ-UHFFFAOYSA-N 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229960003678 selegiline hydrochloride Drugs 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002279 physical standard Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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
-
- 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
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A process and formulation is provided for the manufacture of tablets comprising the active agents selegiline and betahistine wherein dissolution of these active agents in water prior to processing yields tabletted formulations having improved properties.
Description
PROCESSING OF ACTIVE AGENTS
The present invention relates to the processing of active agents prior to formulation in pharmaceutical compositions.
Compressed tablets are defined as solid-unit dosage forms made by compaction of a formulation containing the drug and certain fillers or excipients selected to aid in the processing and proper-ties of the drug product. They are the most widely used of all pharmaceutical dosage forms administered today.
Whatever method of manufacture is used, the resulting tablets must meet physical standards of shock and abrasion resistance, uniformity in weight and drug content, and acceptability of appearance, in addition to biological standards such as bioavailability of the drug content of the tablet, drug stability and drug efficacy.
All formulations are highly dependent on the properties of the raw materials concerned, including the drug substance itself. Many physicochemical factors, such as fluidity, compressibility, hygroscopicity and solubility influence the process of manufacture and must be taken into account when selecting processing conditions.
For example, if a drug substance is judged to be physically or chemically unstable when exposed to moisture, a directcompression or nonaqueous solvent granulation procedure is usually recommended for the preparation of tablets.
Moisture has been recognised by formulators as the primary cause of instability in tablets, affecting not only drug stability but flow and compression characteristics of powders and the hardness of final tablets and granulations.
Since many drug substances have a tendency to absorb moisture, recent developments have been towards dry formulation processes, e.g. using selected excipients which absorb the maximum amount of free moisture, such as sorbitol and sucrose, or "melt" processes which rely on the use of solids having a low softening or melting point such as polyethylene glycols and waxes which, when mixed with a powder formulation and heated, liquefy to act as binders.
Upon cooling, the mixture forms a solid mass in which the powders are bound together by the binder returning to the solid state.
It is an object of the present invention to provide pharmaceutical formulations having improved properties for tabletting.
It has been found that dissolving the pharmaceutical active principles betahistine and selegiline in aqueous solution prior to processing yields tabletted formulations with surprisingly improved dispersion properties, content uniformity and stability. This procedure has not previously been applied to these substances, which are used as a vasodilator and anti-Parkinsonian respectively.
Betahistine in particular is known to be highly hygroscopic and so has conventionally been stored and processed in a dry environment.
In a first aspect, the present invention provides a process for the production of a tabletted formulation comprising an active agent in which the active agent is dissolved in an aqueous medium prior to processing, and in which the active agent is betahistine, selegiline or an analogue or derivative of either of the above.
In a preferred process, the selegiline or betahistine, typically in the form of a salt such as the dihydrochloride, is dissolved completely in the appropriate quantity of water.
The solution may then be granulated. This term refers to any process of size enlargement, or agglomeration, whereby small particles are gathered together into larger, permanent aggregates to render them into a free-flowing state.
Typically, the solution is agitated to form a granular mass, which is then dried and compressed on a suitable tabletting press.
At any of the above formulation stages, suitable excipients may be added to the mixture.
Excipients are inert substances used as diluents or vehicles for a drug. The term includes various groups comprising diluents or fillers, binders or adhesives, disintegrants, lubricants, glidants or flow promoters, colours, flavours, fragrances and sweeteners.
In a further aspect, the present invention provides a tabletted formulation produced by a process as above described.
The invention will now be further illustrated by the following Examples:
Example 1 1. Selegiline Hydrochloride is dissolved in 500ml of the
water in order to yield a clear solution.
2. This solution is then added to mannitol and cellulose
in a planetary mixer and the mass is mixed for 5
minutes.
3. An additional 200ml of water is then added and mixing
continued for a further 5 mins. in order to form a
granular mass.
4. The granulate is fluid bed dried at 60"C for 30 mins.;
granulated through a 20 mesh stainless steel screen
and dried for a further 45 mins. at 60 C.
5. Talc and magnesium stearate are then mixed with a
small quantity of the granulate in a polythene bag.
6. The pre-mix from 5 is blended with the remaining
granulate for 5 mins. in the mixer.
The lubricated granules formed above are compressed on a rotary tabletting press using 6mm normal concave tooling.
