IL107122A - 3-Thienyl carbonyl substituted 2-oxindole-1-carboxamide pharmaceutical compositions - Google Patents
3-Thienyl carbonyl substituted 2-oxindole-1-carboxamide pharmaceutical compositionsInfo
- Publication number
- IL107122A IL107122A IL10712293A IL10712293A IL107122A IL 107122 A IL107122 A IL 107122A IL 10712293 A IL10712293 A IL 10712293A IL 10712293 A IL10712293 A IL 10712293A IL 107122 A IL107122 A IL 107122A
- Authority
- IL
- Israel
- Prior art keywords
- pharmaceutical preparation
- chloro
- weight
- formula
- compound
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
ϋΊ7 )Νυ3ΐηΊϊ7-1-7πΓϋϊ71Ν-2 l l? 71ΠΝ"1Π-3 ΌΊΏ27JJ ΓΠΤΐρΐΊ "•T'tDDH 3-THIENYL CARBONYL SUBSTITUTED 2-OXINDOLE- 1-CARBOXAMIDE PHARMACEUTICAL COMPOSITIONS 107122/3 -1- comprising certain 3- i d i d l b i i (Ca to C10) fatty acid triglyceride and propylene glycol diesters. These carboxamides are useful as analgesics for use in mammals such as man and in ameliorating or alleviating pain encountered while recovering from surgery or other trauma or in eliminating the symptoms of chronic diseases such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis, as shown in United States Patents 4,556,672 (corresponding to IL 74631 and IL 85130) and 5,047,554 (corresponding to IL 94047). The carboxamides are also useful for treating collagenase mediated disorders and diseases, such as bone resorption disorders, corneal ulceration, periodontal disease, inflammatory diseases, and wounds of the skin and burns in a mammal, as shown in United States Patent 5,008,283 (corresponding to IL 97521 ) The carboxamides described in formula I are chemically unstable in water. It is known that the rate of hydrolytic degradation may be reduced by protection of labile drugs e.g. sequestration in the hydrophobic core of micelles or formulation in low water activity, non-aqueous solvent-based vehicles i.e. essential oils. In addition to hydrolytic instability the carboxamides are also prone to oxidative degradation in aqueous e.g. water, and non-aqueous e.g. oils, vehicles. Oxidative instability can be reduced in saturated oils by inclusion of antioxidants or by formulation in unsaturated oils which protect the drug by being preferentially oxidized themselves. However, the carboxamides described in formula I are not readily stabilized in oils commonly used in pharmaceutical preparations e.g. sesame oil, peanut oil, safflower oil, cottonseed oil.
Summary of The Invention The present invention relates to a pharmaceutical preparation comprising: (A) at least one triglyceride or propylene glycol diester of fractionated coconut oil fatty acids; and (B) at least one compound of the formula where R, , R2, and R3 are each independently hydrogen, fluoro, bromo, or chloro, or a pharmaceutically acceptable salt thereof, wherein the weight ratio of (A) to (B) ranges from 5.6 to 999.
The pharmaceutical preparation includes 85 to 99 % by weight of (A) and 0.1 to 15 % by weight of (B).
Preferably, R,, R2, and R3 are each independently fluoro or chloro.
Preferred compounds of formula I include: 5- chloro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-indole-carboxamide; 6- chloro-5-fluoro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-in-dole-carboxamide; and 6-chloro-5-fiuoro-2,3-dihydro-2-oxo-3-(2-(4-chloro)-thienyl-carbonyl)-indole-carboxamide.
The present invention also includes the use of the foregoing pharmaceutical preparation as a collagenase activation inhibiting medicament in a mammal in need thereof.
The present invention also includes the use of the foregoing pharmaceutical preparation as a analgesic response eliciting medicament in a mammal in need thereof.
The present invention also includes the use of the foregoing pharmaceutical preparation as a inflammatory disease treating medicament in a mammal in need thereof.
