CN101460191A - Stable formulation comprising moisture sensitive drugs and manufacturing procedure thereof - Google Patents
Stable formulation comprising moisture sensitive drugs and manufacturing procedure thereof Download PDFInfo
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- CN101460191A CN101460191A CNA2006800548240A CN200680054824A CN101460191A CN 101460191 A CN101460191 A CN 101460191A CN A2006800548240 A CNA2006800548240 A CN A2006800548240A CN 200680054824 A CN200680054824 A CN 200680054824A CN 101460191 A CN101460191 A CN 101460191A
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- Prior art keywords
- pharmaceutical composition
- tablet
- cilazapril
- coating
- attractive
- Prior art date
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- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007886 soft shell capsule Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000001038 titanium pigment Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- 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
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The present invention provides stable pharmaceutical compositions comprising moisture sensitive drugs, in particular an angiotensin converting enzyme (ACE) inhibitor such as Cilazapril, as the active ingredient, and at least one pharmaceutical excipient, wherein the active pharmaceutical ingredient is wet granulated with a solution of at least one pharmaceutical excipient, and methods for preparing such stable pharmaceutical compositions.
Description
Technical field
The present invention relates to comprise wet quick property medicine, particularly angiotensin converting enzyme (ACE) inhibitor such as cilazapril stabilizing pharmaceutical composition as active component, and the method for preparing this stabilizing pharmaceutical composition.
Background technology
Cilazapril obviously is angiotensin converting enzyme (" ACE ") inhibitor, and it suppresses to form Angiotensin II from angiotensin I by suppressing angiotensin converting enzyme.Chemically, it is reported cilazapril be (1S, 9S)-9-[(S)-1-carbethoxyl group-3-phenyl propyl amino]-10-oxo perhydro pyridazine [1,2-a] [1,2] diaza also
-1-carboxylic acid and the known United States Patent (USP) 4,512 that is disclosed in are in 924.Cilazapril is treatment hyperpietic's a prescription drugs.
For one of requirement of acceptable drug compositions is that it must be stable.Stable pharmaceutical composition from preparation of compositions to the substantial decomposition that active pharmaceutical ingredient does not take place it is used by the patient.There are instability problem in cilazapril and many other medicines because described active pharmaceutical ingredient is degraded rapidly in the presence of water/dampness.Therefore the available wet quick property medicine of these active pharmaceutical ingredients (medicine) is represented its feature.
Be well known that tablet mixture can pass through dry mixed, non-slurry pelletizing or wet granulation before film-making.The course of processing, dry mixed, non-slurry pelletizing, the selection of wet granulation or some other prilling process is different and different according to the character of medicine and selected excipient.Usually, think that the dry process process is preferred for wet quick property medicine.
In order to improve wet quick property stability of drug, can in tablet matrix, introduce the chemical compound of removing water.The chemical compound of a this removing water is binding agent copolyvidone (Copovidone) (Plasdone
), this binding agent is used for wet quick property medicine by special recommendation.Yet, in the non-slurry pelletizing method, use this material to prepare the effort success hardly of cilazapril tablet.In this cilazapril tablet, the degraded of active pharmaceutical ingredient is tangible.
Think that processes for wet granulation is not suitable for wet quick property medicine, because the distinctive character of these methods can comprise the existence of water/dampness.
Be surprisingly, the inventor finds to comprise wet quick property medicine and binding agent, and for example the compositions or the preparation of copolyvidone can obtain best stability result, wherein said preparation/compositions uses the processes for wet granulation preparation, and this method comprises moistening and dry compositions at high temperature then.
Summary of the invention
The invention provides stable cilazapril composition and method of making the same.
Stabilizing pharmaceutical composition is provided in one aspect of the invention, and it comprises:
A) wet quick property active pharmaceutical ingredient; With
B) at least a drug excipient,
Wherein active pharmaceutical ingredient is with the solution wet granulation of at least a drug excipient.Preferably, at least a excipient is a binding agent.
The method for preparing the particulate composition of the wet quick property active pharmaceutical ingredient that comprises wet granulation is provided in another embodiment of the invention, and this method may further comprise the steps:
A) provide wet quick property active pharmaceutical ingredient;
B) will wet quick property active pharmaceutical ingredient and at least a pharmaceutically acceptable mixed with excipients except binding agent form mixture; With
C) use be dissolved in the binding agent excipient in one or more process solvent solution to the mixture wet granulation, thereby form granule.
The present invention also provides treatment to suffer from the patient's of disease method, comprise the patient that needs are arranged is given with the stabilizing pharmaceutical composition for the treatment of effective dose, this stabilizing pharmaceutical composition comprises wet quick property active pharmaceutical ingredient (preferred cilazapril) and at least a drug excipient, and wherein active pharmaceutical ingredient is with the solution wet granulation of at least a drug excipient.
Description of drawings
Fig. 1. the aluminum cover that is illustrated in cold forming steeps the of the present invention various cilazapril tablets of inner packing, the comparisons of degraded under 55 ℃ during stability test with non-slurry pelletizing tablet and marketed tablet.Having measured main cilazapril catabolite is the increase of cilazaprilat.
Fig. 2. represented the stable behavior of cilazapril tablet when more water base and ethanol based prilling process.
Fig. 3. expression is when (the stable behavior of cilazapril tablet when Opadry II (85 series) and hydroxypropyl methylcellulose based tablet coating of more PVA-based tablet coating.
Detailed Description Of The Invention
Term used herein " wet sensitive active pharmaceutical ingredient " refers to the condition in water/moisture existence The lower rapidly active pharmaceutical ingredient of degraded.
In one aspect, the invention provides and comprise wet sensitive active component such as Cilazapril and extremely The stabilizing pharmaceutical composition of few a kind of excipient, wherein at least a pharmaceutically acceptable excipient is bonding Agent. Preferably, pharmaceutical composition comprises at least two kinds of pharmaceutically acceptable excipient.
