WO1997004750A2 - Process for preparing solid dosage forms of very low-dose drugs - Google Patents
Process for preparing solid dosage forms of very low-dose drugs Download PDFInfo
- Publication number
- WO1997004750A2 WO1997004750A2 PCT/EP1996/003326 EP9603326W WO9704750A2 WO 1997004750 A2 WO1997004750 A2 WO 1997004750A2 EP 9603326 W EP9603326 W EP 9603326W WO 9704750 A2 WO9704750 A2 WO 9704750A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition according
- drug
- carrier
- daily dose
- pharmaceutical composition
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- 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
- 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
Definitions
- This invention relates to a method of formulating solid dosage forms of drugs and to solid dosage forms produced thereby, in particular solid dosage forms containing low dose of drug.
- the invention also relates to a method of treatment and/or prophylaxis of dementia and unit dosage forms useful therein.
- the usual challenge in manufacturing solid dosage forms of very low-dose drugs for example with active doses around 5-125 microgramme ( ⁇ g) (for example 0.004-0.1% by weight of drug to total solid), is to ensure homogeneity.
- the techmcal problem is how to distribute the drug substance evenly among the large amount of excipient particles.
- Very fine particles of the drug are first mixed with a small portion of excipient; the product then mixed with a slighty larger portion of excipient and so on until the desired mix is obtained.
- This method relies on the fine drug particles adhering electrostatically to the larger excipient ones, thus preventing segregation.
- the method works with some drugs, but success depends on the surface properties of both drug and excipient, and the method is very laborious.
- EP0503521 describes the application of this method to steroidal drugs with high binding affinity and low demixing potential for certain excipients.
- a preferred alternative method for formulating low dose drugs is known as "wet granulation".
- the drug is dissolved in water or another solvent, and blended with excipients including a binder, for example povidone, to form a wet mass containing 5-20% by weight of solution to total weight of granulation mix, which is then dried off in a separate step.
- the binder causes particles of excipient to clump together, and as the mass dries these clumps ("granules”) either contain or are coated with the drug. This is effective but cumbersome since the drying step requires special equipment, and generally involves high temperatures which may degrade labile drugs.
- the use of the binder requires the further inclusion of a disintegrant such as sodium starch glycolate or starch to help the tablet, which is cohesive, to disperse in the stomach.
- Fluid bed granulation has been used to achieve content uniformity of low dose (l ⁇ g-lOmg) tablets (Thiel et al., J. Pharm. Pharmacol. 1986, 38, 335-343).
- the micronised drug is blended as a powder with other excipients, then loaded into a fluid bed granulator, and the powders are agglomerated by spraying on a solution of a binder; drying takes place concomitantly.
- the process does not require a separate drying step, but it does require the use of micronised drug, and also incorporates a separate blending step prior to granulation. It also requires specialised equipment and precise optimisation ofthe process parameters.
- carrier granulation Another process for formulating low dose drugs is known as carrier granulation (Michoel et aL, Pharmaceutical Technology June 1988, 66-84). This functions by spraying a solution of binder such as povidone in water onto relatively large excipient particles such as hydrous lactose and then spraying small dry drug substance particles onto that, thus coating the excipient with drug particles which are stuck on by the binder.
- the quantity of solution used was 3.3-3.5% by weight of solution to total granulation mix.
- the method was applied to a formulation containing 4-5% drug by weight This method also requires drying; the drug particle size needs to be very small, which often requires an extra milling step and the very fine drug powder may not flow at all well; and the formula still requires a disintegrant
- Dahl et al., Drug Development and Industrial Pharmacy 1990, 16 (12), 1881-1891 describes the preparation of solid capsule formulations using a spray-on liquid drug carrier.
- the model drug is dissolved in a non- volatile solvent propylene carbonate, and sprayed onto a compressible sugar at a loading of around 0.01% by weight of drug to total solid, to give a final unit dose of 35 ⁇ g.
