CA1302886C - Pharmaceutical composition containing a benzodiazepin derivative - Google Patents
Pharmaceutical composition containing a benzodiazepin derivativeInfo
- Publication number
- CA1302886C CA1302886C CA000547518A CA547518A CA1302886C CA 1302886 C CA1302886 C CA 1302886C CA 000547518 A CA000547518 A CA 000547518A CA 547518 A CA547518 A CA 547518A CA 1302886 C CA1302886 C CA 1302886C
- Authority
- CA
- Canada
- Prior art keywords
- temazepam
- insomnia
- capsule
- less
- surface area
- 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.)
- Expired - Lifetime
Links
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical class N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 title description 2
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 claims abstract description 51
- 229960003188 temazepam Drugs 0.000 claims abstract description 50
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims abstract description 17
- 206010022437 insomnia Diseases 0.000 claims abstract description 17
- 239000007903 gelatin capsule Substances 0.000 claims description 22
- 239000002775 capsule Substances 0.000 claims description 17
- 239000002245 particle Substances 0.000 claims description 16
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 abstract 1
- 230000004622 sleep time Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000004620 sleep latency Effects 0.000 description 5
- 239000000902 placebo Substances 0.000 description 4
- 229940068196 placebo Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000003326 hypnotic agent Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract A low dosage of temazepam for use in the treatment of chronic and transient insomnia.
Description
~3~`Z8~
Pharmaceutical Composition Containing a Benzodiazepin Derivative This invention relates to new pharmaceutical forms of temazepam and their use as hypnotic agents.
More particularly, it relates to low dose temazepam capsules and their use in the treatment of insomnia, especially, transient insomnia.
Temazepam, whose chemical name is 7-chloro-1, 3-dihydro-3-hydroxy-l-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, is a well known hypnotic agent used in the treatment of insomnia. The commercial product is sold both in the form of hard gelatin capusles containing 15 and 30 milligrams of temazepam and soft gelatin capsules containing 10 and 20 milligrams of temazepam. The hard gelatin capsule has been studied in great depth and has been found to be generally effective at doses of 15 and 30 milli-grams of temazepam. At doses of 10 and 20 milligrams, the soft gelatin capsules have also been found to be effective, although Nicholson, et al. (Br. J. Clin. Pharmac., 3,543-550, 1976) have reported that at 10 milligrams, no change in total sleep time was found, whereas at 20 milli-grams, total sleep time was markedly increased. Lower dose forms of temazepam containing 5 milligrams of the compound have been used in a number of investigations (LaReforma Medica, 16,425 427, 1970; Bombay Hosp. J., 16,222-223, 1974, Neuropsychobiology 9(1), 52-65, 1983) but have never been found to be useful in treating insomnia. In the Neuro-psychobiology publication, the authors indicate that at 5 milligrams, temazepam is known to be of no clinical importance as a hypnotic agent.
13~ 6 600-7046 Although the side effects of temazepam are minimal, the lowest effective dose of the product would be desirable. It would be especially useful in treating transient insomnia, which occurs in healthy individuals whose sleep pattern has been temporarily disrupted, for example by airplane travel or by changing work shifts. It has now been found that a hard gelatin capsule comprising up to 10 milligrams of temazepam, in which the temazepam particles have a specific surface area of from 0.65 to 1.1 square meters per gram (m2/g) and 95% of the particles have a particle size diameter of less than 65 microns (u), is effective in the treatment of insomnia, especially in improving sleep latency. Such a formulation is also useful for the treatment of chronic insomnia. Preferably the capsule contains the temazepam in amounts of from 5 to 10 milligrams, more preferably 6 to 8 milligrams, especially 7.5 milligrams, in combination with a pharmaceutically acceptable carrier. The capsule is normally administered just before bedtime.
It has also been found that a soft gelatin capsule comprising 5 to 9 mg of temazepam, and especially 5mg, in combination with a pharma-ceutically acceptable carrier, is useful in the treatment of transient insomnia.
Crystalline temazepam can be synthesized with a purity of not less than 98~ using known procedures such as that disclosed in U.S.P.