Stabilizing pharmaceutical composition is provided in one embodiment of the invention, and it comprises: a) wet Quick property active pharmaceutical ingredient; And b) at least a drug excipient, wherein active pharmaceutical ingredient is used extremely The solution wet granulation of few a kind of drug excipient. Preferably, the wet sensitive active pharmaceutical ingredient is the west Drawing Puli and at least a drug excipient is adhesive.
Preferably, the amount of wet sensitive active pharmaceutical ingredient in composition is the pact of composition total weight 0.1%-is about 25%, and more preferably from about 0.5%-about 15%. The optimum of active pharmaceutical ingredient in composition The amount of choosing is about 0.6%-about 2.7% of composition total weight.
In yet another aspect, the invention provides and comprise wet sensitive active pharmaceutical ingredient and at least a The stabilizing pharmaceutical composition of pharmaceutically acceptable excipient, wherein said preparation has the wet sensitive barrier Comprising the at the most degraded of 3% (w/w is in the primary quantity of active pharmaceutical ingredient) after storing in the packing produces Thing, described packing are at least the same effective with the aluminium of cold forming-aluminium cover bubble. Preferably, as mentioned above Storage after in the stabilizing pharmaceutical composition of the present invention the concentration of catabolite be no more than 2%. More Preferably, catabolite in the stabilizing pharmaceutical composition of the present invention after aforesaid storage Concentration is no more than 1%. Storage can be included in and store 14 days under 55 ℃ the temperature and 40 ℃ temperature Storage is 3 months under degree and 75% the relative humidity. Catabolite can pass through the HPLC analyzing and testing. Preferably, the wet sensitive active pharmaceutical ingredient is that Cilazapril and catabolite are that its main degraded is produced The thing cilazaprilat.
Therefore, stabilizing pharmaceutical composition of the present invention provides the wet sensitive active pharmaceutical ingredient (preferred Cilazapril) pharmaceutical composition is characterized in that after storage with respect to described drug ingedient Weight comprises at the most 3 % by weight, preferred 2 % by weight at the most, most preferably its of 1 % by weight at the most The main degradation products cilazaprilat.
Preferably, stabilizing pharmaceutical composition of the present invention comprise account for composition total weight at least about 4% adhesive. Preferably, this pharmaceutical composition comprises the about 4%-pact that accounts for composition total weight 20%, the adhesive of 5%-about 10% more preferably from about. Adhesive for example comprises following a kind of or many Kind: cellulose derivative, PVP (PVP) and derivative thereof, polyvinyl acetate Ester (PVA) or polyvinyl alcohol. In the present invention as the suitable cellulose derivative of adhesive Example is HPMC (HPMC) or hydroxy propyl cellulose (HPC). More preferably, sticking Mixture is copolyvidone, for exampleS-630 (Copovidone), it is the 60:40 that synthesizes N-vinyl-2 pyrrolidones and the linear random copolymer of vinyl acetate, and itself and poly-second Thiazolinyl pyrrolidones (PVP) homopolymers is compared hydrophily with reduction and the polymer glass of reduction Change transition temperature (Tg).
The stabilizing pharmaceutical composition that comprises the wet sensitive active pharmaceutical ingredient of the present invention can comprise in addition Excipient such as Tablet and Capsula filler and diluent (microcrystalline cellulose for example, lactose, starch and Tricalcium orthophosphate), disintegrant (for example starch, cross-linked carboxymethyl cellulose sodium, Crospovidone and starch hydroxyl Guanidine-acetic acid sodium), and glidant (for example cataloid and talcum), lubricant (dolomol for example, Lauryl sodium sulfate, stearic acid and stearyl fumarate).
More particularly, suitable diluent and the filler for pharmaceutical composition of the present invention comprises that microcrystalline cellulose (for exampleLactose, starch, pregelatinized starch, calcium carbonate, sulfuric acid Calcium, sugar, dextrates (dextrates), dextrin, glucose, calcium phosphate dibasic dihydrate, just Calcium phosphate, magnesium carbonate, magnesia, maltodextrin, sweet mellow wine, cellulose powder, sodium chloride, Sorbierite and talcum.
The solid composite medicament of the present invention that is compressed into such as the formulation of tablet can comprise to group Add disintegrant in the compound. Disintegrant comprises cross-linked carboxymethyl cellulose sodium (Ac Di for example Crospovidone (for example Microcrystalline cellulose, polacrilin potassium, cellulose powder, pregelatinized starch, sodium starch glycolate are (for example And starch.
Can add fluidizer before the compacting with the flowability of improving solid composite and the dosage accuracy that is used for improving during compacting and dress capsule.The excipient that can play the fluidizer effect comprises silica sol, magnesium trisilicate, cellulose powder and Talcum.
Can in compositions, add lubricant with the adhesiveness that reduces product and/or be easy to the disengaging of product and for example punch die.Lubricant comprises magnesium stearate, calcium stearate, glyceryl monostearate, palmitostearate, castor oil hydrogenated, hydrogenated vegetable oil, mineral oil, Polyethylene Glycol, sodium lauryl sulphate, stearyl fumarate, stearic acid, Talcum and zinc stearate.
Other excipient that can be introduced in the preparation comprises antiseptic, surfactant, antioxidant, or any other be used in excipient in the pharmaceuticals industry usually.
In preferred version of the present invention, stabilization formulations also comprises copolyvidone except comprising cilazapril, a Lactose hydrate, sodium starch glycolate, special fine talc (talc extra fine) and stearyl fumarate.
Solid composite of the present invention comprises the compositions of powder, granule, aggregation and compacted form.Dosage comprise be suitable for per os, through the dosage of cheek and rectally.Although any to optimal route of administration under the situation will be according to the character of the patient's condition of just being treated and seriousness different and different, most preferred route of the present invention is an oral administration.Dosage can be present in easily in the unit dosage forms and be produced according to the known method of drug world.
