CA2176460C - Method for dry blend compression of medicaments - Google Patents
Method for dry blend compression of medicaments Download PDFInfo
- Publication number
- CA2176460C CA2176460C CA002176460A CA2176460A CA2176460C CA 2176460 C CA2176460 C CA 2176460C CA 002176460 A CA002176460 A CA 002176460A CA 2176460 A CA2176460 A CA 2176460A CA 2176460 C CA2176460 C CA 2176460C
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- Canada
- Prior art keywords
- group
- composition
- excipient
- estrogen
- agglomerated
- 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
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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
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Disclosed is a method of dry blend compression of potent drugs with low solubility, such as steroidal medicaments using directly compressible agglomerated excipients that are not a conventional or spray dried polyalcohol or lactose. The agglomerated excipients include mannitol, maltodextrin or corn syrup solids which hold the medicaments (s) in the crevices of the agglomerates. Also disclosed are the critical ratios of the agglomerated excipients to steroidal agent, specifically estradiol, that is distributed uniformly throughout the dry blend and then compressed into tablets.
Description
Description Method for Dry Blend Compression of Medicaments Technical Field This invention relates to a method of dry blend compression of insoluble potent drug substances using a directly compressible, agglomerated excipient that is not a conventional spray dried polyalcohol or lactose.
Backgrround Art Inadequate distribution of low-dose potent drugs is a constant threat to the uniform potency of tablets and capsules containing such drugs.
The greatest potential for drug-diluent segregation in a tablet system occurs with powder or particulate mixtures intended for direct compression or wet granulation in which the drug migration occurs (Dale E. Former et. al., Pharmaceutical Dosage Forms: Tablets, Volume 2, pp. 253.).
European Patent No. 0503521 B1, AKZO N.V. p. 6 describes the inadequate homogeneity encountered with compositions containing hydrous lactose DT (U. S. Patent 4,544,554 etc. issued to Samuel A. Pasquale). The migration of a low-dose potent drug disrupts the distribution throughout the mix, giving rise to inconsistency in the content uniformity of the dosage form.
U.S. Patent No. 3,568,828 issued to Leonard Joseph Lerner describes wet processes using potent drug substances such as estrogens with organic solvents such as chloroform.
Such processes are now regarded as environmentally unsafe and can incur considerable manufacturing expenses, in that appropriate solvent scrubbing and/or explosion proof equipment must be acquired at substantial capital expenditure.
Estradiol and a number of other low-dose potent drugs precipitate in a variety of polymorphs and/or crystal habits.
The changes in the crystal structure on drying can affect the bioavailability of the drug. It is well known in the WO 95/17169 a 217 6 4 6 0 pCT/US94/14639 literature that the micronized form is more bioavailable than larger drug particle size. This invention offers an important alternative to wet granulation, thus eliminating recrystallization and the issue of polymorphism and bioavailability. It also offers the choice of dry mixing or direct compression with materials other than the conventional spray dried polyalcohols or lactoses.
Disclosure the Invention The following describes the use of low dose medicinal agents such as micronized steroidal medicinal agents;
estradiol, equilin, estrone, spironolactone, and non-micronized materials; such as, estropipate, conjugated estrogens, esterified estrogens, progestins or other medicinal agents having the structure which includes the cyclopentanoperhydrophenanthrene ring system which agents are formulated by a drug pharmaceutical preparation. The dry preparation makes use of excipients that have been prepared by agglomeration methods other than by spray drying. Such excipients include granular mannitol, agglomerated maltodextrin, corn syrup solids and mixtures of these agents with added conventional direct compression excipients.
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 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, conjugated estrogens, 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.
SLJ~STITUTf SHEET (RULE 2fi) WO 95117169 ~ ~ ~ n' ..'' PCT/US94/14639 The progestins are 3-ketodesogestrel, desogestrel, levo-desogestrel, norgestrel, gestodene, 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 HCL, alprazolam.