3,296,245. The bulk temazepam is milled to obtain the required particle size and surface area with an Alpine 160 UPZ mill using a stainless steel pin. The particle size is determined using a Malverne Particle 13~8~6 Sizer, Model 3600 E equipped with a 14.3 mm flow cell and a 100 mm lens.
Surface area measurements are made essentially in accordance with the standard B.E.T. procedure of Brunauer, Emmet and Teller (J. Am. Chem.
Soc. _ , 2682, 1937 and J. Am. Chem. Soc., 60, 309, 1938). The temazepam is formulated with standard hard gelatin capsule excipients and encapsulated in conventional hard gelatin capsules using known procedures.
Similarly for the formation of the soft gelatin capsules, temazepam is mixed with standard soft gelatin capsule excipients, and encapsulated using known procedures, in conventional soft gelatin capsules.
The use of low dose temazepam capsules in the treatment of transient insomnia is evaluated in a double blind, parallel group, placebo-controlled sleep laboratory study using 201 healthy subjects. Just before bedtime each subject is given a capsule containing placebo, or the appropriate amount of temazepam. Testing is carried out over a period of one night in the sleep laboratory. The key parameters of sleep latency and total sleep time are among those measured by EEG analysis (polysomnography).
In the case of the hard gelatin capsule dosages of 7.5, 15 or 30 mg of temazepam per capsule are employed. The number of subjects in the four treatment groups is placebo - 50; 7.5 milligrams - 51; 15 milligrams - 49; and 30 milligrams - 51. The mean values for sleep latency and total sleeptime obtained with the hard gelatin capsule in each treatment group were as follows:
~3~288~
Group Sleep Latency (m-i-n.) Total Sleep Time (min.) Placebo 37 411 7.5 m.g. 26 422 15 m.g. 22 429 30 m.g. 18 441 As can be seen from the above data 7.5 milligrams of temazepam was effect-ive in reducing both sleep latency and increasing total sleep time in the study. The most unexpected result is that the effect occurred as the dosage dropped below the 15 milligram dosage level. The usual effect-no effect results, which would have been expected between 7.5 and 15 milligrams of temazepam based on previous hard gelatin capsule studies did not occur.
Similar results are obtained employing a soft gelatin capsule containing 5 mg of temazepam.
13~2~3~6 Example 1 White crystalline temazepam having a purity of not less than 98%
is prepared according to the procedure described in USP 3,296,245. The bulk temazepam obtained is fed into an Alpine 160 UPZ mill with a stain-less steel pin at a rate of about 40 kilograms (kg) per hour using a mill speed of about 11,000 RPM to obtain temazepam particles having a specific surface area of 0.65 to 1.1 m2/g area and 95% of the particles having a particle size diameter of less than 65 u. The surface area measurement is made with the Quantector Gas Flow System and Quantasorb Surface Area Analyser at the temperature of liquid nitrogen (-196C) using krypton as the absorbant and helium as the carrier gas. The particle size diameter is determined with the Malverne Particle Sizer at an obscur-ation value of 0.2 to 0.25 using a 0.1% Twee@ 80 solution in water satur-ated with temazepam in which 1 to 2 grams of temazepam sample to be tested has been dispersed. After the feed rate and mill speed of the Alpine mill have been set, they are monitored at regular intervals to maintain the required particle size and surface area.
Example 2 To prepare hard gelatin capsules containing 7.5 milligrams of the temazepam of example 1, 12 kg of temazepam and 12 kg of lactose are passed through an 18 mesh screen. This mixture is added to 372 kg of lactose, which has also been passed through an 18 mesh screen, and and 4 kg of magnesium stearate in a 30 cu. ft. PK Mixer without an intensi-ty bar. The capsule ingredients mixed for 30 minutes using tumbling ~3~sZ~6 action only. The capsule mix is encapsulated in number 3 Lock hard gelatin capsules with opaque blue caps and opaque pink bodies, and the capsules are then passed through a capsule polisher. Each capsule contains 250 milligrams of capsule mix of which 7.5 milligrams are temazepam.
Example 3 For the preparation of the soft gelatin capsules, containing 5 mg of temazepam, 8 kg of the temazepam is dissolved in 356.8 kg of poly-ethylene glycol 400. When dissolved the solution is encapuslated by standard techniques in number 4 oval soft gelatin capsule shells which are opaque and maroon in colour. Each capsule contains 228 mg of capsule mix of which 5 mg are temazepam.