- the solvent being non-volatile remains in the blend. It is added at around 5% by weight of the total formulation; lower ratios of solvent to solid resulted in decreased ability to disintegrate and dissolve.
- the resulting, somewhat sticky, powder showed some difficulties in automated encapsulation machines, and would be likely to give significant problems in tabletting.
- Yalkowski (US4,489,026) describes a process which involves very slowly spraying a dilute solution of drug in a volatile inert solvent preferably an organic solvent having a boiling point lower than 80°C, onto excipient powder in an open coating pan; a continuous flow of air dries the product during the spraying process.
- This process was applied to drugs with a unit dose of lOug or less.
- the spray rate is limited to 1-lOml/min, making the process suitable only for very small batch-sizes (the example quoted prepared 1000 tablets).
- the weight ratio of solution to carrier used was 15%; also, the use of volatile organic liquids is now regarded as a significant hazard, requiring solvent-recovery processes and explosion-proof equipment
- Katdare (US4,898,736) describes a simplified version of this process, suitable for unit doses of 50-1000 ⁇ g; the drug, dissolved in an easily evaporated solvent such as ethanol, methanol, acetone or tetrahydrofuran, is simply blended with excipients in a ratio of 2.26% or 6.75% and then dried, followed by lubrication and tabletting.
- This process is in principle suitable for commercial scale manufacture, but does still have the problems associated with the use of volatile organic solvents.
- a drug formulation process which comprises admixing carrier particles with a solution of drug in water in a quantity of 1-3% by weight of solution to total mix.
- the resulting mixture may be formulated into suitable unit dose presentation, for example by tabletting and optionally film coating the tablets or by encapsulation.
- the separate blending step aids drying by the dilution effect that is, the residual water is distributed through a greater quantity of carrier powder, and by the longer mixing time.
- the dilution is conveniently in the range 4/1 to 40/1 carrier/concentrate by weight depending upon the processing characteristics of the carrier.
- a convenient dilution ratio for lactose monohydrate is 10/1.
- the solution/mix weight ratio is more preferably up to 2% by weight
- the optimum quantity of solution will depend upon the absorbent qualities of the carrier particles, the solubility of the drug and the characteristics of the mixing device, the quantity of solution being chosen so as to allow even distribution of drug while avoiding the need for a heated drying step.
- the mixing step is preferably carried out in a high shear mixer.
- the carrier may be any suitable soluble, directly compressible pharmaceutically acceptable excipient such as anhydrous lactose, lactose monohydrate, mannitol, or an insoluble, directly compressible pharmaceutically acceptable excipient such as microcrystalline cellulose or dicalcium phosphate, preferably a soluble excipient
- Any drug having a sufficient degree of solubility in water may be formulated by the process of the invention.
- the concentration of drug in the soluuon is dependent on the unit dose of drug required, the upper limit being dependent on the solubility ofthe drug.
- the carrier particles are evenly coated with a very thin film of drug solution. Some of the water naturally dries off during the mixing since there is normally a small airflow through the mixer; the remaining amount is so low that drying is not specifically required. If the tablets are film-coated, a degree of further drying may be obtained during the coating process.
- the process of the invention has a number of advantages: - it does not require any milling of the drug substance - there is no need for a drying step. This simplifies processing and reduces production costs; heat labile drugs do not suffer at the temperature required for drying; for drugs which are highly potent the omission of the drying step makes it easier to contain dust r improving safety for the factory worker
- Optional additives in the final mix include a disintegrant; a range of acidic or alkaline excipients to improve chemical stability of the drug in the formulation such as sodium dihydrogen citrate, preferably included in the initial mix; a lubricant such as magnesium stearate; and a glidant such as colloidal silica.
- the present invention further provides a pharmaceutical composition comprising a drug formulated in accordance with the process of the invention and the use of said composition as an active therapeutic substance.