The agglomerated excipients used in this method are those listed above. These are differentiated from those used in the AKZO method of reference in not having the AKZO
prescribed affinity-demixing range of properties of active ingredient to dry excipient. The latter property gives the method of this invention a commercial advantage in manufacturing procedure.
Studies comparing the properties of the AKZO
preferred excipient (spray dried lactose) with applicant's lead species (agglomerated mannitol) demonstrated that the former retained 2 to 3 times the quantity of estradiol on its surface than did the claimed ingredient. The tablet of this invention, however, gave good drug distribution figures despite not having the high affinity AKZO states to be necessary.
Also, photomicrographs of the samples demonstrated that the AKZO mix had drug uniformly attached to all the surfaces of the excipient. In contrast, the mix of this invention had drug located in crevices of the agglomerate.
This indicates a different mechanism of attachment.
The method of this invention, therefore, comprises mixing one or more low-dose medicaments with the agglomerated excipient, usually in a ratio of from about 1:40 to 1:100, medicament to excipient. Other excipients, ' disintegrating agents or lubricants are optionally added.
After dry mixing, the mix is compressed into tablets.
The following examples illustrate the method of this invention in more detail.
~BSTITUFE S#if ET (RtkE 2f'~3 Example I
ESTRAD10L 2 mg TABLETS
Materials A (%) B (%) C (%) Microcrystalline Cellulose TM
(Avicel PHI 02) 45.89 23.20 Starch 1500 - 20.00 20.00 Dibasic Calcium Phosphate (Cal-StarTM) - - 23.20 Agglomerated Mannitol 47.39 50.08 50.08 Croscarmellose Sodium (Ac-Di-SolTM ) 5. 00 5. 00 5.00 Magnesium Stearate 0.50 0.50 0.50 Estradiol 1.22 1.22 1.22 1. Screen estradiol and mannitol together through a #20 mesh screen into a slant-cone high speed mixer.
2. Screen Avicel PH 102 and Ac-Di-Sol through the screen and force any remaining estradiol through as well.
3. Blend for fourteen (14) minutes with the agitator bar off, two (2) minutes with the agitator bar on, and blend fourteen (14) minutes with the agitator bar off (total of thirty (30) minutes).
4. Add the magnesium stearate and blend for three (3) minutes with the agitator bar off.
Backgrround Art Inadequate distribution of low-dose potent drugs is a constant threat to the uniform potency of tablets and capsules containing such drugs.
The greatest potential for drug-diluent segregation in a tablet system occurs with powder or particulate mixtures intended for direct compression or wet granulation in which the drug migration occurs (Dale E. Former et. al., Pharmaceutical Dosage Forms: Tablets, Volume 2, pp. 253.).
European Patent No. 0503521 B1, AKZO N.V. p. 6 describes the inadequate homogeneity encountered with compositions containing hydrous lactose DT (U. S. Patent 4,544,554 etc. issued to Samuel A. Pasquale). The migration of a low-dose potent drug disrupts the distribution throughout the mix, giving rise to inconsistency in the content uniformity of the dosage form.
U.S. Patent No. 3,568,828 issued to Leonard Joseph Lerner describes wet processes using potent drug substances such as estrogens with organic solvents such as chloroform.
Such processes are now regarded as environmentally unsafe and can incur considerable manufacturing expenses, in that appropriate solvent scrubbing and/or explosion proof equipment must be acquired at substantial capital expenditure.
Estradiol and a number of other low-dose potent drugs precipitate in a variety of polymorphs and/or crystal habits.
The changes in the crystal structure on drying can affect the bioavailability of the drug. It is well known in the WO 95/17169 a 217 6 4 6 0 pCT/US94/14639 literature that the micronized form is more bioavailable than larger drug particle size. This invention offers an important alternative to wet granulation, thus eliminating recrystallization and the issue of polymorphism and bioavailability. It also offers the choice of dry mixing or direct compression with materials other than the conventional spray dried polyalcohols or lactoses.