Detailed Description of the Invention It has been found that pharmaceutical preparations including the carboxamides of formula I and C8 to C10 saturated fatty acid triglycerides and propylene glycol diesters have superior product viability and shelf life. As the result of utilizing such a formulation, the carboxamides are less susceptible to hydrolysis and oxidation which can deteriorate them and ultimately render them ineffective. Stabilization of the carboxamides in these preparations do not require the addition of an antioxidant or other auxiliary stabilizers.
The triglycerides used in the claimed invention are neutral oils which are composed of esters of medium chain (C8 to C10) fatty acids, also referred to as fractionated coconut oil. These fatty acids are esterified with either glycerin or propylene glycol and are sold under the name MIGLYOL® (i.e. MIGLYOL® 810, MIGLYOL® 812, and MIGLYOL® 840). MIGLYOLS are also described as triglycerides of fractionated coconut oil fatty acids or caprylic acid/ capric acid triglycerides. Fractionated coconut oil is prepared from the fixed oils obtained from the dried solid part of the endosperm of Cocos nucifera L by hydrolysis, fractionation of the liberated fatty acids and re-esterification with glycerol or propylene glycol. It consists of a mixture of short and medium-chain saturated fatty acids, mainly octanoic and decanoic acids. Miglyol® is the trade name for fractionated coconut oil or caprylic acid/capric acid triglycerides from Dynamit Nobel Ltd., Germany and the U.K. These vehicles have demonstrated stability against oxidation and rancidification as well as outstanding safety and biocompatibility. Furthermore, since only saturated fatty acids are used the oils do not generate peroxides or other free radicals which could destabilize the pharmaceutical contained therein. The low water content also minimizes the hydrolysis of the carboxamide. In the preferred composition, a carboxamide of formula I is dispersed in an oil vehicle comprising Miglyol® 812 and other oil-soluble additives described below under agitation to produce a homogenous suspension of the drug substance in the oil vehicle.
Other additives which can be present in the pharmaceutical preparation can include an anticaking agent such as, for example, propylene glycol, polyethylene glycol, glycerin, sorbitol, benzyl alcohol, lecithin, or aluminum stearate. The amount of anticaking agent can range from approximately 0.05 to 5 % by weight. The pharmaceutical preparation can also contain preservative in an amount ranging from 0.5 to 2.0 % by weight. Such preservatives can include, for example, phenol, benzyl alcohol, parabens, chlorbutanol, and benzyl benzoate. Gelling agents, such as aluminum monostearate can also be included in the pharmaceutical preparation in an amount ranging from o.5 to 3.0 % by volume.
The stability of these pharmaceutical preparations can be evaluated, for example, under accelerated storage conditions after subjecting suspensions of the carboxamides (6% by weight of the drug substance) packaged in glass vials to high temperatures of up to 70 °C for up to nine weeks. During the stability challenge the level of intact drug remaining in the preparation, as well as hydrolytic and oxidative decomposition products is quantified by high performance liquid chromatography (HPLC). For assay, the suspension is diluted with methanol/triethylamine 100/1 volume-by-volume to give a final drug concentration of 0.6 to 1.2 mg/mL. This solvent dissolves the suspended drug to produce a solution which can be directly injected on the HPLC column. For chromatography, the mobile phase is methanol/water 90/10 v/v + 1 % triethylamine, the column is a reversed phase octadecasilane and the solvent flow rate was 1 mL/minute. Drug detection was by UV absorbance at 246 nm. Such an assay has shown there to be virtually no decomposition of carboxamide in suspension after nine weeks.