- the invention additionally provides a pharmaceutical composition comprising a drug, obtainable by the process of the invention and the use of said composition as an active therapeutic substance.
- the process of the invention is particularly useful for formulating [R-(Z)]- ⁇ - (me ⁇ oxyimino)- ⁇ -(l-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride (compound X) with active doses around 5-125 microgramme ( ⁇ g).
- Compound X and methods for its preparation are disclosed in EP-A-0392803, WO95/31456 and WO93/17018.
- the compound enhances acetylcholine function via an action at muscarinic receptors within the central nervous system, and is therefore of potential use in the treatment and/or prophylaxis of dementia in mammals.
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and compound X at a level of up to 0.1% by weight of drug to carrier, 0% volatile organic solvent and 0% binder.
- EP-A-0392803 suggests the suitable daily dose for compound X and other compounds disclosed therein as 0.01-5mg/kg. It has been su ⁇ risingly found through administration to human patients that efficacy as a cognition enhancer may be obtained at daily doses below O.Olmg/kg more particularly 0.003mg/kg and below, for example 0.0001-0.003mg/kg, such as 0.00035-0.003mg/kg, 0.0007-0.003mg/kg, 0.0001- 0.0007mg/kg or 0.00035-0.002mg/kg.
- the present invention provides a method of treatment and/or prophylaxis of dementia, and more particularly a method of enhancing cognition in a patient, which method comprises administering to the patient compound X at a daily dose below O.Olmg/kg, more preferably 0.003mg/kg or less.
- the invention also relates to the use of compound X in the manufacture of a medicament for the treatment and/or prophylaxis of dementia at a daily dose below O.Olmg/kg, more preferably of 0.003mg/kg or less.
- the invention further relates to a pharmaceutical composition for ' the treatment and/or prophylaxis of dementia which comprises compound X at a unit dose suitable for admimstration at a daily dose below O.Olmg kg, more preferably of 0.003mg kg or less, and a pharmaceutically acceptable carrier.
- Suitable unit doses to achieve such daily doses are 5, 12.5, 25, 50 or 75 ⁇ g, administered twice daily and, in the case of 50 ⁇ g, once daily.
- Such unit doses are calculated on the basis of 50-70kg individuals.
- the invention extends to the method, use or composition defined above wherein compound X is provided in such unit doses.
- the invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising compound X of the invention and/or formulated in accordance with the process of the invention, in unit dose form selected from the range 5-125 ⁇ g per unit dose, such as 5, 12.5, 25, 50 or 75 ⁇ g per unit dose and the use of said composition as an active therapeutic substance, in pa ⁇ icular in the treatment and or prophylaxis of dementia.
- the amount of drug used in the above methods is 50, 33.6, 16.8, 8.4 and 3.3g respectively.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EA199800179A EA000740B1 (ru) | 1995-07-29 | 1996-07-29 | Способ получения твердого терапевтически активного лекарственного средства, содержащего лекарство в малых дозах, и лекарственное средство, полученное этим способом |