Disclosure the Invention The following describes the use of low dose medicinal agents such as micronized steroidal medicinal agents;
estradiol, equilin, estrone, spironolactone, and non-micronized materials; such as, estropipate, conjugated estrogens, esterified estrogens, progestins or other medicinal agents having the structure which includes the cyclopentanoperhydrophenanthrene ring system which agents are formulated by a drug pharmaceutical preparation. The dry preparation makes use of excipients that have been prepared by agglomeration methods other than by spray drying. Such excipients include granular mannitol, agglomerated maltodextrin, corn syrup solids and mixtures of these agents with added conventional direct compression excipients.
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 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, conjugated estrogens, 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.
SLJ~STITUTf SHEET (RULE 2fi) WO 95117169 ~ ~ ~ n' ..'' PCT/US94/14639 The progestins are 3-ketodesogestrel, desogestrel, levo-desogestrel, norgestrel, gestodene, 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 HCL, alprazolam.
The agglomerated excipients used in this method are those listed above. These are differentiated from those used in the AKZO method of reference in not having the AKZO
prescribed affinity-demixing range of properties of active ingredient to dry excipient. The latter property gives the method of this invention a commercial advantage in manufacturing procedure.
Studies comparing the properties of the AKZO
preferred excipient (spray dried lactose) with applicant's lead species (agglomerated mannitol) demonstrated that the former retained 2 to 3 times the quantity of estradiol on its surface than did the claimed ingredient. The tablet of this invention, however, gave good drug distribution figures despite not having the high affinity AKZO states to be necessary.
Also, photomicrographs of the samples demonstrated that the AKZO mix had drug uniformly attached to all the surfaces of the excipient. In contrast, the mix of this invention had drug located in crevices of the agglomerate.
This indicates a different mechanism of attachment.
The method of this invention, therefore, comprises mixing one or more low-dose medicaments with the agglomerated excipient, usually in a ratio of from about 1:40 to 1:100, medicament to excipient. Other excipients, ' disintegrating agents or lubricants are optionally added.
After dry mixing, the mix is compressed into tablets.
The following examples illustrate the method of this invention in more detail.
~BSTITUFE S#if ET (RtkE 2f'~3 Example I
ESTRAD10L 2 mg TABLETS
Materials A (%) B (%) C (%) Microcrystalline Cellulose TM
(Avicel PHI 02) 45.89 23.20 Starch 1500 - 20.00 20.00 Dibasic Calcium Phosphate (Cal-StarTM) - - 23.20 Agglomerated Mannitol 47.39 50.08 50.08 Croscarmellose Sodium (Ac-Di-SolTM ) 5. 00 5. 00 5.00 Magnesium Stearate 0.50 0.50 0.50 Estradiol 1.22 1.22 1.22 1. Screen estradiol and mannitol together through a #20 mesh screen into a slant-cone high speed mixer.
2. Screen Avicel PH 102 and Ac-Di-Sol through the screen and force any remaining estradiol through as well.
3. Blend for fourteen (14) minutes with the agitator bar off, two (2) minutes with the agitator bar on, and blend fourteen (14) minutes with the agitator bar off (total of thirty (30) minutes).
4. Add the magnesium stearate and blend for three (3) minutes with the agitator bar off.
5. Compress into tablets on a high speed tablet press.
Tablet weight of 1 64 ~ 3%.
Other illustrations are:
1. Using the process of example 1 with agglomerated maltodextrin blended with estradiol and a progestin.
2. Using the process of example 1 with a combination of agglomerated mannitol and maltodextrin blended with an estrogen or a progestin or a combination of estrogen and progestin.
WO 95/17169 _ PCT/US94/14639 ~~ ~ w6F~~~ ~
3. Using the process of example 1 with a combination of agglomerated mannitol and maltodextrin blended with conjugated estrogens alone or in combination with a progestin.
SUBSTITUTE SHEET (RULE 26)
Tablet weight of 1 64 ~ 3%.