When a compound of formula I or salt thereof is used in a human subject, the daily dosage will normally be determined by the prescribing physicians. Moreover, the dosage will vary according to the age, weight and response of the individual patient, as well as the severity of the patient's symptoms and the potency of the particular compound being administered. However, for acute administration to relieve pain, an effective dose in most instances will be 0.01 to 0.25 g as needed (e.g., one- to four-times-a-day). For chronic administration, in most instances an effective dose will be from 0.01 to 0.5 g per day, and preferably 0.1 to 0.25 g per day in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
Preferably the pharmaceutical compositions of the present invention are parenteral pharmaceutical compositions. The pharmaceutical compositions of this invention may be produced by formulating a compound of formula I (as the active ingredient) in dosage unit form. Some examples of dosage unit forms are sterile suspensions for intramuscular, subcutaneous or intra-articular injection, sterile ophthalmic suspensions for topical application to the eye, capsules for oral administration, rectal suppositories, or topical lotion for application to the skin or scalp.
An example of a suitable pharmaceutical dosage for oral administration are soft gelatin capsules. Orally administered suspensions can be delivered, e.g., upon encapsulation of a suspension of compound I in the oil, i.e. Miglyol 812, in a soft gelatin capsule. A rectal suppository may be formulated by dispersing the carboxamide in a neutral oil along with compatible suppository bases, such as cocoa butter or Whitepsol W35, which have melting points above body temperature. A topical product for application to the skin would contain the carboxamide as the active agent dispersed in the neutral oil, e.g., Miglyol 812, and also containing one or more pharmaceutical inactive ingredients, such as: cetyl alcohol, stearic acid, propylene glycol, aluminum monostearate, benzyl alcohol, as diluents and preservatives. A parenteral composition is preferably a suspension of the carboxamide in the neutral oil, and may also contain other inactive pharmaceutical components, such as: benzyl alcohol as preservative, aluminum monostearate as a gelling agent and propylene glycol as a dispersing agent.
The following Example illustrates how the pharmaceutical preparations can be prepared. Commercial reagents can be utilized without further purification.
EXAMPLE 1 800 mL of Miglyol 812 was heated to 45°C in a compounding vessel equipped with an agitator and homogenizer. 10 g of benzyl alcohol was added to the oil under agitation (about 60-80 R.P.M.). The oil solution was sterile filtered into a sterile compounding vessel equipped wait an agitator and homogenizer. 120 g of micronized, sterile carboxamide powder was dispersed into the oil phase under agitation. The suspension was homogenized under high shear for ten minutes and then was allowed to cool to room temperature under mild agitation (60-80 R.P.M.). The suspension was brought to a total batch weight of 1000 grams with the addition of the required amount of sterile Miglyol 812 to the suspension to give a final concentration of 12 % by weight of carboxamide in the final formulation. The suspension was aseptically filled into 50 cc, Type I, flint glass vials using an automated filling apparatus. The vials were capped with teflon-coated rubber stoppers and crimped with aluminum shells.
EXAMPLE 2 800 mL of Miglyol 812 was heated to 45°C in a compounding vessel equipped with an agitator and homogenizer. 10 g of benzyl alcohol was added to the oil under agitation ("60-80 R.P.M.). The oil solution was sterile filtered into a sterile compounding vessel equipped with an agitator and homogenizer. 20 g of sterile, aluminum monostearate powder was added to the oil solution in divided portions under agitation to gel the oil. The gelled oil was allowed to cool to room temperature and allowed to stand for six hours without agitation. 120 g of micronized, sterile carboxamide powder was then dispersed into the gelled oil under agitation. The suspension was brought to a total batch weight of 1000 grams with the addition of the required amount of sterile, gelled Miglyol 812 to the suspension to give a final concentration of 12% by weight of carboxamide in the final formulation. The suspension was aseptically filled into 50 cc, Type I, flint glass vials using an automated filling apparatus. The vials were capped with teflon-coated rubber stoppers and crimped with aluminum shells.
EXAMPLE 3 800 ml_ of Miglyol 812 was heated to 45°C in a compounding vessel equipped with an agitator and homogenizer. 10 g of benzyl alcohol was added to the oil under agitation (about 60-80 R.P.M.). 120 g of micronized, sterile carboxamide powder was dispersed into the oil phase under agitation. The suspension was homogenized under high shear for ten minutes and then was allowed to cool to room temperature under mild agitation (60-80 R.P.M.). The suspension was brought to a total batch weight of 1000 grams with the addition of the required amount of Miglyol 812 to the suspension to give final concentration of 12% by weight carboxamide in the final formulation. The suspension was filled into soft gelatin capsules using an automated filling apparatus for oral ingestion.