MX9800809A MX9800809A (es) | 1995-07-29 | 1996-07-29 | Procedimiento para preparar formas de dosis solidas de dosis muy bajas del farmaco. |
EA199901055A EA199901055A1 (ru) | 1995-07-29 | 1996-07-29 | Фармацевтическая композиция для лечения и/или профилактики деменции |
AU67384/96A AU716961B2 (en) | 1995-07-29 | 1996-07-29 | Process for preparing solid dosage forms of very low-dose drugs |
IL14957996A IL149579A0 (en) | 1995-07-29 | 1996-07-29 | Process for preparing solid dosage forms of low-dose drugs |
EP96927621A EP0841902A2 (en) | 1995-07-29 | 1996-07-29 | Process for preparing solid dosage forms of very low-dose drugs |
IL12289796A IL122897A0 (en) | 1995-07-29 | 1996-07-29 | Process for preparing solid dosage forms of very low-dose drugs |
SK110-98A SK11098A3 (en) | 1995-07-29 | 1996-07-29 | Process for preparing solid dosage forms of very low-dose drugs |
NZ315632A NZ315632A (en) | 1995-07-29 | 1996-07-29 | Process for preparing solid dosage forms of very low-dose drugs comprising admixing 1-3% by weight of carrier particles with a solution of drug in water |
JP9507243A JPH11510493A (ja) | 1995-07-29 | 1996-07-29 | 非常に低用量の薬剤の固形剤形の製造方法 |
BR9609804A BR9609804A (pt) | 1995-07-29 | 1996-07-29 | Processo para a preparação de formas farmacéuticas sólidas com drogas de dosagens muíto baixas |
APAP/P/1998/001170A AP858A (en) | 1995-07-29 | 1996-07-29 | Process for preparing solid dosage forms of very low-dose drugs. |
NO980384A NO980384L (no) | 1995-07-29 | 1998-01-28 | Fremgangsmåte for fremstilling av fastdoseformer av svært lav-dose legemidler |
BG102266A BG102266A (en) | 1995-07-29 | 1998-02-20 | Method for the preparation of solid batched forms having very low doses of the medicamentous form |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9515624.6A GB9515624D0 (en) | 1995-07-29 | 1995-07-29 | Novel process |
GB9515624.6 | 1995-07-29 | ||
GBGB9606684.0A GB9606684D0 (en) | 1996-03-29 | 1996-03-29 | Novel process |
GB9606684.0 | 1996-03-29 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09000252 A-371-Of-International | 1998-07-08 | ||
US09/759,575 Continuation US20010018074A1 (en) | 1995-07-29 | 2001-01-12 | Process for preparing solid dosage forms of very low-dose drugs |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1997004750A2 true WO1997004750A2 (en) | 1997-02-13 |
WO1997004750A3 WO1997004750A3 (en) | 1997-03-27 |
Family
ID=26307485
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1996/003326 WO1997004750A2 (en) | 1995-07-29 | 1996-07-29 | Process for preparing solid dosage forms of very low-dose drugs |
Country Status (25)
Country | Link |
---|---|
EP (1) | EP0841902A2 (ru) |
JP (1) | JPH11510493A (ru) |
KR (1) | KR19990035972A (ru) |
CN (1) | CN1196677A (ru) |
AP (1) | AP858A (ru) |
AR (1) | AR004178A1 (ru) |
AU (1) | AU716961B2 (ru) |
BG (1) | BG102266A (ru) |
BR (1) | BR9609804A (ru) |
CA (1) | CA2228048A1 (ru) |
CZ (1) | CZ24798A3 (ru) |
DZ (1) | DZ2077A1 (ru) |
EA (2) | EA000740B1 (ru) |
HU (1) | HUP9900521A3 (ru) |
IL (1) | IL122897A0 (ru) |
MA (1) | MA23953A1 (ru) |
MX (1) | MX9800809A (ru) |