Pharmaceutical composition of the present invention can be made into any dosage form, such as the granule that is compressed of tablet form.In addition, the granule of the uncompressed that obtains in the precommpression step by method of the present invention and mixture of powders can be simply be provided with the dosage form of capsule or pouch (sachet) form.Therefore, the dosage form of pharmaceutical composition of the present invention comprises solid dosage forms such as tablet, powder, capsule, pouch etc.Dosage form of the present invention can also be to comprise compositions of the present invention, be preferably capsule Powdered or the granular solids compositions, and this capsule is hard-shell capsule or soft shell capsule.Capsule shells can be from gelatin preparation and optional plasticizer for example glycerol and sorbitol and opacifier or the coloring agent of comprising.
When the solid composite of the wet preferred cilazapril of quick property active pharmaceutical ingredient produced according to the present invention, preferably it is mixed with the pharmaceutical preparation of dosage form (comprising tablet and capsule) such as routine.Tablet is preferred dosage form.In addition, tablet can have optional usefulness attractive in appearance (cosmetic) tablet coating.More preferably this attractive in appearancely has moisture barrier character with coating.The wet quick property nuclear of this moisture barrier character protection is avoided the influence of ambient moisture, strengthens product stability and improves the shelf life.Preferably, the tablet coating that is based on polyvinyl alcohol with coating attractive in appearance.More preferably, attractive in appearancely comprise polyvinyl alcohol with coating, Talcum and Polyethylene Glycol (PEG).Most preferably, attractive in appearancely comprise opacifier and/or coloring agent in addition, as titanium dioxide and/or ferrum oxide with coating.
As shown in Figure 3, compared with the tablet of OpadryII 85F (coating) coating and use coating based on HPMC to carry out stability between the tablet of coating with moisture barrier character.Commercially available series with
The mixture of powders that is used for the coating suspension (it is based on polyvinyl alcohol) that 85F series (deriving from Colorcon) is sold is this example with coating attractive in appearance.Except polyvinyl alcohol, these Opadry series of products comprise Talcum, PEG 3350, titanium dioxide and pigment.Preferably, tablet of the present invention comprises the coating of using attractive in appearance of the about 2%-about 6% that accounts for tablet weight, more preferably accounts for the coating of using attractive in appearance of about 2.5%-about 4.5% of tablet weight, most preferably accounts for the coating of using attractive in appearance of about 3%-about 3.5% of tablet weight.
Provide preparation to comprise the method for the particulate composition of the wet quick property active pharmaceutical ingredient (preferred cilazapril) through wet granulation in another embodiment of the invention, this method may further comprise the steps:
A) provide wet quick property active pharmaceutical ingredient;
B) will wet quick property active pharmaceutical ingredient and preferred at least a pharmaceutically acceptable mixed with excipients except binding agent form mixture; With
C) solution that uses the binding agent in process solvent forms granule to the mixture wet granulation.
In preparation pharmaceutical composition of the present invention, typical prilling process is included in the blender active component and possible mixed with excipients.The binding agent that use is dissolved in the solvent carries out pelletize, although the binding agent or other the binding agent of part can be one of excipient that is added under the dry mixture state in addition.Pelletize is added in the dry powder in the blender with solvent, solution or suspension and mixes up to realizing required feature.This produces the granule that has suitable feature for the tablet that preparation has suitable hardness, dissolution, content uniformity and other physical property usually.After wet granulation step, the most normally with product drying, after drying, grind then, cause the major part of product to be in the required particle size range.Preferably, the product behind wet granulation is about at the most 1.5% up to loss on drying (LOD) through super-dry, and more preferably about at the most 1.1%.Preferably, product more preferably passes through 0.8 millimeter sieve through grinding or passing through 1 millimeter sieve.
Preferably, stabilizing pharmaceutical composition of the present invention adopts appropriate solvent/process solvent to carry out the wet granulation preparation.Appropriate solvent/process solvent can be dissolved selected binding agent.Preferably, solvent/process solvent can dissolved adhesive, thereby reaches the concentration at least about 10% W/W.More preferably, solvent/process solvent is selected from ethanol, isopropyl alcohol, water and combination thereof.Preferably, the stabilization formulations by wet granulation preparation comprises and accounts at least 4% of weight of formulation, and preferably about 4%-is about 20%, more preferably from about the binding agent of 5%-about 10%.Preferably, binding agent comprises copolyvidone at least, and more preferably, binding agent is applied with the solution form in ethanol or water.The solution of binding agent in ethanol or water preferably comprises the binding agent of about 25%-about 55% (w/w), and preferred copolyvidone more preferably comprises the binding agent of about 30%-about 50% (w/w), preferably copolyvidone.
Surprisingly, determined that the selection of the process solvent used influences the stability of final products in wet granulation, this influence is according to the difference of the dosage/quantity of cilazapril in the final products and different.Therefore, for the compositions that comprises 1 milligram of cilazapril, determined that for example the pharmaceutical composition that obtains of the pelletize process solvent of ethanol (95%) is more stable than the pharmaceutical composition that the same procedure with the aqueous process solvent of main bag obtains with mainly comprising ethanol.
By contrast, for the pharmaceutical composition that comprises 5 milligrams of cilazapril, determined that the stabilizing pharmaceutical composition that obtains with the main aqueous pelletize process solvent of bag (aqueous pelletize) is more stable than the pharmaceutical composition that obtains with the main same procedure that comprises the process solvent of ethanol (95%).
This effect may be relevant with the wet concentration of quick property active pharmaceutical ingredient in dried particles.Therefore, the dried particles that comprises about 0.6% active pharmaceutical ingredient is preferentially by using the wet granulation preparation of alcohol pelletize process solvent, and the dried particles that comprises about 2.7% active pharmaceutical ingredient is preferentially by making the wet granulation preparation of use pelletize process solvent.Particle performance with active pharmaceutical ingredient of intermediate concentration goes out between intermediary effect.