EXAMPLE 4 200 g of Miglyol 812 and 800 g of Whitepsol W35 were heated to 60°C in a compounding vessel equipped with an agitator and homogenizer. Carboxamide powder was dispersed into the resulting oil solution under agitation. The suspension was allowed to filled into suppository molds and congealed by cooling to room temperature. 107122/2
Claims (23)
1. A pharmaceutical preparation comprising: (A) at least one triglyceride or propylene glycol diester of fractionated coconut oil fatty acids; and (B) at least one compound of the formula where R, , R2, and R3 are each independently hydrogen, fluoro, bromo, or chloro, or a pharmaceutically acceptable salt thereof, wherein the weight ratio of (A) to (B) ranges from 5.6 to 999.
2. The pharmaceutical preparation of claim 1 , wherein the preparation includes 85 to 99 % by weight of (A) and 0.1 to 15 % by weight of (B).
3. The pharmaceutical preparation of claim 1 , wherein R,, R2, and R3 are each independently fluoro or chloro.
4. The pharmaceutical preparation of claim 1 , wherein the compound of formula I is selected from the group consisting of 5- chloro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-indole-carboxamide; 6-chloro-5-fIuoro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-indole-carbox-amide; and 6- chloro-5-fluoro-2,3-dihydro-2-oxo-3-{2-(4-chloro)-thienylcarbonyl)-indole-carboxamide.
5. The pharmaceutical preparation of claim 1 , wherein the compound of formula I is 5-chloro-2,3-dihydro-2-oxo-3-(2-thienyl- carbonyl)-indole-carboxamide.
6. The pharmaceutical preparation of claim 1 , wherein the compound of formula I is 6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-indole-carboxamide. 107122/2 -8-
7. The pharmaceutical preparation of claim 1 , wherein the compound of formula I is 6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-(2-(4-chloro)-thienylcarbonyl)-indole-carboxamide.
8. The pharmaceutical preparation of claim 1 , wherein said coconut oil fatty acids include C8 to C10 fatty acids.
9. The pharmaceutical preparation of claim 8, wherein said coconut oil fatty acids include caprylic acid, caproic acid, lauric acid, and linoleic acid.
10. The pharmaceutical preparation of claim 1 , further including 0.05 to 5 % by weight of an anticaking agent .
11. The pharmaceutical preparation of claim 10, wherein said anticaking agent is propylene glycol, polyethylene glycol, glycerin, sorbitol, benzyl alcohol, lecithin, or aluminum stearate.
12. The pharmaceutical preparation of claim 10, further including 0.5 to 2.0 % by weight of a preservative.
13. The pharmaceutical preparation of claim 12, wherein said preservative is phenol, benzyl alcohol, parabens, chlorbutanol, or benzyl benzoate.
14. The pharmaceutical preparation of claim 1 , wherein said pharmaceutical preparation is adapted to be orally, topically, ophthalmically, parentally, or rectaliy administered.
15. The pharmaceutical preparation of claim 1 , wherein the pharmaceutical preparation includes from 0.01 to 1.0 g of a compound of formula I.
16. The pharmaceutical preparation of claim 15, wherein the pharmaceutical composition includes from 20 to 250 mg of a compound of formula I.
17. A pharmaceutical preparation according to claim 1 for use as a collagenase activation inhibiting medicament in a mammal in need thereof which comprises administering to said mammal a collagenase activation inhibiting amount of the pharmaceutical preparation of claim 1.
18. A pharmaceutical preparation according to claim 1 for use as a analgesic response eliciting medicament in a mammal which comprises administering to said mammal an analgesic response eliciting amount of the pharmaceutical preparation of claim 1.