Cutting weight of the granulate may be calculated from the formula as 100.Omg per tablet and in process checks are made to ensure that the mean tablet weight remains at this level plus or minus 2%. Also the compression pressure of the press is set so that tablets are well formed, free from pits and blemishes and with a hardness value of at least 3 units when assessed using a Manesty hardness tester.
The finished tablets are finally packed within blister packs on a semi-automatic line. Clear, uncoloured PVC sheet is thermoformed into blisters using tooling appropriate for the tablet size. Tablets are then filled into the blisters which are in turn sealed onto a backing strip of aluminium foil, prior to cutting to appropriate pack size.
Example 2
Formula
Unit Reference to
Names of Inaredients Formula (m/tab) Function Standards
Active Ingredients:
Selegiline Hydrochloride 5.00 Anti-Parkinsonian HSE
Other Ingredients:
Microcrystalline Cellulose 72.50 Diluent EP
Mannitol 20.00 Binder EP
Talc 2.00 Flow Promoter EP
Magnesium Stearate 0.50 Lubricant EP
Example 3 1. Betahistine Dihydrochloride is dissolved in 500ml of
water and filtered if necessary in order to yield a
clear solution.
2. This solution is then added to mannitol and cellulose
in a planetary mixer and the mass is mixed for 5
minutes.
3. An additional 300ml of water is then added and mixing
continued for a further 5 mins. in order to form a
granular mass.
4. The granulate is fluid bed dried at 600C for 30 mins.;
granulated through a 20 mesh stainless steel screen
and dried for a further 60 mins. at 60 0C.
5. Talc, magnesium stearate and fumed silica are then
mixed with a small quantity of the granulate in a
polythene bag.
6. The pre-mix from 5 is blended with the remaining
granulate for 5 mins. in the mixer.
The lubricated granules formed above are compressed on a rotary tabletting press using 6mm normal concave tooling.
Cutting weight of the granulate may be calculated from the formula as 100.5mg per tablet and in process checks are made to ensure that the mean tablet weight remains at this level plus or minus 2%. Also the compression pressure of the press is set so that tablet are well formed, free of pits and blemishes and with a hardness value of at least 3 units when assessed using a Manesty hardness tester.
Due to the hygroscopic nature of betahistine, weighing and compression is undertaken under relative humidity conditions of less than 30%.
Example 4
Formula
Unit Reference to
Names of Inaredients Formula (mq/tab) Function Standards
Active Ingredients:
Betahistine Dihydrochloride 8.00 Vasodilator HSE
Other Ingredients:
Microcrystalline Cellulose 69.00 Diluent EP
Mannitol 20.00 Binder EP
Fumed Silica 1.00 Desiccant EP
Talc 2.00 Flow Promoter EP
Magnesium Stearate 0.50 Lubricant EP
It will be understood that the above Examples are by way of illustration only and modifications of detail can be made within the scope of the invention as defined in the appended claims.
Claims (5)
1. A process for the production of a tabletted formulation comprising an active agent in which the active agent is dissolved in an aqueous medium prior to processing, and in which the active agent is betahistine, selegiline or an analogue or derivative of either of the above.
2. A process according to Claim 1 comprising the steps of dissolving selegiline dihydrochloride or betahistine dihydrochloride completely in water, granulating the solution so obtained, and drying and compressing the granulate.