Pharmaceutical Composition Containing a Benzodiazepin Derivative This invention relates to new pharmaceutical forms of temazepam and their use as hypnotic agents.
More particularly, it relates to low dose temazepam capsules and their use in the treatment of insomnia, especially, transient insomnia.
Temazepam, whose chemical name is 7-chloro-1, 3-dihydro-3-hydroxy-l-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, is a well known hypnotic agent used in the treatment of insomnia. The commercial product is sold both in the form of hard gelatin capusles containing 15 and 30 milligrams of temazepam and soft gelatin capsules containing 10 and 20 milligrams of temazepam. The hard gelatin capsule has been studied in great depth and has been found to be generally effective at doses of 15 and 30 milli-grams of temazepam. At doses of 10 and 20 milligrams, the soft gelatin capsules have also been found to be effective, although Nicholson, et al. (Br. J. Clin. Pharmac., 3,543-550, 1976) have reported that at 10 milligrams, no change in total sleep time was found, whereas at 20 milli-grams, total sleep time was markedly increased. Lower dose forms of temazepam containing 5 milligrams of the compound have been used in a number of investigations (LaReforma Medica, 16,425 427, 1970; Bombay Hosp. J., 16,222-223, 1974, Neuropsychobiology 9(1), 52-65, 1983) but have never been found to be useful in treating insomnia. In the Neuro-psychobiology publication, the authors indicate that at 5 milligrams, temazepam is known to be of no clinical importance as a hypnotic agent.
13~ 6 600-7046 Although the side effects of temazepam are minimal, the lowest effective dose of the product would be desirable. It would be especially useful in treating transient insomnia, which occurs in healthy individuals whose sleep pattern has been temporarily disrupted, for example by airplane travel or by changing work shifts. It has now been found that a hard gelatin capsule comprising up to 10 milligrams of temazepam, in which the temazepam particles have a specific surface area of from 0.65 to 1.1 square meters per gram (m2/g) and 95% of the particles have a particle size diameter of less than 65 microns (u), is effective in the treatment of insomnia, especially in improving sleep latency. Such a formulation is also useful for the treatment of chronic insomnia. Preferably the capsule contains the temazepam in amounts of from 5 to 10 milligrams, more preferably 6 to 8 milligrams, especially 7.5 milligrams, in combination with a pharmaceutically acceptable carrier. The capsule is normally administered just before bedtime.
It has also been found that a soft gelatin capsule comprising 5 to 9 mg of temazepam, and especially 5mg, in combination with a pharma-ceutically acceptable carrier, is useful in the treatment of transient insomnia.
Crystalline temazepam can be synthesized with a purity of not less than 98~ using known procedures such as that disclosed in U.S.P.
3,296,245. The bulk temazepam is milled to obtain the required particle size and surface area with an Alpine 160 UPZ mill using a stainless steel pin. The particle size is determined using a Malverne Particle 13~8~6 Sizer, Model 3600 E equipped with a 14.3 mm flow cell and a 100 mm lens.
Surface area measurements are made essentially in accordance with the standard B.E.T. procedure of Brunauer, Emmet and Teller (J. Am. Chem.
Soc. _ , 2682, 1937 and J. Am. Chem. Soc., 60, 309, 1938). The temazepam is formulated with standard hard gelatin capsule excipients and encapsulated in conventional hard gelatin capsules using known procedures.
Similarly for the formation of the soft gelatin capsules, temazepam is mixed with standard soft gelatin capsule excipients, and encapsulated using known procedures, in conventional soft gelatin capsules.
The use of low dose temazepam capsules in the treatment of transient insomnia is evaluated in a double blind, parallel group, placebo-controlled sleep laboratory study using 201 healthy subjects. Just before bedtime each subject is given a capsule containing placebo, or the appropriate amount of temazepam. Testing is carried out over a period of one night in the sleep laboratory. The key parameters of sleep latency and total sleep time are among those measured by EEG analysis (polysomnography).