Other illustrations are:
1. Using the process of example 1 with agglomerated maltodextrin blended with estradiol and a progestin.
2. Using the process of example 1 with a combination of agglomerated mannitol and maltodextrin blended with an estrogen or a progestin or a combination of estrogen and progestin.
WO 95/17169 _ PCT/US94/14639 ~~ ~ w6F~~~ ~
3. Using the process of example 1 with a combination of agglomerated mannitol and maltodextrin blended with conjugated estrogens alone or in combination with a progestin.
SUBSTITUTE SHEET (RULE 26)
Claims (13)
1. A method of making pharmaceutical tablets comprising the steps of:
blending a unit dosage quantity of one or more low dosage medicaments with an agglomerated excipient in a ratio of from 1:40 to 1:100 of medicament to excipient, wherein the medicament is selected from the group consisting of estrogens and progestins, and the excipient is selected from the group consisting of mannitol, maltodextrin, corn syrup solid, and mixtures thereof;
adding optional tabletting aids selected from the group consisting of one or more tabletting fillers, disintegrating agents and lubricants; and compressing the blended mixture.
blending a unit dosage quantity of one or more low dosage medicaments with an agglomerated excipient in a ratio of from 1:40 to 1:100 of medicament to excipient, wherein the medicament is selected from the group consisting of estrogens and progestins, and the excipient is selected from the group consisting of mannitol, maltodextrin, corn syrup solid, and mixtures thereof;
adding optional tabletting aids selected from the group consisting of one or more tabletting fillers, disintegrating agents and lubricants; and compressing the blended mixture.
2. The method of claim of 1 wherein the estrogen is estradiol.
3. The method of claim 1 wherein the estrogen is a conjugated estrogen.
4. The method of claim 1 wherein the progestin is selected from the group consisting of 3-ketodesogestrel, desogestrel, levodesogestrel, norgestrel, gestodene, norethindrone, and norethindrone acetate.
5. The method of any of claims 1 to 4, wherein the excipient is selected from the group consisting of mannitol, maltodextrin and a combination thereof.
6. A pharmaceutical composition comprising one or more low dosage medicaments and an agglomerated excipient in a ratio from about 1:40 to about 1:100 of medicament to excipient, wherein the agglomerated excipient is selected from the group consisting of mannitol, maltodextrin, corn syrup solid, and mixtures thereof and one or more optional excipients, disintegrating agents, or lubricants.
7. The composition of claim 6 wherein said medicament is selected from the group consisting of an estrogen and a progestin.
8. The composition of claim 7 wherein said estrogen is estradiol.
9. The composition of claim 7 wherein said estrogen is a conjugated estrogen.
10. The composition of claim 7 wherein the progestin is selected from the group consisting of 3-ketodesogestrel, desogestrel, levodesogestrel, norgestrel, gestodene, norethindrone, and norethindrone acetate.
11. The composition of claim 9 wherein said progestin is medroxyprogesterone acetate.
12. The composition of any one of claims 6 or 7 wherein the excipient is selected from the group consisting of mannitol, maltodextrin, and a combination thereof.
13. The composition of any one of claims 6 or 7 wherein said composition is in the form of a tablet.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA93/9566 | 1993-12-21 | ||
| ZA939566A ZA939566B (en) | 1993-12-21 | 1993-12-21 | Method for dry blend compression od medicaments. |
| PCT/US1994/014639 WO1995017169A1 (en) | 1993-12-21 | 1994-12-20 | Method for dry blend compression of medicaments |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2176460A1 CA2176460A1 (en) | 1995-06-29 |
| CA2176460C true CA2176460C (en) | 2007-03-13 |
Family
ID=38007968
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002176460A Expired - Lifetime CA2176460C (en) | 1993-12-21 | 1994-12-20 | Method for dry blend compression of medicaments |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2176460C (en) |
-
1994
- 1994-12-20 CA CA002176460A patent/CA2176460C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2176460A1 (en) | 1995-06-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20141222 |