CA2176461C - Method for preparing low dose pharmaceutical products - Google Patents
Method for preparing low dose pharmaceutical products Download PDFInfo
- Publication number
- CA2176461C CA2176461C CA002176461A CA2176461A CA2176461C CA 2176461 C CA2176461 C CA 2176461C CA 002176461 A CA002176461 A CA 002176461A CA 2176461 A CA2176461 A CA 2176461A CA 2176461 C CA2176461 C CA 2176461C
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- CA
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- Prior art keywords
- composition
- surfactant
- pharmaceutically acceptable
- aqueous medium
- granulation
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
Abstract
Disclosed is a wet method for preparing solid pharmaceutical composition for oral administration of low-dose medications whose active ingredients have steroidal or steroid-like structures. The method sus pends medicaments with low solubility in an aqueous bind er solution with a trace amount of amount. The aqueous suspension is then blend ed with fillers and granulated. The dried granules can b e made into capsules, tablets, lozenges, troches, sustained or delayed release products or suspensions.
Description
WO 95/17168 ' ' PGT/US94/14638 METHOD FOR PREPARING IOW DOSE PHARMACEUTICAL PRODUCTS
This invention relates to a new method for preparing solid pharmaceutical compositions for oral administration of low-dose medications whose active ingredients have steroidal or steroid-like structures.
BACKGROUND OF THE INVENTION
The pharmaceutical art recognizes that, when highly active medicaments are prepared in pharmaceutical form for administration to subjects in need of therapy, the even distribution of active ingredient throughout the carrier is important for insuring a proper dosage and no toxic effects due to hot spots of drug. The problem is especially applicable to low dose steroidal compounds; for example, estrogens, progestins, digitalis, spironolactone. These are known to migrate through the carrier upon drying.
The prior art of low dose pharmaceutical formulation is illustrated in the literature for estrogen (e. g., estradiol). Much of the prior art comprises broad disclosures of standard preparative methods; for example, Pasquale, U.S. Patent No. 4,544,554, etc., or Lerner, U.S.
Patent No. 3,568,828, with no mention of the problem of non-uniform distribution. The latter reference describes the preparation of low dose drugs using conventional wet granulating methods with organic solvents such as chloroform.
DeEaan (Akzo), European Patent Application No. 0503521 , discusses the problem of uneven distribution of low dose medicaments in solid pharmaceutical dose units.
This, as stated above, may be due in part to migration of the medicament. DeHaan further states that liquid granulation methods for preparing solid dosage units of low dose medicaments are also not acceptable because of the cost and environmental handicaps of the organic solvents which are unacceptable for this use.
DeHaan suggests an alternative method of manufacture which uses the compression of a dry solid mix containing an SiJBSTITUTE SHEET (RULE 26}
WO 95/17168 (, CA 02176461 2004-08-11 PCTIU S94/14638 excipient having a prescribed binding-demixing ratio of the medicament to excipient.
There remains a need in the art for other methods of preparing solid dosage forms, mainly tablets of low-dosage medicaments, which can be adapted by manufacturing pharmaceutical companies to available equipment.
SUGARY OF THE INVENTION
This invention relates to a method for preparing solid pharmaceutical dosage units containing low dose active ingredients using a wet. granulation technique which employs aqueous solvents and applicable surfactants.
DETAILED DESCRIPTION OF THE INVENTION
This method utilizes an aqueous medium Which contains the active ingredient or ingredients, a quantity of one or more surfactants sufficient to dissolve or suspend said active ingredients uniformly throughout the medium and other manufacturing additives as known to the art. The latter include granulating-binding agents such as gelatin; natural gums, such as acacia, tragacanth; starches, sodium alginate, sugars, polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethylcellulose, polyvinyloxoazolidones;
pharmaceutical fillers such as lactose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, calcium sulfate, dextrose, mannitol, sucrose; tabletting lubricants if needed such as calcium and magnesium stearate, stearic acid, talc, steroteX (alkaline stearate).
The components are granulated, the resulting granules are dried, sieved and compressed into tablets or filled into capsules. Other oral product forms may be similarly prepared by art methods such as chewable tablets, lozenges, troches, sustained or delayed release products or suspensions.