19. A pharmaceutical preparation according to claim 1 for use as a inflammatory disease treating medicament in a mammal which comprises administering to said mammal an inflammatory disease treating amount of the pharmaceutical preparation of claim 1.
20. A pharmaceutical preparation comprising: 107122/2 -9- (A) at least one triglyceride or propylene glycol diester of fractionated coconut oil fatty acids; (B) at least one compound of the formula where R, , R2, and R3 are each independently hydrogen, fluoro, bromo, or chioro, or a pharmaceutically acceptable salt thereof; (C) 0 to 5 % by weight of an anticaking agent; and (D) 0 to 2.0 % by weight of a preservative, wherein the ratio of % by weight of (A) to % by weight of (B) ranges from 5.6 to 999.
21. Use of a pharmaceutical preparation according to claim 1 as a collagenase activation inhibiting medicament.
22. Use of a pharmaceutical preparation according to claim 1 as an analgesic response eliciting medicament.
23. Use of a pharmaceutical preparation according to claim 1 as an inflammatory disease treating medicament.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US95793092A | 1992-10-07 | 1992-10-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL107122A0 IL107122A0 (en) | 1993-12-28 |
| IL107122A true IL107122A (en) | 1998-08-16 |
Family
ID=25500362
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL10712293A IL107122A (en) | 1992-10-07 | 1993-09-27 | 3-Thienyl carbonyl substituted 2-oxindole-1-carboxamide pharmaceutical compositions |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0662831A1 (en) |
| JP (1) | JP2721042B2 (en) |
| KR (1) | KR950703338A (en) |
| CN (1) | CN1089138A (en) |
| AU (1) | AU676200B2 (en) |
| BR (1) | BR9307182A (en) |
| CA (1) | CA2146448A1 (en) |
| CZ (1) | CZ282702B6 (en) |
| EG (1) | EG20289A (en) |
| FI (1) | FI934387L (en) |
| HU (1) | HUT68533A (en) |
| IL (1) | IL107122A (en) |
| MX (1) | MX9306222A (en) |
| MY (1) | MY109680A (en) |
| NO (1) | NO951350L (en) |
| NZ (1) | NZ256164A (en) |
| PL (1) | PL174170B1 (en) |
| RU (1) | RU2119353C1 (en) |
| TW (1) | TW438798B (en) |
| WO (1) | WO1994007488A1 (en) |
| ZA (1) | ZA937405B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2076106B1 (en) * | 1993-08-26 | 1996-06-16 | Pfizer | PHARMACEUTICAL COMPOSITIONS BASED ON 2-OXINDOL-1-CARBOXAMIDES 3-SUBSTITUTED |
| WO1995031979A1 (en) * | 1994-05-19 | 1995-11-30 | R.P. Scherer International Corporation | Solutions of aryl or heteroaryl substituted alkanoic acids in lipophilic solvents and soft gelatin capsules containing such solutions |
| RU2109510C1 (en) * | 1995-04-24 | 1998-04-27 | Пфайзер Инк. | Method of inhibition, tablet and capsule |
| WO1998029136A1 (en) * | 1996-12-27 | 1998-07-09 | Takeda Chemical Industries, Ltd. | Stabilized tricyclic compound |
| JP5869764B2 (en) * | 2011-01-07 | 2016-02-24 | 中日本カプセル 株式会社 | Capsule filling composition |
| CA3157812C (en) * | 2019-10-25 | 2024-10-22 | Cardiol Therapeutics Inc. | Cannabidiol compositions for use in treating heart conditions |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4556672A (en) * | 1984-03-19 | 1985-12-03 | Pfizer Inc. | 3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents |
