CN101641083A - The pharmaceutical solid dosage forms that comprises micro-embedded chemical compound in ionic water-insoluble polymers - Google Patents
The pharmaceutical solid dosage forms that comprises micro-embedded chemical compound in ionic water-insoluble polymers Download PDFInfo
- Publication number
- CN101641083A CN101641083A CN200780037684A CN200780037684A CN101641083A CN 101641083 A CN101641083 A CN 101641083A CN 200780037684 A CN200780037684 A CN 200780037684A CN 200780037684 A CN200780037684 A CN 200780037684A CN 101641083 A CN101641083 A CN 101641083A
- Authority
- CN
- China
- Prior art keywords
- ionic water
- treatment
- insoluble polymers
- dosage forms
- solid dosage
- 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.)
- Pending
Links
Images
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides the new pharmaceutical solid dosage forms that is used for oral administration, its comprise the treatment effective dose micro-embedded in ionic water-insoluble polymers unstable crystal form or the treatment compounds effective of amorphous form.Described treatment compounds effective with gel tendency, is had fast, can reproduce to provide and the dosage form of stripping curve fully in ionic water-insoluble polymers substrate by micro-embedded.These new solid pharmaceutical dosage formulations are effective to treatment or control numerous disease.
Description
The invention provides the new pharmaceutical solid dosage forms that is used for oral administration, its comprise the treatment effective dose micro-embedded in ionic water-insoluble polymers unstable crystal form or the treatment compounds effective of amorphous form.Described treatment compounds effective with gel tendency, is had fast, can reproduce to provide and the dosage form of stripping curve fully in ionic water-insoluble polymers substrate by micro-embedded.These new solid pharmaceutical dosage formulations are effective to treatment or control numerous disease.The present invention also provides a kind of method for the treatment of disease, and described method comprises to its described new solid pharmaceutical dosage formulation of experimenter's administering therapeutic effective dose of needs.The present invention also provides a kind of method that is used to prepare described pharmaceutical dosage form.
Whole documents that this paper quotes clearly are incorporated into this by reference.
The chemical compound of many therapeutic activities exists with amorphous form, and amorphous form lacks the long-term packing of molecules of (long-range order) in order that crystal form shows usually.Compare with crystalline compounds, the amorphous compound of therapeutic activity shows higher dissolubility and the dissolution rate of Geng Gao usually, and higher bioavailability is provided thus.Yet there are the many difficulties relevant with processability with their unstability in amorphous compound.Amorphous compound tends to fabrication process condition more responsive, described fabrication process condition such as high temperature and humidity level, the drug load of shearing and increasing.Amorphous compound gel during the manufacturing process of being everlasting, it is extremely difficult that feasible preparation has the solid dosage forms amorphous compound that can reproduce dissolution rate.The treatment compounds effective of many unsettled crystal forms also has the tendency of gel in process for making, and has similar physical stability and stripping problem.Because the hygroscopicity that they are higher, amorphous compound also often need special packing.
Because for the treatment compounds effective of the preferred solid unit dosage form of oral administration, be useful with the method that keeps desirable stripping character so the gel problem that overcomes the treatment active compound of amorphous compound and unstable crystal form during the manufacturing process is provided.
The invention provides the pharmaceutical solid dosage forms that is used for oral administration, it comprises the unstable crystal form for the treatment of effective dose or the treatment compounds effective of amorphous form, in ionic water-insoluble polymers, the ratio of wherein said treatment compounds effective and described ionic water-insoluble polymers was respectively 5: 1 to 1: 5 this chemical compound by micro-embedded (micro-embedded).
The present invention also provides the method for treatment disease, described method comprises to its experimenter of needs uses the solid pharmaceutical dosage formulation that is used for oral administration, described solid pharmaceutical dosage formulation comprises the unstable crystal form for the treatment of effective dose or the treatment compounds effective of amorphous form, in ionic water-insoluble polymers, the ratio of wherein said treatment compounds effective and described ionic water-insoluble polymers was respectively 5: 1 to 1: 5 this chemical compound by micro-embedded.
The present invention also provides a kind of preparation to be used for the method for the pharmaceutical solid dosage forms of oral administration, described method comprises: the treatment compounds effective that will treat the unstable crystal form of effective dose or amorphous form is micro-embedded in ionic water-insoluble polymers, and the ratio of wherein said amorphous compound and described ionomer carrier was respectively 5: 1 to 1: 5.