The active ingredients comprise any medicament which has a low effective dose such as those below 10 mg per dosage unit. Most useful are those medicaments having a steroidal nucleus, the cyclopentanoperhydrophenanthrene ring system, in * denotes trade mark sIJBSTITUTE SHEET (RULE Z6~
_ CA 02176461 2004-08-11 WO 95/17168 ~. . ( PGTlUS94/14638 their chemical structures such as the estrogens or progestins.
Examples of the former are ethinylestradiol, estrone, mestranol, 17-alpha-ethinyl estradiol-3-methylether esterified estrogens, and, especially estradiol, methyl testosterone. The dosage amounts and indications of these and other active ingredients are those described in the literature such as the Physician's Desk Reference (PDR 56 EDITION 2002).
The progestins are 3-ketodesogestrel, desogestrel, levo-desogestrel, norgestrel, gestodene, mestranol, norethindrone, norethindrone acetate.
Other medications known to the art which are used in low doses are spironolactone, digoxin, glipizide, estazolam, clorazepate dipotassium, albuterol sulfate, clonidine HCZ, alprazolam.
The term "aqueous medium" for the second ingredient of this invention is used within the custom of the pharmaceutical art. Primarily, it connotes a water medium, with added water-miscible solvents such as isopropanol or ethanol when needed, to support the active ingredient or pharmaceutical aids.
The third ingredient of the critical step of this invention is a surfactant acceptable in pharmaceutical manufacturing practice and selected from the three categories of surfactants: cationic, anionic and non-ionic compounds.
Exemplary of useful surfactants are sodium lauryl sulfate, sorbitan monolaurate, sorbitan monostearate,'polysorbate 80, polysorbate 60, poloxamer 407, poloxamer 188 (polyoxethylene, polyoxypropylene block polymers), polyoxyl 20 cetostearyl ether, dioctyl sodium sulfosuccinate, dioctyl calcium sulfosuccinate, nonoxynol, benzalkonium chloride, sorbitan monooleate.
The quantity of surfactant in the granulating mixture is enough to be non-toxic and to support the steroidal active ingredient in solution or suspension. Usually, this means very small, almost catalytic, quantities, such as less than glJBSTTfLITE SHEET (RUt.E 26~
WO 95/17168 ~ ! ~ ~ PCT/US94/14638 0.01% by weight. Applicant has devised a simple test procedure for determining the applicability of a selected surfactant for this process. Details are presented below.
Other pharmaceutically acceptable additives are used in the first step granulation but are not considered critical to this invention. These include binding-granulating agents such as polyacrylamides, polyvinyloxoazolidones, sucrose, and sodium carboxymethylcellulose; fillers such as lactose, talc, cellulosics, dibasic calcium phosphate, starches;
disintegrants if a tablet or capsule is formed, such as croscarmellose sodium, starch, sodium carboxymethyl starch;
veegum, ion exchange resins (amberlite), sodium bicarbonate;
or lubricants for tablet compression such as polyethylene glycol 4000 and 5000, hydrogenated vegetable oils, light mineral oil.
The practice of this invention depends on the novelty and practical benefits of using a low dose medicament, a pharmaceutically acceptable quantity of surfactant and an aqueous medium. The preferred ingredients are estradiol, sodium lauryl sulfate and water from a povidone solution.
The final product form is a tablet containing 2.00 mg of medicament per tablet. The therapeutic utility is demonstrated by oral administration of such a dosage unit from 1-5 times daily to a subject in need of treatment, for example for menopausal abnormalities.
In practice, the estradiol is suspended in a 1%
povidone solution containing a trace (0.005%) of surfactant.
The aqueous suspension is blended with fillers and granulated in a granulating vessel. The granulation is dried, screened and blended with fillers, disintegrants and lubricants. The granulation is then compressed into tablets.
Alternatively, the dried granules may be filled into a capsule. Where extended or delayed release of the low dose medicament is desired the granules or capsule may be coated as known to the art.
* denotes trade mark gtJBSTITUTE SHEET (RULE 26~
WO 95/17168 ~ ~j, .. PGT/US94/14638 The following examples are designed to teach the operation of this invention.