| WO1988005656A1 (en) * | 1987-02-02 | 1988-08-11 | Pfizer Inc. | Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide |
| US5047554A (en) * | 1989-04-18 | 1991-09-10 | Pfizer Inc. | 3-substituted-2-oxindole derivatives |
| ES2082196T3 (en) * | 1990-03-02 | 1996-03-16 | Shiseido Co Ltd | OIL EMULSION COMPOSITION IN WATER CONTAINING A NON-STEROID ANTIGLOGISTIC ANALGESIC. |
| US5008283A (en) * | 1990-03-19 | 1991-04-16 | Pfizer Inc. | Use of tenidap to inhibit activation of collagenase and to inhibit the activity of myeloperoxidase |
| WO1993013758A1 (en) * | 1992-01-13 | 1993-07-22 | Pfizer Inc. | Preparation of tablets of increased strength |
-
1993
- 1993-08-17 TW TW082106612A patent/TW438798B/en active
- 1993-09-02 CZ CZ95878A patent/CZ282702B6/en unknown
- 1993-09-02 RU RU95111378A patent/RU2119353C1/en active
- 1993-09-02 PL PL93308307A patent/PL174170B1/en unknown
- 1993-09-02 KR KR1019950701320A patent/KR950703338A/en not_active Ceased
- 1993-09-02 BR BR9307182A patent/BR9307182A/en not_active Application Discontinuation
- 1993-09-02 JP JP6509043A patent/JP2721042B2/en not_active Expired - Lifetime
- 1993-09-02 WO PCT/US1993/008063 patent/WO1994007488A1/en not_active Ceased
- 1993-09-02 CA CA002146448A patent/CA2146448A1/en not_active Abandoned
- 1993-09-02 AU AU48392/93A patent/AU676200B2/en not_active Ceased
- 1993-09-02 EP EP93921210A patent/EP0662831A1/en not_active Withdrawn
- 1993-09-02 NZ NZ256164A patent/NZ256164A/en unknown
- 1993-09-27 IL IL10712293A patent/IL107122A/en not_active IP Right Cessation
- 1993-10-04 EG EG64393A patent/EG20289A/en active
- 1993-10-05 MY MYPI93002026A patent/MY109680A/en unknown
- 1993-10-06 ZA ZA937405A patent/ZA937405B/en unknown
- 1993-10-06 CN CN93118904A patent/CN1089138A/en active Pending
- 1993-10-06 HU HU9302821A patent/HUT68533A/en unknown
- 1993-10-06 MX MX9306222A patent/MX9306222A/en unknown
- 1993-10-06 FI FI934387A patent/FI934387L/en not_active Application Discontinuation
-
1995
- 1995-04-06 NO NO951350A patent/NO951350L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ256164A (en) | 1997-03-24 |
| ZA937405B (en) | 1995-04-06 |
| JPH07507809A (en) | 1995-08-31 |
| AU4839293A (en) | 1994-04-26 |
| EP0662831A1 (en) | 1995-07-19 |
| CZ282702B6 (en) | 1997-09-17 |
| FI934387A7 (en) | 1994-04-08 |
| PL174170B1 (en) | 1998-06-30 |
| KR950703338A (en) | 1995-09-20 |
| TW438798B (en) | 2001-06-07 |
| NO951350L (en) | 1995-06-06 |
| FI934387A0 (en) | 1993-10-06 |
| AU676200B2 (en) | 1997-03-06 |
| RU2119353C1 (en) | 1998-09-27 |
| FI934387L (en) | 1994-04-08 |
| WO1994007488A1 (en) | 1994-04-14 |
| CN1089138A (en) | 1994-07-13 |
| HU9302821D0 (en) | 1993-12-28 |
| MY109680A (en) | 1997-04-30 |
| NO951350D0 (en) | 1995-04-06 |
| JP2721042B2 (en) | 1998-03-04 |
| IL107122A0 (en) | 1993-12-28 |
| PL308307A1 (en) | 1995-07-24 |
| MX9306222A (en) | 1994-04-29 |
| CZ87895A3 (en) | 1995-10-18 |
| HUT68533A (en) | 1995-04-27 |
| EG20289A (en) | 1998-07-30 |
| BR9307182A (en) | 1999-03-30 |
| CA2146448A1 (en) | 1994-04-14 |
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