In the case of the hard gelatin capsule dosages of 7.5, 15 or 30 mg of temazepam per capsule are employed. The number of subjects in the four treatment groups is placebo - 50; 7.5 milligrams - 51; 15 milligrams - 49; and 30 milligrams - 51. The mean values for sleep latency and total sleeptime obtained with the hard gelatin capsule in each treatment group were as follows:
~3~288~
Group Sleep Latency (m-i-n.) Total Sleep Time (min.) Placebo 37 411 7.5 m.g. 26 422 15 m.g. 22 429 30 m.g. 18 441 As can be seen from the above data 7.5 milligrams of temazepam was effect-ive in reducing both sleep latency and increasing total sleep time in the study. The most unexpected result is that the effect occurred as the dosage dropped below the 15 milligram dosage level. The usual effect-no effect results, which would have been expected between 7.5 and 15 milligrams of temazepam based on previous hard gelatin capsule studies did not occur.
Similar results are obtained employing a soft gelatin capsule containing 5 mg of temazepam.
13~2~3~6 Example 1 White crystalline temazepam having a purity of not less than 98%
is prepared according to the procedure described in USP 3,296,245. The bulk temazepam obtained is fed into an Alpine 160 UPZ mill with a stain-less steel pin at a rate of about 40 kilograms (kg) per hour using a mill speed of about 11,000 RPM to obtain temazepam particles having a specific surface area of 0.65 to 1.1 m2/g area and 95% of the particles having a particle size diameter of less than 65 u. The surface area measurement is made with the Quantector Gas Flow System and Quantasorb Surface Area Analyser at the temperature of liquid nitrogen (-196C) using krypton as the absorbant and helium as the carrier gas. The particle size diameter is determined with the Malverne Particle Sizer at an obscur-ation value of 0.2 to 0.25 using a 0.1% Twee@ 80 solution in water satur-ated with temazepam in which 1 to 2 grams of temazepam sample to be tested has been dispersed. After the feed rate and mill speed of the Alpine mill have been set, they are monitored at regular intervals to maintain the required particle size and surface area.
Example 2 To prepare hard gelatin capsules containing 7.5 milligrams of the temazepam of example 1, 12 kg of temazepam and 12 kg of lactose are passed through an 18 mesh screen. This mixture is added to 372 kg of lactose, which has also been passed through an 18 mesh screen, and and 4 kg of magnesium stearate in a 30 cu. ft. PK Mixer without an intensi-ty bar. The capsule ingredients mixed for 30 minutes using tumbling ~3~sZ~6 action only. The capsule mix is encapsulated in number 3 Lock hard gelatin capsules with opaque blue caps and opaque pink bodies, and the capsules are then passed through a capsule polisher. Each capsule contains 250 milligrams of capsule mix of which 7.5 milligrams are temazepam.
Example 3 For the preparation of the soft gelatin capsules, containing 5 mg of temazepam, 8 kg of the temazepam is dissolved in 356.8 kg of poly-ethylene glycol 400. When dissolved the solution is encapuslated by standard techniques in number 4 oval soft gelatin capsule shells which are opaque and maroon in colour. Each capsule contains 228 mg of capsule mix of which 5 mg are temazepam.
Claims (11)
1. The use of temazepam for the manufacture of a medicament for the treatment of insomnia characterised in that a) the temazepam has a surface area of from 0.65 to 1.1 m2/g and 95%
thereof has a particle diameter of less than 65 microns and is present in a quantity of up to 10 mg per dosage unit b) alternatively in the case of transient insomnia is in the form of a soft gelatin capsule containing less than 10 mg of temazepam.
thereof has a particle diameter of less than 65 microns and is present in a quantity of up to 10 mg per dosage unit b) alternatively in the case of transient insomnia is in the form of a soft gelatin capsule containing less than 10 mg of temazepam.
2. The use of temazepam in insomnia characterised in that the temazepam a) has a surface area of from 0.65 to 1.1 m2/g and 95% thereof has a particle diameter of less than 65 microns and is present in a quantity of up to 10 mg per dosage unit or b) alternatively in the case of transient insomnia is in the form of a soft gelatin capsule containing less than 10 mg of temazepam.