Example 1 ESTRADIOL 2 mg TABLETS
Formula Materials Percent MgjTablet Microcrystalline Cellulose 20.00 32.80 (Avicel''-PH102), NF
Lactose 316 (Fast Flo), NF 51.94 85.18 Dibasic Calcium Phosphate 23.70 38.87 Cal-Star ) ; ' USP
Colloidal Silicone Dioxide 1.00 1.64 (Cab-o-sil); NF
Croscarmellose Sodium 1.00 1.64 ( Ac-Di-Sol ) ; ! NF
Magnesium Stearate 1.00 1.64 Povidone K92-32, NF 0.14 0.23 Sodium Lauryl Sulfate, NF 0.0003 Trace (Trace) Estradiol, USP 1.22 2.00 Procedure 1. Suspend the estradiol in a 1% povidone solution in which 0.005% sodium lauryl sulfate has been dispersed.
2. Blend the Cal-Star and lactose until homogeneous.
3. Granulate the blend from Step 2 with the suspension of estradiol in povidone solution from Step 1.
4. Dry the above granulation.
This invention relates to a new method for preparing solid pharmaceutical compositions for oral administration of low-dose medications whose active ingredients have steroidal or steroid-like structures.
BACKGROUND OF THE INVENTION
The pharmaceutical art recognizes that, when highly active medicaments are prepared in pharmaceutical form for administration to subjects in need of therapy, the even distribution of active ingredient throughout the carrier is important for insuring a proper dosage and no toxic effects due to hot spots of drug. The problem is especially applicable to low dose steroidal compounds; for example, estrogens, progestins, digitalis, spironolactone. These are known to migrate through the carrier upon drying.
The prior art of low dose pharmaceutical formulation is illustrated in the literature for estrogen (e. g., estradiol). Much of the prior art comprises broad disclosures of standard preparative methods; for example, Pasquale, U.S. Patent No. 4,544,554, etc., or Lerner, U.S.
Patent No. 3,568,828, with no mention of the problem of non-uniform distribution. The latter reference describes the preparation of low dose drugs using conventional wet granulating methods with organic solvents such as chloroform.
DeEaan (Akzo), European Patent Application No. 0503521 , discusses the problem of uneven distribution of low dose medicaments in solid pharmaceutical dose units.
This, as stated above, may be due in part to migration of the medicament. DeHaan further states that liquid granulation methods for preparing solid dosage units of low dose medicaments are also not acceptable because of the cost and environmental handicaps of the organic solvents which are unacceptable for this use.
DeHaan suggests an alternative method of manufacture which uses the compression of a dry solid mix containing an SiJBSTITUTE SHEET (RULE 26}
WO 95/17168 (, CA 02176461 2004-08-11 PCTIU S94/14638 excipient having a prescribed binding-demixing ratio of the medicament to excipient.
There remains a need in the art for other methods of preparing solid dosage forms, mainly tablets of low-dosage medicaments, which can be adapted by manufacturing pharmaceutical companies to available equipment.
SUGARY OF THE INVENTION
This invention relates to a method for preparing solid pharmaceutical dosage units containing low dose active ingredients using a wet. granulation technique which employs aqueous solvents and applicable surfactants.
DETAILED DESCRIPTION OF THE INVENTION
This method utilizes an aqueous medium Which contains the active ingredient or ingredients, a quantity of one or more surfactants sufficient to dissolve or suspend said active ingredients uniformly throughout the medium and other manufacturing additives as known to the art. The latter include granulating-binding agents such as gelatin; natural gums, such as acacia, tragacanth; starches, sodium alginate, sugars, polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethylcellulose, polyvinyloxoazolidones;
pharmaceutical fillers such as lactose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, calcium sulfate, dextrose, mannitol, sucrose; tabletting lubricants if needed such as calcium and magnesium stearate, stearic acid, talc, steroteX (alkaline stearate).
The components are granulated, the resulting granules are dried, sieved and compressed into tablets or filled into capsules. Other oral product forms may be similarly prepared by art methods such as chewable tablets, lozenges, troches, sustained or delayed release products or suspensions.
The active ingredients comprise any medicament which has a low effective dose such as those below 10 mg per dosage unit. Most useful are those medicaments having a steroidal nucleus, the cyclopentanoperhydrophenanthrene ring system, in * denotes trade mark sIJBSTITUTE SHEET (RULE Z6~
_ CA 02176461 2004-08-11 WO 95/17168 ~. . ( PGTlUS94/14638 their chemical structures such as the estrogens or progestins.