Therefore, in dried particles, comprise the of the present invention final pharmaceutical composition of about at the most 1.7% wet quick property active component preferably by using the wet granulation preparation of alcohol pelletize process solvent.Preferably, use the wet granulation of alcohol process solvent to be used in dried particles, to comprise in about at the most 0.6% the wet quick property composition of active components.In dried particles, comprise be higher than about 1.7% wet quick property active component pharmaceutical composition of the present invention preferably by making the wet granulation preparation of water as pelletize process solvent (aqueous pelletize).Preferably, make the wet granulation of use process solvent be used in dried particles, comprise at least about in 2.7% the wet quick property composition of active components.Preferred wet quick property active pharmaceutical ingredient is a cilazapril.
Method of the present invention also can comprise the step of the tablet for preparing pharmaceutical composition of the present invention.In this tablet of preparation, this method is further comprising the steps of:
D), form final blend with granule and one or more mixed with excipients;
E) final blend is compressed into tablet; With
F) randomly use attractive in appearance with coating to tablet coating.Preferably, attractive in appearance have moisture barrier character with coating.This example with coating attractive in appearance is based on the tablet coating of polyvinyl alcohol.
Optional tablet attractive in appearance preferably includes preparation with coating, and to comprise about 10%-about 25%, and preferably about 12%-is about 15%, the suspension of the mixture of powders that is used for usefulness coating attractive in appearance of 12%-about 13% more preferably from about, and this suspension is applied on the tablet.Attractive in appearancely be prepared as preferably with the coating suspension that to make that tablet comprises about 2%-about 6%, the tablet coating of using attractive in appearance of preferred 2.5%-about 4.5%.Attractive in appearance among the present invention have " moisture barrier " character with tablet coating.Commercially available series with
The mixture of powders (based on polyvinyl alcohol) that the conduct that II85F series (deriving from Colorcon) is sold is used for the coating suspension is this example with coating attractive in appearance.
Can prepare and comprise compositions of the present invention and comprise duricrust or the capsule of soft shell.Capsule shells can and randomly comprise plasticizer for example glycerol and sorbitol from the gelatin preparation, and opacifier or coloring agent.Capsule filling of the present invention can comprise about the described granule of film-making, the final mixture of particulate composition of the present invention and one or more excipient, yet they are not subjected to the influence of final film-making step, and this capsule can be by any known method preparation of drug world.
In addition, in preferred version, the invention provides the method for preparing stabilizing pharmaceutical composition, this method comprises:
A) with cilazapril, lactose, Talcum and sodium starch glycolate mix;
B) solution of adding copolyvidone in the mixture that derives from step a) forms granule;
C) particle drying is ground then;
D) will be through the granule that grinds with other sodium starch glycolate merging and mix; With
E) in the mixture that derives from step d), add stearoyl glycolic sodium and mixing, obtain final mixture.
In more preferably scheme, pharmaceutical composition is that 1 milligram tablet and use comprises alcoholic acid granulation solution implementation step b).In alternative preferred version, pharmaceutical composition is 5 milligrams tablet and makes use granulation solution implementation step b).
The present invention also provides treatment to suffer from the patient's of disease method, comprise the patient that needs are arranged is given with the stabilizing pharmaceutical composition for the treatment of effective dose, this stabilizing pharmaceutical composition comprises wet quick property active pharmaceutical ingredient (preferred cilazapril) and at least a drug excipient, and wherein active pharmaceutical ingredient is with the solution wet granulation of at least a drug excipient.Preferably, described disease is a hypertension.
Provide following examples to be used to further specify the present invention.These embodiment do not limit the present invention in any way.
Embodiment
1 milligram of tablet, non-slurry pelletizing, *~5% (w/w) binding agent (comparative example)
(*, the percent of the binding agent that calculates with respect to each tablet core)
In Polythene Bag, mix 8.4 gram cilazapril monohydrates, the lactose monohydrate of 1360 grams, the copolyvidone of the special fine talc of 64 grams and 80 grams.Mixture is crossed 0.71 mm sieve, is transferred in the dry blending device of bivalve (Y-taper) and mixes 25 minutes.Adding 16 restrains the stearyl fumarate of sieving and mix all material in the Y-cone blender and reaches 5 minutes in this mixture.
Mixture is pressed into block on rotary tablet machine, and in the vibration nodulizer, block is ground to form granule through 0.8 mm sieve.The granule that obtains mixes to be incorporated in the sodium starch glycolate (A type) that 64 grams sieve and mixed in the Y-cone blender 10 minutes.Adding 8 restrains the stearyl fumarate of sieving and mix all material in the Y-cone blender and reaches 5 minutes in this granulate mixture.
Compressed tablets in rotary tablet machine.Subsequently, with the following coating of a part of tablet core:
A)
II 85F22055 (Huang), it comprises polyvinyl alcohol, Talcum, PEG 3350, and titanium dioxide and ferrum oxide are 13% aqueous suspension, use Glatt film coating machine, obtain the coating of about 2.7% w/w.Then tablet is packaged in (the aluminum cover bubble of cold forming) in the aluminum cover bubble that covers with aluminium foil.
The following coating of tablet core core of another part:
B)
02G222555 (Huang), it comprises hydroxypropyl emthylcellulose (HPMC), Talcum, PEG, titanium dioxide and ferrum oxide are 11% aqueous suspension, use Glatt film coating machine, obtain the coating of about 2.2% w/w.Then tablet is packaged in the aluminum bubble-cap that covers with aluminium foil (the aluminum bubble-cap of cold forming).