NO (1) | NO980384L (ru) |
NZ (1) | NZ315632A (ru) |
OA (1) | OA10659A (ru) |
PL (1) | PL325242A1 (ru) |
SK (1) | SK11098A3 (ru) |
TR (1) | TR199800156T1 (ru) |
UY (1) | UY24297A1 (ru) |
WO (1) | WO1997004750A2 (ru) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998010762A2 (en) * | 1996-09-12 | 1998-03-19 | Smithkline Beecham Plc | Controlled release dosage form of r-(z)-alpha-methoxyimino-alpha-(1-azabicyclo2.2oct-c-yl)acetonitrile monohydrochloride |
WO1999045924A1 (en) * | 1998-03-11 | 1999-09-16 | Smithkline Beecham Plc | Composition |
JP2003505402A (ja) * | 1999-07-26 | 2003-02-12 | ラボラトワール デ プロデュイ エチク エチファルム | 低用量錠剤および調製方法 |
WO2005097076A2 (en) * | 2004-04-09 | 2005-10-20 | Smithkline Beecham Corporation | Low dose pharmaceutical products |
US7867990B2 (en) | 2000-12-14 | 2011-01-11 | Ortho-Mcneil Pharmaceutical, Inc. | Steroid hormone products and methods for preparing them |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4489026A (en) * | 1982-09-07 | 1984-12-18 | The Upjohn Company | Process for preparing solid unit dosage forms of ultra-low dose drugs |
US4898736A (en) * | 1988-03-09 | 1990-02-06 | Merck & Co., Inc. | Method for tablet preparation |
EP0392803A1 (en) * | 1989-04-13 | 1990-10-17 | Beecham Group p.l.c. | Novel compounds |
WO1995017168A1 (en) * | 1993-12-21 | 1995-06-29 | Applied Analytical Industries, Inc. | Method for preparing low dose pharmaceutical products |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5970614A (ja) * | 1982-10-14 | 1984-04-21 | Asahi Chem Ind Co Ltd | 微量主薬系湿式固形製剤方法 |
-
1996
- 1996-07-25 AR ARP960103748A patent/AR004178A1/es not_active Application Discontinuation
- 1996-07-26 UY UY24297A patent/UY24297A1/es not_active IP Right Cessation
- 1996-07-26 MA MA24329A patent/MA23953A1/fr unknown
- 1996-07-27 DZ DZ960121A patent/DZ2077A1/fr active
- 1996-07-29 IL IL12289796A patent/IL122897A0/xx unknown
- 1996-07-29 EA EA199800179A patent/EA000740B1/ru not_active IP Right Cessation
- 1996-07-29 NZ NZ315632A patent/NZ315632A/xx unknown
- 1996-07-29 CN CN96197054A patent/CN1196677A/zh active Pending
- 1996-07-29 SK SK110-98A patent/SK11098A3/sk unknown
- 1996-07-29 AP APAP/P/1998/001170A patent/AP858A/en active
- 1996-07-29 JP JP9507243A patent/JPH11510493A/ja active Pending
- 1996-07-29 EA EA199901055A patent/EA199901055A1/ru unknown
- 1996-07-29 WO PCT/EP1996/003326 patent/WO1997004750A2/en not_active Application Discontinuation
- 1996-07-29 CA CA002228048A patent/CA2228048A1/en not_active Abandoned
- 1996-07-29 AU AU67384/96A patent/AU716961B2/en not_active Ceased
- 1996-07-29 KR KR1019980700633A patent/KR19990035972A/ko not_active Application Discontinuation
- 1996-07-29 BR BR9609804A patent/BR9609804A/pt not_active Application Discontinuation
- 1996-07-29 PL PL96325242A patent/PL325242A1/xx unknown
- 1996-07-29 CZ CZ98247A patent/CZ24798A3/cs unknown
- 1996-07-29 TR TR1998/00156T patent/TR199800156T1/xx unknown
- 1996-07-29 EP EP96927621A patent/EP0841902A2/en not_active Withdrawn
- 1996-07-29 HU HU9900521A patent/HUP9900521A3/hu unknown
- 1996-07-29 MX MX9800809A patent/MX9800809A/es unknown
-
1998
- 1998-01-28 OA OA9800013A patent/OA10659A/en unknown