Examples of the former are ethinylestradiol, estrone, mestranol, 17-alpha-ethinyl estradiol-3-methylether esterified estrogens, and, especially estradiol, methyl testosterone. The dosage amounts and indications of these and other active ingredients are those described in the literature such as the Physician's Desk Reference (PDR 56 EDITION 2002).
The progestins are 3-ketodesogestrel, desogestrel, levo-desogestrel, norgestrel, gestodene, mestranol, norethindrone, norethindrone acetate.
Other medications known to the art which are used in low doses are spironolactone, digoxin, glipizide, estazolam, clorazepate dipotassium, albuterol sulfate, clonidine HCZ, alprazolam.
The term "aqueous medium" for the second ingredient of this invention is used within the custom of the pharmaceutical art. Primarily, it connotes a water medium, with added water-miscible solvents such as isopropanol or ethanol when needed, to support the active ingredient or pharmaceutical aids.
The third ingredient of the critical step of this invention is a surfactant acceptable in pharmaceutical manufacturing practice and selected from the three categories of surfactants: cationic, anionic and non-ionic compounds.
Exemplary of useful surfactants are sodium lauryl sulfate, sorbitan monolaurate, sorbitan monostearate,'polysorbate 80, polysorbate 60, poloxamer 407, poloxamer 188 (polyoxethylene, polyoxypropylene block polymers), polyoxyl 20 cetostearyl ether, dioctyl sodium sulfosuccinate, dioctyl calcium sulfosuccinate, nonoxynol, benzalkonium chloride, sorbitan monooleate.
The quantity of surfactant in the granulating mixture is enough to be non-toxic and to support the steroidal active ingredient in solution or suspension. Usually, this means very small, almost catalytic, quantities, such as less than glJBSTTfLITE SHEET (RUt.E 26~
WO 95/17168 ~ ! ~ ~ PCT/US94/14638 0.01% by weight. Applicant has devised a simple test procedure for determining the applicability of a selected surfactant for this process. Details are presented below.
Other pharmaceutically acceptable additives are used in the first step granulation but are not considered critical to this invention. These include binding-granulating agents such as polyacrylamides, polyvinyloxoazolidones, sucrose, and sodium carboxymethylcellulose; fillers such as lactose, talc, cellulosics, dibasic calcium phosphate, starches;
disintegrants if a tablet or capsule is formed, such as croscarmellose sodium, starch, sodium carboxymethyl starch;
veegum, ion exchange resins (amberlite), sodium bicarbonate;
or lubricants for tablet compression such as polyethylene glycol 4000 and 5000, hydrogenated vegetable oils, light mineral oil.
The practice of this invention depends on the novelty and practical benefits of using a low dose medicament, a pharmaceutically acceptable quantity of surfactant and an aqueous medium. The preferred ingredients are estradiol, sodium lauryl sulfate and water from a povidone solution.
The final product form is a tablet containing 2.00 mg of medicament per tablet. The therapeutic utility is demonstrated by oral administration of such a dosage unit from 1-5 times daily to a subject in need of treatment, for example for menopausal abnormalities.
In practice, the estradiol is suspended in a 1%
povidone solution containing a trace (0.005%) of surfactant.
The aqueous suspension is blended with fillers and granulated in a granulating vessel. The granulation is dried, screened and blended with fillers, disintegrants and lubricants. The granulation is then compressed into tablets.
Alternatively, the dried granules may be filled into a capsule. Where extended or delayed release of the low dose medicament is desired the granules or capsule may be coated as known to the art.
* denotes trade mark gtJBSTITUTE SHEET (RULE 26~
WO 95/17168 ~ ~j, .. PGT/US94/14638 The following examples are designed to teach the operation of this invention.
Example 1 ESTRADIOL 2 mg TABLETS
Formula Materials Percent MgjTablet Microcrystalline Cellulose 20.00 32.80 (Avicel''-PH102), NF
Lactose 316 (Fast Flo), NF 51.94 85.18 Dibasic Calcium Phosphate 23.70 38.87 Cal-Star ) ; ' USP
Colloidal Silicone Dioxide 1.00 1.64 (Cab-o-sil); NF
Croscarmellose Sodium 1.00 1.64 ( Ac-Di-Sol ) ; ! NF
Magnesium Stearate 1.00 1.64 Povidone K92-32, NF 0.14 0.23 Sodium Lauryl Sulfate, NF 0.0003 Trace (Trace) Estradiol, USP 1.22 2.00 Procedure 1. Suspend the estradiol in a 1% povidone solution in which 0.005% sodium lauryl sulfate has been dispersed.