With the tablet of packing at 55 ℃ or in the storage down of 40 ℃ and 75% relative humidity (RH).Use the HPLC method to measure the existence of main degradation products cilazaprilat.In Fig. 1, shown the existence of the main degradation products of cilazapril after above-mentioned storage.In addition, Fig. 3 has compared and has scribbled
85 F22055 attractive in appearance with coating tablet and scribble
The coated tablet of using attractive in appearance of 02G222555 (based on HPMC), after storing, the degraded of cilazapril tablet is as the function of the existence of main degradation products.
1 milligram of tablet, wet granulation, *~5% (w/w) binding agent
In high-shear mixer, mix 2.1 gram cilazapril monohydrates, 333.9 gram lactose monohydrates, 16 cut fine talcs and 16 gram sodium starch glycolates (A type) reach 1 minute.The solution of 28.6% (w/w) of the copolyvidone (binding agent) in alcohol (95%) of adding 70 grams also mixed 2.5 minutes in high-shear mixer.Adding 10 gram alcohol (95%) also mixed 1 minute.The granule that obtains uses the fluidized bed dryer drying to be no more than (NMT) 1.1% up to the loss on drying (LOD) of dried particles (measuring for 5 times at 80 ℃, level according to MettlerHR73).Granule grinds or " screening " through 0.8 mm sieve in the vibration nodulizer.
Merge and in the Y-cone blender, mixed 10 minutes with 8 gram sodium starch glycolate A types (disintegrating agent) through the granule that grinds.Adding 4 in mixture restrains the stearyl fumarate (lubricant) of sieving and mixed the acquisition final mixture 5 minutes.
In rotary tablet machine from the final mixture tabletting.Tablet is with commercially available tablet coating mixture of powders
85F22055 (Huang) is 12% aqueous suspension, uses Glatt film coating machine to carry out coating, obtains the coating of about 3%w/w.
Tablet is packaged in the aluminum cover bubble that covers with aluminium foil.With the packing tablet 55 ℃ of storages.Use the HPLC method to measure the existence of main degradation products cilazaprilat.
1 milligram of tablet, wet granulation, *~9% (w/w) binding agent
In high-shear mixer, mix 20.1 gram cilazapril monohydrates, 3099.1 gram lactose monohydrates, 160 cut fine talcs and 160 gram sodium starch glycolates (A type) reach 2 minutes; The solution of 45.57% (w/w) of the copolyvidone in alcohol (95%) of adding 790 grams also mixed 5 minutes in high-shear mixer.The granule that obtains uses the fluidized bed dryer drying to be no more than (NMT) 1.1% up to the loss on drying (LOD measures down at 80 ℃) of dried particles.Dried granules is ground through 0.84 mm sieve in beater grinder.
Merge and in the Y-cone blender, mixed 10 minutes with the sodium starch glycolate (A type) that 160 grams sieve through the granule that grinds.Adding 40 in mixture restrains the stearyl fumarate of sieving and mixed the acquisition final mixture 5 minutes.
In rotary tablet machine from the final mixture tabletting.Tablet is used
The 85F22055 Huang is 13% aqueous suspension, uses O ' HARA film coating machine to carry out coating, obtains the coating of about 3.5% w/w.
Tablet is packaged in the aluminum cover bubble that covers with aluminium foil.The tablet of packing is stored down or under 40 ℃ and 75% RH at 55 ℃.Use the HPLC method to measure the existence of main degradation products cilazaprilat.
1 milligram of tablet, wet granulation, *~10% (w/w) binding agent
In high-shear mixer, mix 2.1 gram cilazapril monohydrates, 305.9 gram lactose monohydrates, 16 cut fine talcs and 16 gram sodium starch glycolates (A type) reach 1 minute; The solution of 38.1% (w/w) of the copolyvidone in alcohol (95%) of adding 105 grams also mixed 1 minute in high-shear mixer.The granule that obtains uses the fluidized bed dryer drying to be no more than (NMT) 1.1% up to the loss on drying (LOD is 80 ℃ of mensuration) of dried particles.Dried granules sieve through 0.8 millimeter in the vibration nodulizer grinds.
Merge and in the Y-cone blender, mixed 10 minutes with 16 gram sodium starch glycolates (A type) through the granule that grinds.Adding 4 in mixture restrains the stearyl fumarate of sieving and mixed 5 minutes the acquisition final mixture in the Y-cone blender.
Tabletting on rotary tablet machine.Tablet is used
The 85F22055 Huang is 12% aqueous suspension, uses Glatt film coating machine to carry out coating, obtains the coating of about 3% w/w.
Tablet is packaged in the aluminum cover bubble that covers with aluminium foil.The tablet of packing is stored down at 55 ℃.Use the HPLC method to measure the existence of main degradation products cilazaprilat.
5 milligrams of tablets, aqueous wet granulation, *~5% (w/w) binding agent
In high-shear mixer, following component was mixed 1 minute: the cilazapril monohydrate of 10.4 grams, 318 gram lactose monohydrates, 16 cut fine talcs and 16 gram sodium starch glycolates (A type), the aqueous solution of 40% (w/w) of the copolyvidone of adding 50 grams also mixed 5 minutes in high-shear mixer.The granule that obtains uses the fluidized bed dryer drying to be no more than (NMT) 1.1% up to the loss on drying (LOD measures down at 80 ℃) of dried particles.Dried granules is ground through 0.8 mm sieve in the vibration nodulizer.
Merge and in the Y-cone blender, mixed 10 minutes with the sodium starch glycolate (A type) that 16 grams sieve through the granule that grinds.The stearyl fumarate that adding 4 grams sieve in the mixture that obtains was also mixed 5 minutes in the Y-cone blender, obtained final mixture.
Tabletting on rotary tablet machine.Tablet is packaged in the aluminum cover bubble that covers with aluminium foil.The tablet of packing is stored down or under 40 ℃ and 75% RH at 55 ℃.Use the HPLC method to measure the existence of main degradation products cilazaprilat.