3. The use according to claim 2 wherein the temazepam a) has a surface area of from 0.65 to 1.1 m2/g and 95% thereof has a particle diameter of less than 65 microns and is present in a quantity of 5 to 10 mg or b) alternatively in the case of transient insomnia, is in the form of a soft gelatin capsule containing 5 to 9 mg of temazepam.
4. The use according to claim 3 wherein each dosage unit contains 6 to 8 mg of temazepam.
5. The use according to claim 3 wherein each dosage unit contains 7.5 mg of temazepam.
6. The use according to claim 3 wherein each dosage unit contains 5 mg of temazapem.
7. The use according to claim 1,2,3,4,5 or 6 for treating transient insomnia.
8. A hard gelatin capsule containing up to 10 mg of temazepam in which the temazepam has a surface area of from 0.65 to 1.1 m2/g and 95% thereof has a particle diameter of less than 65 microns and a pharmaceutically acceptable carrier therefor.
9. A capsule according to claim 8 containing 5 to 10 mg of temazepam.
10. A capsule according to claim 8 containing 6 to 8 mg of temazepam.
11. A capsule according to claim 8 containing 7.5 mg of temazepam.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US910,571 | 1978-05-30 | ||
| US91057186A | 1986-09-23 | 1986-09-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1302886C true CA1302886C (en) | 1992-06-09 |
Family
ID=25429005
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000547518A Expired - Lifetime CA1302886C (en) | 1986-09-23 | 1987-09-22 | Pharmaceutical composition containing a benzodiazepin derivative |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS63101325A (en) |
| BE (1) | BE1000318A4 (en) |
| CA (1) | CA1302886C (en) |
| CH (1) | CH673947A5 (en) |
| DE (1) | DE3731840A1 (en) |
| FR (1) | FR2604091B1 (en) |
| GB (1) | GB2195242A (en) |
| IT (1) | IT1221509B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19603402A1 (en) * | 1995-02-24 | 1996-08-29 | Basf Ag | Soft gelatin capsules |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL60806A0 (en) * | 1979-09-14 | 1980-10-26 | Sparamedica Ag | Pharmaceutical compositions containing a benzodiazepine derivatives and a neuroleptic |
| DE3033919A1 (en) * | 1980-09-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | SOLID PHARMACEUTICAL PREPARATIONS CONTAINING NIFEDIPINE AND METHOD FOR THE PRODUCTION THEREOF |
| GB8305693D0 (en) * | 1983-03-02 | 1983-04-07 | Scherer Ltd R P | Pharmaceutical compositions |
| DE3307353C2 (en) * | 1983-03-02 | 1985-01-31 | R.P. Scherer GmbH, 6930 Eberbach | Soft gelatin capsule containing polyethylene glycol and process for their production |
| WO1987000428A1 (en) * | 1985-07-24 | 1987-01-29 | Pyare Seth | Oxazepam containing pharmaceutical composition |
-
1987
- 1987-09-18 CH CH3616/87A patent/CH673947A5/de not_active IP Right Cessation
- 1987-09-21 BE BE8701058A patent/BE1000318A4/en not_active IP Right Cessation
- 1987-09-21 GB GB08722205A patent/GB2195242A/en not_active Withdrawn
- 1987-09-21 FR FR878713108A patent/FR2604091B1/en not_active Expired
- 1987-09-22 IT IT48408/87A patent/IT1221509B/en active
- 1987-09-22 CA CA000547518A patent/CA1302886C/en not_active Expired - Lifetime
- 1987-09-22 JP JP62236428A patent/JPS63101325A/en active Pending
- 1987-09-22 DE DE19873731840 patent/DE3731840A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| IT8748408A0 (en) | 1987-09-22 |
| GB2195242A (en) | 1988-04-07 |
| GB8722205D0 (en) | 1987-10-28 |
| FR2604091A1 (en) | 1988-03-25 |
| BE1000318A4 (en) | 1988-10-18 |
| DE3731840A1 (en) | 1988-03-31 |
| FR2604091B1 (en) | 1989-05-05 |
| JPS63101325A (en) | 1988-05-06 |
| CH673947A5 (en) | 1990-04-30 |
| IT1221509B (en) | 1990-07-06 |
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