2. Blend the Cal-Star and lactose until homogeneous.
3. Granulate the blend from Step 2 with the suspension of estradiol in povidone solution from Step 1.
4. Dry the above granulation.
5. Screen and blend the dried granulation from Step 4 with the other ingredients.
6. Compress the blend from Step 5 into 164 mg tablets.
Each tablet containing 2 mg of estradiol.
* denotes trade mark SUBSnME SHEfT (RULE 26) WO 95/17168 ~ t ~~ PCT/US94/14638 Example 2 PROTOCOL FOR SCREENING SURFACTANT FOR
LOW DOSE DRUG SUSPENSIONS
I. Prepare a 1% povidone stock solution in water.
II. Prepare reference solution of 1% povidone - 0.005%
sodium lauryl sulfate (SLS).
A. Prepare a 14.3% w/w solution with the SLS solution and estradiol.~
B. Prepare a 14.3% w/w solution with the SLS solution and spironolactone.
C. Compare the estradiol solution and the spironolactone solution. If they have the same appearance, spironolactone can be used as the model drug and estradiol can be used for a check.
III. Use the stock povidone solution to prepare solutions with the other surfactants to be investigated, such as, but not limited to, dioctyl sodium sulfosuccinate, dioctyl calcium sulfosuccinate, nonoxynol, benzalkonium chloride, sorbitan monooleate.
A. Prepare 1% povidone - 1% surfactant solutions.
1. Prepare 14.3% w/w solution with the surfactant and the steroidally derived drug.
2. Compare to reference solution.
3. If the surfactant/steroidal solution conforms to the reference solution:
a. Dilute surfactant solution with 1%
povidone solution in 0.5% increments.
b. Determine the lowest concentration of surfactant that a flocculated suspension can be formed.
SUBST~TUf E SHEET (RULE 26~
Each tablet containing 2 mg of estradiol.
* denotes trade mark SUBSnME SHEfT (RULE 26) WO 95/17168 ~ t ~~ PCT/US94/14638 Example 2 PROTOCOL FOR SCREENING SURFACTANT FOR
LOW DOSE DRUG SUSPENSIONS
I. Prepare a 1% povidone stock solution in water.
II. Prepare reference solution of 1% povidone - 0.005%
sodium lauryl sulfate (SLS).
A. Prepare a 14.3% w/w solution with the SLS solution and estradiol.~
B. Prepare a 14.3% w/w solution with the SLS solution and spironolactone.
C. Compare the estradiol solution and the spironolactone solution. If they have the same appearance, spironolactone can be used as the model drug and estradiol can be used for a check.
III. Use the stock povidone solution to prepare solutions with the other surfactants to be investigated, such as, but not limited to, dioctyl sodium sulfosuccinate, dioctyl calcium sulfosuccinate, nonoxynol, benzalkonium chloride, sorbitan monooleate.
A. Prepare 1% povidone - 1% surfactant solutions.
1. Prepare 14.3% w/w solution with the surfactant and the steroidally derived drug.
2. Compare to reference solution.
3. If the surfactant/steroidal solution conforms to the reference solution:
a. Dilute surfactant solution with 1%
povidone solution in 0.5% increments.
b. Determine the lowest concentration of surfactant that a flocculated suspension can be formed.
SUBST~TUf E SHEET (RULE 26~
Claims (26)
1. A process for making oral pharmaceutical dosage units containing a therapeutic quantity of one or more low dosage medicinal agents comprising the steps of:
(a) preparing an aqueous medium comprising one or more pharmaceutically acceptable surfactants, wherein the quantity of said surfactant or surfactants is sufficient to support said medical agent in solution; and (b) granulating said one or more low dosage medicinal agents in said aqueous medium to form a granulation.