The stability of various cilazapril pharmaceutical compositions relatively
The stability of pharmaceutical composition of the present invention and the stability of non-slurry pelletizing cilazapril tablet comparative example and the stability of commercially available prod are compared.The sample of commercially available prod is
1 milligram of tablet, by F.Hoffmann-La Roche Ltd, Basel, Switzerland produces.The preparation of these pharmaceutical compositions of table 1 expression, difference is that the commercially available prod obtains with final product form.
The comparison of table 1. preparation and production method
*Comparative example
Measure stability by the existence of measuring the main degradation products cilazaprilat that stores the cilazapril in the pharmaceutical composition of back.Implement the amount of HPLC test method(s) with the catabolite of mensuration cilazapril.Mobile phase is the mixture of triethylamine buffer agent, oxolane and acetonitrile.Detector is the UV spectrophotometer that is set in the 214nm place.
Fig. 1 represents the stability test result, compared 55 ℃ store 14 days after, according to the present invention by the various cilazapril tablets of processes for wet granulation preparation with by (contrast) tablet of non-slurry pelletizing preparation and the degraded of marketed tablet.All is packaged in the aluminum cover bubble for the test piece agent.Also the commercially available prod is packaged in the aluminum cover bubble.The level of having measured cilazaprilat increases along with the increase of time.In addition, table 2 shows under the standard stressed condition result of the test of the degraded of some preparations in these preparations.
Table 2. standard " stress " under the condition (40 ℃ and 75%RH), the degraded of the cilazapril that different preparations and production method are shown.
*Comparative example (embodiment 1)
* Embodiment 3
* * Embodiment 5
1 milligram of tablet, wet granulation ,~9% (w/w) binding agent (calculates with respect to each tablet core core
The percent of binding agent), (lot number: K-33603, as shown in table 3).
In high-shear mixer, following component was mixed 2 minutes: the cilazapril monohydrate of 20.9 grams, 3099.1 gram lactose monohydrate, 160 cut fine talcs and 160 gram sodium starch glycolates (A type), the solution of 46.8% (w/w) of the copolyvidone in alcohol (95%) of adding 770 grams also mixed 5 minutes in high-shear mixer.The fluidized bed dryer drying is used in the pelletize that obtains, and the LOD of dried particles is no more than (NMT is by Mettler HR73,80 ℃, 5 times mensuration of level) 1.1%, and dried granules is ground in beater grinder by 0.84 mm sieve.
Merge and in the Y-cone blender, mixed 15 minutes with the sodium starch glycolate (A type) that 160 grams sieve through the granule that grinds.In mixture, add stearyl fumarate that 40 grams sieve and in the Y-cone blender with material mixing 5 minutes, obtain final mixture.
Tabletting in rotary tablet machine.Tablet is used
85F22055 Yellow (be 13% aqueous suspension) carries out coating, uses O ' HARA film coating machine, obtains the coating of about 3.5% w/w.
Tablet is packaged in the aluminum cover bubble that covers with aluminium foil.Package troche is stored under 40 ℃ and 75% RH.Use the HPLC method to measure the existence of main degradation products cilazaprilat as mentioned above.
2.5 the milligram tablet, wet granulation, *~9% (w/w) binding agent
*(percent of the binding agent that calculates with respect to each tablet core core), (lot number: K-33604, as shown in table 3).
In high-shear mixer, following component was mixed 2 minutes: the cilazapril monohydrate of 52.2 grams, the lactose monohydrate of 3068 grams, 160.00 cut fine talc and 160.00 gram sodium starch glycolates (A type), the solution of 46.8% (w/w) of the copolyvidone in alcohol (95%) of adding 770 grams also mixed 5 minutes in high-shear mixer.The granule that obtains uses the fluidized bed dryer drying, and the LOD of drying-granulating (by Mettler HR73, measuring down at 80 ℃) is no more than (NMT) 1.1%, and grinds by 0.84 mm sieve in beater grinder.
Merge and in the Y-cone blender, mixed 15 minutes with the sodium starch glycolate (A type) that 160.00 grams sieve through the granule that grinds.In mixture, add stearyl fumarate that 40.00 grams sieve and in the Y-cone blender with material mixing 5 minutes.
Tabletting in rotary tablet machine.Tablet is used
85F24033 Pink (be 13% aqueous suspension) carries out coating, uses O ' HARA film coating machine, obtains the coating of about 3.5%w/w.
Tablet is packaged in the aluminum cover bubble that covers with aluminium foil.Package troche is stored under 40 ℃ and 75%RH.Use the HPLC method to measure the existence of main degradation products cilazaprilat as mentioned above.
5 milligrams of tablets, wet granulation, *~9% (w/w) binding agent
*(percent of the binding agent that calculates with respect to each tablet core core), (lot number: K-33749, as shown in table 3).
In high-shear mixer, following component was mixed 2 minutes: the cilazapril monohydrate of 522 grams, the lactose monohydrate of 30678 grams, 1600 cut fine talcs and 1600 gram sodium starch glycolates (A type), the solution of 54.55% (w/w) of the copolyvidone in alcohol (95%) of adding 6600 grams also mixed 3.5 minutes in high-shear mixer.The fluidized bed dryer drying is used in the pelletize that obtains, and is no more than (NMT) 1.1% up to the LOD of dried particles (by Mettler HR73,80 ℃, 5 times mensuration of level), and dried granules is ground in beater grinder by 0.84 mm sieve.
Merge and in the Y-cone blender, mixed 15 minutes with the sodium starch glycolate (A type) that 1600 grams sieve through the granule that grinds.In mixture, add stearyl fumarate that 400 grams sieve and in the Y-cone blender with material mixing 5 minutes, obtain final blend.
In rotary tablet machine from final blend tabletting.Tablet is used
85F25401Red (be 13% aqueous suspension) carries out coating, uses O ' HARA film coating machine, obtains the coating of about 3.5% w/w.