3. A process, substantially as hereinabove described, with reference to Examples 1 or 3.
4. A tabletted formulation produced by a process according to any one of Claims 1 to 3.
5. A tabletted formulation, substantially as hereinabove described, with reference to Examples 2 or 4.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9313739A GB2280604B (en) | 1993-07-02 | 1993-07-02 | Processing of active agents |
| IE940521A IE81025B1 (en) | 1993-07-02 | 1994-06-23 | Processing of active agents |
| ZA944729A ZA944729B (en) | 1993-07-02 | 1994-06-30 | Processing of active agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9313739A GB2280604B (en) | 1993-07-02 | 1993-07-02 | Processing of active agents |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB9313739D0 GB9313739D0 (en) | 1993-08-18 |
| GB2280604A true GB2280604A (en) | 1995-02-08 |
| GB2280604B GB2280604B (en) | 1997-04-30 |
Family
ID=10738209
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9313739A Expired - Fee Related GB2280604B (en) | 1993-07-02 | 1993-07-02 | Processing of active agents |
Country Status (3)
| Country | Link |
|---|---|
| GB (1) | GB2280604B (en) |
| IE (1) | IE81025B1 (en) |
| ZA (1) | ZA944729B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000053162A1 (en) * | 1999-03-05 | 2000-09-14 | Farmaceutici Formenti S.P.A. | Controlled-release compositions of betahistine |
| EP1493435A1 (en) * | 2003-07-04 | 2005-01-05 | FARMACEUTICI FORMENTI S.p.A. | Controlled Release Compositions of Betahistine |
| EP2314296A1 (en) * | 2009-10-22 | 2011-04-27 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Orally Disintegrating Tablets of Betahistine |
| WO2011139250A3 (en) * | 2010-05-04 | 2012-03-01 | Mahmut Bilgic | Water dispersible formulation comprising betahistine |
| US8642631B2 (en) | 2008-05-27 | 2014-02-04 | University Of Melbourne | Methods of treating mammals with eustachian tube dysfunctions |
| CN104013595A (en) * | 2013-03-01 | 2014-09-03 | 安徽贝克生物制药有限公司 | Hydrochloric acid selegiline preparation and preparation process thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111249237A (en) * | 2019-12-21 | 2020-06-09 | 乐普恒久远药业有限公司 | Betahistine hydrochloride medicine and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1031425A (en) * | 1962-03-30 | 1966-06-02 | Chinoin Gyogyszer Es Vegyeszet | New aralkylamines and their preparation |
| WO1988004552A1 (en) * | 1986-12-19 | 1988-06-30 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Composition to prevent seasickness |
| GB2245559A (en) * | 1990-06-25 | 1992-01-08 | Farmos Oy | Bioceramic system for delivery of a bioactive compound. |
-
1993
- 1993-07-02 GB GB9313739A patent/GB2280604B/en not_active Expired - Fee Related
-
1994
- 1994-06-23 IE IE940521A patent/IE81025B1/en not_active IP Right Cessation
- 1994-06-30 ZA ZA944729A patent/ZA944729B/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1031425A (en) * | 1962-03-30 | 1966-06-02 | Chinoin Gyogyszer Es Vegyeszet | New aralkylamines and their preparation |
| WO1988004552A1 (en) * | 1986-12-19 | 1988-06-30 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Composition to prevent seasickness |
| GB2245559A (en) * | 1990-06-25 | 1992-01-08 | Farmos Oy | Bioceramic system for delivery of a bioactive compound. |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000053162A1 (en) * | 1999-03-05 | 2000-09-14 | Farmaceutici Formenti S.P.A. | Controlled-release compositions of betahistine |
| RU2248791C2 (en) * | 1999-03-05 | 2005-03-27 | ФАРМАЧЕУТИЧИ ФОРМЕНТИ С.п.А. | Beta-histin-based controlled-release compositions |
| CZ299510B6 (en) * | 1999-03-05 | 2008-08-20 | Farmaceutici Formenti S. P. A. | Tablet |
| EP1493435A1 (en) * | 2003-07-04 | 2005-01-05 | FARMACEUTICI FORMENTI S.p.A. | Controlled Release Compositions of Betahistine |
| WO2005004850A1 (en) * | 2003-07-04 | 2005-01-20 | Farmaceutici Formenti S.P.A. | Controlled release compositions of betahistine |
| EA011569B1 (en) * | 2003-07-04 | 2009-04-28 | ФАРМАЧЕУТИЧИ ФОРМЕНТИ С.п.А. | Controlled release compositions of betahistine |
| US8642631B2 (en) | 2008-05-27 | 2014-02-04 | University Of Melbourne | Methods of treating mammals with eustachian tube dysfunctions |
| EP2314296A1 (en) * | 2009-10-22 | 2011-04-27 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Orally Disintegrating Tablets of Betahistine |
| WO2011139250A3 (en) * | 2010-05-04 | 2012-03-01 | Mahmut Bilgic | Water dispersible formulation comprising betahistine |
| CN104013595A (en) * | 2013-03-01 | 2014-09-03 | 安徽贝克生物制药有限公司 | Hydrochloric acid selegiline preparation and preparation process thereof |
| CN104013595B (en) * | 2013-03-01 | 2016-08-24 | 安徽贝克生物制药有限公司 | A kind of SelegilineHydrochloride preparation and preparation technology thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2280604B (en) | 1997-04-30 |
| ZA944729B (en) | 1996-01-02 |
| IE81025B1 (en) | 1999-10-20 |
| GB9313739D0 (en) | 1993-08-18 |
| IE940521A1 (en) | 1995-01-11 |
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| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20010702 |