(a) preparing an aqueous medium comprising one or more pharmaceutically acceptable surfactants, wherein the quantity of said surfactant or surfactants is sufficient to support said medical agent in solution; and (b) granulating said one or more low dosage medicinal agents in said aqueous medium to form a granulation.
2. The process of claim 1 wherein one or more low dosage medicinal agent has a steroidal structure.
3. The process of claim 2 wherein said medicinal agent is an estrogen and, optionally, a progestin.
4. The process of claim 3 wherein said estrogen is estradiol or esterified estrogens.
5. The process of any one of claims 1, 2, 3, and 4 wherein the aqueous medium is water and said surfactant is sodium lauryl sulfate.
6. The process of claim 5 wherein the product form made by said process is a tablet.
7. A pharmaceutical composition comprising a therapeutic quantity of one or more low dosage medicinal agent and one or more pharmaceutically acceptable surfactant in an aqueous medium and, optionally, one or more manufacturing additives and binding-granulating agents.
8. The composition of claim 7 wherein said one or more low dosage medicinal agent has a steroidal structure.
9. The composition of claim 8 wherein said medicinal agent is an estrogen and, optionally, a progestin.
10. The composition of claim 9 wherein said estrogen is estradiol or esterified estrogens.
11. The composition of any one of claims 7 to 10 wherein the aqueous medium is water, water from a povidone solution, or water and a water-miscible solvent.
12. The composition of claim 11 wherein said composition is in the form of a tablet, lozenge, troche, or capsule.
13. The composition of claim 12 wherein said composition is in the form of a tablet.
14. The composition of claim 11 wherein said surfactant is sodium lauryl sulfate.
15. The composition of claim 13 wherein said surfactant is sodium lauryl sulfate.
16. A method for evenly distributing the active ingredient of a low dosage medicinal agent in a pharmaceutically acceptable carrier comprising:
(a) preparing an aqueous medium comprising one or more pharmaceutically acceptable surfactants, wherein the quantity of said surfactant or surfactants is sufficient to support said medicinal agent in solution; and (b) granulating said active ingredient in said aqueous medium to form a granulation.
(a) preparing an aqueous medium comprising one or more pharmaceutically acceptable surfactants, wherein the quantity of said surfactant or surfactants is sufficient to support said medicinal agent in solution; and (b) granulating said active ingredient in said aqueous medium to form a granulation.
17. A method of claim 16 wherein said medicinal agent is an estrogen and, optionally, a progestin.
18. A method of claim 17 wherein said medicinal agent is estradiol.
19. The process of claim 1, wherein said quantity of said one or more pharmaceutically acceptable surfactants is less than 0.01% by weight of said granulation.
20. The process of claim 19, wherein the quantity of said one or more pharmaceutically acceptable surfactant is not more than 0.005% by weight of said granulation.
21. The composition of claim 7 wherein said quantity of said one or more pharmaceutically acceptable surfactants is less than 0.01% by weight of the composition.
22. The composition of claim 21 wherein the quantity of said one or more pharmaceutically acceptable surfactant is not more than 0.005% by weight of the composition.
23. The process of claim 1, further comprising the step of processing said granulation into a tablet or capsule dosage unit.
24. The method of claim 16, further comprising the step of processing said granulation into a tablet or capsule dosage unit.
25. A pharmaceutical composition made by the process as claimed in any one of claims 1, 2, 3, 4, 16, 19, 20, 23 or 24.
26. A pharmaceutical composition as claimed in claim 25 wherein the aqueous medium is water and the surfactant is sodium lauryl sulfate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA939565A ZA939565B (en) | 1993-12-21 | 1993-12-21 | Method for preparing low dose pharmaceutical products. |
| ZA93/9565 | 1993-12-21 | ||
| PCT/US1994/014638 WO1995017168A1 (en) | 1993-12-21 | 1994-12-20 | Method for preparing low dose pharmaceutical products |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2176461A1 CA2176461A1 (en) | 1995-06-29 |
| CA2176461C true CA2176461C (en) | 2007-03-13 |
Family
ID=38007970
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002176461A Expired - Lifetime CA2176461C (en) | 1993-12-21 | 1994-12-20 | Method for preparing low dose pharmaceutical products |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2176461C (en) |
-
1994
- 1994-12-20 CA CA002176461A patent/CA2176461C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2176461A1 (en) | 1995-06-29 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20141222 |