Tablet is packaged in the aluminum cover bubble that covers with aluminium foil.Package troche is stored under 40 ℃ and 75% RH.Use the HPLC method to measure the existence of main degradation products cilazaprilat as mentioned above.
Table 3. uses ethanol (95%) as process solvent by the composition of the cilazapril tablet of processes for wet granulation preparation.
*Be removed in dry run
Lot number R-02474-1 milligram tablet, the aqueous wet granulation, *~7.5% binding agent is (as table 4
Show).
In high-shear mixer, following component was mixed 1 minute: the cilazapril monohydrate of 2.09 grams, 315.91 gram lactose monohydrate, 16.00 cut fine talc and 16.00 gram sodium starch glycolates (A type), the aqueous solution of 46.2% (w/w) of the copolyvidone of adding 65 grams also mixed 4 minutes in high-shear mixer.The granule that obtains uses the fluidized bed dryer drying, is no more than (NMT) 1.1% up to the LOD of dried particles (by Mettler HR73,80 ℃, 5 times mensuration of level), and grinds by 0.8 mm sieve in the vibration nodulizer.
Merge and in the Y-cone blender, mixed 15 minutes with the sodium starch glycolate (A type) that 15.13 grams sieve through the granule (359.34 gram) that grinds.In mixture, add stearyl fumarate that 3.78 grams sieve and in the Y-cone blender with material mixing 5 minutes.
Tabletting in the single punching tablet.Tablet is packaged in the aluminum cover bubble that covers with aluminium foil.The tablet of packing is stored down or under 40 ℃ and 75%RH at 55 ℃.Use the HPLC method to survey the existence of catabolite cilazaprilat.
Table 4. makes water as process solvent by the compositions of the cilazapril tablet of processes for wet granulation preparation.
*Be removed in dry run
Embodiment 11.
The stability of various cilazapril pharmaceutical compositions relatively
Compared use ethanol (95%) or water stability as the pharmaceutical composition of the present invention of process solvent preparation.In addition, under identical experimental condition, measured the stability of commercially available prod.The sample of commercially available prod is
Tablet, by F.Hoffmann-La Roche Ltd, Basel, Switzerland produces.As shown in table 5, mainly adopt the comparable preparation of the cilazapril of ethanol processing, it is difference aspect the milligram number of every middle cilazapril, has diverse degradation curve.Thereby 1 milligram tablet is the most stable, and 5 milligrams tablet is least stable.
Table 5. under the stressed condition (40 ℃ and 75% RH) of standard, the monitored results of cilazapril tablet and commercially available prod.Packing " aluminum bubble-cap ".
By contrast, table 6 shows the comparable preparation of the cilazapril that main employing water prepares as process solvent, and it is difference aspect the milligram number of every middle cilazapril, has opposite degraded feature, thereby 5 milligrams of tablets are the most stable, and 1 milligram of tablet is least stable.
Table 6. under the stressed condition (40 ℃ and 75% RH) of standard, the monitored results of cilazapril tablet.Packing " aluminum bubble-cap "
Claims (47)
1. pharmaceutical composition, it comprises:
A) wet quick property active pharmaceutical ingredient; With
B) at least a drug excipient,
Wherein active pharmaceutical ingredient is with the solution wet granulation of at least a drug excipient.
2. the pharmaceutical composition of claim 1, the quick property of its being attacked by dampness active pharmaceutical ingredient is a cilazapril.
3. the pharmaceutical composition of claim 2, wherein compositions comprises the cilazapril of the about 0.1%-about 25.0% that accounts for composition total weight.
4. the pharmaceutical composition of claim 1, wherein at least a excipient is a binding agent.
5. the pharmaceutical composition of claim 4, wherein pharmaceutical composition comprises at least 4% the binding agent that accounts for composition total weight.
6. the pharmaceutical composition of claim 5, wherein about 4%-about 20% of binder constitutes pharmaceutical composition weight.
7. the pharmaceutical composition of claim 6, wherein about 5%-about 10% of binder constitutes composition total weight.
8. the pharmaceutical composition of claim 1, wherein at least a excipient is selected from: cellulose derivative, polyvinyl pyrrolidone (PVP) and derivant thereof, polyvinyl acetate (PVA), polyvinyl alcohol and composition thereof.
9. the pharmaceutical composition of claim 8, wherein excipient is a copolyvidone.
10. the pharmaceutical composition of claim 9, wherein copolyvidone is Plasdone S-630.
11. the pharmaceutical composition of claim 4 comprises at least two kinds of pharmaceutically acceptable excipient.
12. the pharmaceutical composition of claim 2, the cilazapril main degradation products cilazaprilat that comprises the 3 weight % at the most that account for the cilazapril primary quantity in packing after it stores, wherein this packing has at least the same effective moisture barrier character of aluminum-aluminum bubble-cap with cold forming.
13. the pharmaceutical composition of claim 12 wherein saves as at 55 ℃ following 14 days.
14. the pharmaceutical composition of claim 12 wherein saved as under the relative humidity of 40 ℃ temperature and 75% 3 months.
15. the pharmaceutical composition of claim 14 comprises the cilazapril main degradation products of about at the most 2 weight %.
16. the pharmaceutical composition of claim 14 comprises the cilazapril main degradation products of about at the most 1 weight %.
17. the pharmaceutical composition of claim 1, wherein pharmaceutical composition is to be selected from following solid dosage forms: tablet, powder, capsule, pouch agent, lozenge and dragee.
18. the pharmaceutical composition of claim 17, wherein solid dosage forms is a tablet.
19. the pharmaceutical composition of claim 18, wherein tablet comprises the tablet coating of using attractive in appearance of the about 6 weight % of about 2 weight %-.