- 1998-01-28 NO NO980384A patent/NO980384L/no unknown
- 1998-02-20 BG BG102266A patent/BG102266A/xx unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4489026A (en) * | 1982-09-07 | 1984-12-18 | The Upjohn Company | Process for preparing solid unit dosage forms of ultra-low dose drugs |
US4898736A (en) * | 1988-03-09 | 1990-02-06 | Merck & Co., Inc. | Method for tablet preparation |
EP0392803A1 (en) * | 1989-04-13 | 1990-10-17 | Beecham Group p.l.c. | Novel compounds |
WO1995017168A1 (en) * | 1993-12-21 | 1995-06-29 | Applied Analytical Industries, Inc. | Method for preparing low dose pharmaceutical products |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACTS, vol. 101, no. 8, 20 August 1984 Columbus, Ohio, US; abstract no. 60165, XP002024576 & JP 59 070 614 A (ASAHI) 21 April 1984 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998010762A2 (en) * | 1996-09-12 | 1998-03-19 | Smithkline Beecham Plc | Controlled release dosage form of r-(z)-alpha-methoxyimino-alpha-(1-azabicyclo2.2oct-c-yl)acetonitrile monohydrochloride |
WO1998010762A3 (en) * | 1996-09-12 | 1998-06-04 | Smithkline Beecham Plc | Controlled release dosage form of r-(z)-alpha-methoxyimino-alpha-(1-azabicyclo2.2oct-c-yl)acetonitrile monohydrochloride |
WO1999045924A1 (en) * | 1998-03-11 | 1999-09-16 | Smithkline Beecham Plc | Composition |
US6451343B1 (en) | 1998-03-11 | 2002-09-17 | Smithkline Beecham Corporation | Composition for treating dementia and Alzheimer's disease |
JP2003505402A (ja) * | 1999-07-26 | 2003-02-12 | ラボラトワール デ プロデュイ エチク エチファルム | 低用量錠剤および調製方法 |
BG65535B1 (bg) * | 1999-07-26 | 2008-11-28 | Laboratoires Des Produits Ethiques Ethypharm S.A. | Таблетки с ниска доза и метод за получаването им |
US7867990B2 (en) | 2000-12-14 | 2011-01-11 | Ortho-Mcneil Pharmaceutical, Inc. | Steroid hormone products and methods for preparing them |
WO2005097076A2 (en) * | 2004-04-09 | 2005-10-20 | Smithkline Beecham Corporation | Low dose pharmaceutical products |
WO2005097076A3 (en) * | 2004-04-09 | 2006-01-05 | Smithkline Beecham Corp | Low dose pharmaceutical products |
Also Published As
Publication number | Publication date |
---|---|
NO980384D0 (no) | 1998-01-28 |
JPH11510493A (ja) | 1999-09-14 |
AP9801170A0 (en) | 1998-01-31 |
SK11098A3 (en) | 1998-07-08 |
BR9609804A (pt) | 1999-07-06 |
HUP9900521A2 (hu) | 1999-06-28 |
AR004178A1 (es) | 1998-11-04 |
IL122897A0 (en) | 1998-08-16 |
WO1997004750A3 (en) | 1997-03-27 |
EA199800179A1 (ru) | 1998-10-29 |
EP0841902A2 (en) | 1998-05-20 |
EA000740B1 (ru) | 2000-02-28 |
CA2228048A1 (en) | 1997-02-13 |
BG102266A (en) | 1998-10-30 |
NZ315632A (en) | 1999-11-29 |
AP858A (en) | 2000-07-12 |
EA199901055A1 (ru) | 2000-06-26 |
MX9800809A (es) | 1998-04-30 |
CN1196677A (zh) | 1998-10-21 |
MA23953A1 (fr) | 1997-04-01 |
AU716961B2 (en) | 2000-03-09 |
TR199800156T1 (xx) | 1998-04-21 |
KR19990035972A (ko) | 1999-05-25 |
NO980384L (no) | 1998-03-26 |
OA10659A (en) | 2002-09-18 |
AU6738496A (en) | 1997-02-26 |
DZ2077A1 (fr) | 2002-07-22 |
PL325242A1 (en) | 1998-07-06 |
HUP9900521A3 (en) | 2001-04-28 |
UY24297A1 (es) | 1997-01-23 |
CZ24798A3 (cs) | 1998-06-17 |
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