20. the pharmaceutical composition of claim 19, wherein tablet comprises the tablet coating of using attractive in appearance of the about 4.5 weight % of about 2.5 weight %-.
21. the pharmaceutical composition of claim 19, wherein attractive in appearance have moisture barrier character with tablet coating.
23. preparation comprises the method through the pharmaceutical composition of the wet quick property active pharmaceutical ingredient of wet granulation, this method may further comprise the steps:
A) provide wet quick property active pharmaceutical ingredient;
B) will wet quick property active pharmaceutical ingredient and at least a pharmaceutically acceptable mixed with excipients form mixture;
C) use the solution of binding agent in process solvent with the mixture wet granulation, form pharmaceutical composition.
24. the method for claim 23, the quick property of its being attacked by dampness active pharmaceutical ingredient is a cilazapril.
25. the method for claim 24, wherein compositions comprises the cilazapril of the about 0.1%-about 25.0% that accounts for composition total weight.
26. the method for claim 23, wherein at least 4% of the binder constitutes composition total weight.
27. the method for claim 23, wherein binding agent is selected from: cellulose derivative, polyvinyl pyrrolidone (PVP) and derivant thereof, polyvinyl acetate (PVA), polyvinyl alcohol and composition thereof.
28. the method for claim 27, wherein binding agent is a copolyvidone.
29. the method for claim 28, wherein copolyvidone is Plasdone S-630.
30. the method for claim 23, wherein process solvent be selected from can dissolved adhesive to reach the solvent of the concentration of 10%W/W at least.
31. the method for claim 23, wherein process solvent is selected from: water, ethanol, isopropyl alcohol and combination thereof.
32. the method for claim 31, wherein process solvent is that dense alcoholic solution and the concentration of the quick property of its being attacked by dampness active pharmaceutical ingredient in pharmaceutical composition are no more than about 1.7%.
33. the method for claim 32, the concentration of the quick property of its being attacked by dampness active pharmaceutical ingredient in pharmaceutical composition is no more than about 0.6%.
34. the method for claim 31, wherein process solvent is that water and the concentration of the quick property of its being attacked by dampness active pharmaceutical ingredient in pharmaceutical composition are higher than about 1.7%.
35. the method for claim 34, the concentration of the quick property of its being attacked by dampness active pharmaceutical ingredient in pharmaceutical composition is not less than about 2.7%.
36. the method for claim 23 is further comprising the steps of:
D) with granule and one or more mixed with excipients, form final blend; With
E) final blend is pressed into tablet.
37. the method for claim 36 is further comprising the steps of:
F) tablet is carried out coating with attractive in appearance with tablet coating.
38. the method for claim 37, wherein attractive in appearance have moisture barrier character with tablet coating.
42. the method for claim 37, the about 2%-about 6% that accounts for pharmaceutical composition with tablet coating wherein attractive in appearance.
43. the method for claim 37, the about 2.5%-about 4.5% that accounts for pharmaceutical composition with tablet coating wherein attractive in appearance.
44. treatment suffers from the patient's of disease method, comprise and give pharmaceutical composition that wherein active pharmaceutical ingredient is with at least a drug excipient wet granulation with wet comprising of treatment effective dose quick property active pharmaceutical ingredient and at least a pharmaceutically acceptable excipient to patient that needs are arranged.
45. the method for claim 44, the quick property of its being attacked by dampness active pharmaceutical ingredient is a cilazapril.
46. the method for claim 45, wherein at least a pharmaceutically acceptable excipient is a binding agent.
47. the method for claim 46, wherein disease is a hypertension.
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PCT/US2006/021586 WO2007142628A1 (en) | 2006-06-02 | 2006-06-02 | Stable formulation comprising moisture sensitive drug/s and manufacturing procedure thereof |
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CN (1) | CN101460191A (en) |
BR (1) | BRPI0621739A2 (en) |
CA (1) | CA2652620A1 (en) |
IL (1) | IL195060A0 (en) |
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Cited By (2)
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CN104519868A (en) * | 2012-06-01 | 2015-04-15 | 法国诗华动物保健公司 | Palatable oral veterinary compositions |
CN107441495A (en) * | 2012-02-17 | 2017-12-08 | 埃吉斯药物私人有限公司 | Stability-enhanced pharmaceutical preparation |
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DE102008020701A1 (en) | 2008-04-24 | 2009-10-29 | Bayer Technology Services Gmbh | Formulation with reduced hygroscopicity |
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DE3739690A1 (en) * | 1987-11-24 | 1989-06-08 | Hoechst Ag | STABILIZED MEDICINAL PRODUCTS, METHOD FOR THEIR PRODUCTION AND STABLE MEDICAL PREPARATIONS |
DE19952030A1 (en) * | 1999-10-28 | 2001-05-03 | Basf Ag | Process for the production of highly reactive polyisobutenes |
WO2003075842A2 (en) * | 2002-03-08 | 2003-09-18 | Teva Pharmeceuticals Usa, Inc. | Stable formulations of angiotensin converting enzyme (ace) inhibitors |
US6869963B2 (en) * | 2003-07-11 | 2005-03-22 | Sandoz Ag | Stable pharmaceutical compositions containing an ACE inhibitor |
TW201240679A (en) * | 2004-03-12 | 2012-10-16 | Capsugel Belgium Nv | Pharmaceutical formulations |
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CN107441495A (en) * | 2012-02-17 | 2017-12-08 | 埃吉斯药物私人有限公司 | Stability-enhanced pharmaceutical preparation |
CN104519868A (en) * | 2012-06-01 | 2015-04-15 | 法国诗华动物保健公司 | Palatable oral veterinary compositions |
CN110934835A (en) * | 2012-06-01 | 2020-03-31 | 法国诗华动物保健公司 | Palatable oral veterinary compositions |
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CA2652620A1 (en) | 2007-12-13 |
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WO2007142628A1 (en) | 2007-12-13 |
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