Below the simple accompanying drawing of describing.
Fig. 1 is the diagram that illustrates preferred micro-embedded method, and the alcoholic solution that described method uses the fluid bed spreader will treat compounds effective and ionic water-insoluble polymers is deposited on the microcrystalline cellulose spheres.
Fig. 2 illustrates with isopropanol solvent compound (compd A IPA) to compare; amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta]-chart of the powder X-ray-ray pattern of the pharmaceutical solid dosage forms (embodiment 3) of N-(pyrazine-2-yl)-propionic acid amide. (compd A); described isopropanol solvent compound is the crystal form as raw-material a kind of physical instability, and the selected micro-embedded method of this graph shows preferentially changes crystal form into amorphous form.
Fig. 3 illustrates with the compd B as raw-material physical instability crystal form to compare; amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S); the 2-dihydroxy ethyl)-pyrazine-2-yl]-chart of the powder X-ray-ray pattern of the pharmaceutical solid dosage forms (embodiment 8) of propionic acid amide. (compd B), the selected micro-embedded method of this graph shows preferentially changes crystal form into amorphous form.
Fig. 4 illustrates with the conventional amorphous solid dosage form (embodiment 2) of using non-ionic water-soluble polymer to compare, micro-embedded amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta in ionic water-insoluble polymers]-chart of the stripping curve of the pharmaceutical solid dosage forms of the present invention (embodiment 1) of N-(pyrazine-2-yl)-propionic acid amide. (compd A).
Fig. 5 illustrates with the conventional amorphous solid dosage form (embodiment 6-7) of using non-ionic water-soluble polymer to compare, micro-embedded amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta in ionic water-insoluble polymers]-chart of the stripping curve of the pharmaceutical solid dosage forms (embodiment 4-5) of N-(pyrazine-2-yl)-propionic acid amide. (compd A).
Fig. 6 illustrates with the conventional amorphous solid dosage form (embodiment 9) of using non-ionic water-soluble polymer to compare; micro-embedded amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S), 2-dihydroxy ethyl)-pyrazine-2-yl in ionic water-insoluble polymers]-chart of the stripping curve of the pharmaceutical solid dosage forms (embodiment 8) of propionic acid amide. (compd B).
Fig. 7 is illustrated in amorphous 2 (R) of lay up period-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta]-chart of the stripping curve of the pharmaceutical solid dosage forms (embodiment 3) of N-(pyrazine-2-yl)-propionic acid amide. (compd A), this graph shows stripping curve does not change.
Fig. 8 is illustrated in amorphous 2 (R) of lay up period-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S); the 2-dihydroxy ethyl)-pyrazine-2-yl]-chart of the stripping curve of the pharmaceutical solid dosage forms (embodiment 8) of propionic acid amide. (compd B), this graph shows stripping curve does not change.
Fig. 9 is illustrated in amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta after 3 months the storage]-chart of the powder X-ray-ray pattern of the pharmaceutical solid dosage forms (embodiment 3) of N-(pyrazine-2-yl)-propionic acid amide. (compd A); the described chemical compound of this graph shows remains amorphous form, and the condition of described storage is under acceleration environment (40 ℃/75%RH) have in the opaque high-density polyethylene bottle of induction insulating (induction-sealed) of vinyl cover.
Figure 10 is illustrated in amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S) after 6 months the storage; the 2-dihydroxy ethyl)-pyrazine-2-yl]-chart of the powder X-ray-ray pattern of the pharmaceutical solid dosage forms (embodiment 8) of propionic acid amide. (compd B); the described chemical compound of this graph shows remains amorphous form, and the condition of described storage is under acceleration environment (40 ℃/75%RH) have in the insulating opaque high-density polyethylene bottle of induction of vinyl cover.
Figure 11 be illustrated among the embodiment 4-5 pharmaceutical solid dosage forms of the present invention of the compd A by micro-embedded method preparation and the stripping curve of the solid dosage forms of the compd A that in embodiment 10-11, prepares by conventional method between the chart of comparison.
Figure 12 be illustrated among the embodiment 8 pharmaceutical solid dosage forms of the present invention of the compd B by micro-embedded method preparation and the stripping curve of the solid dosage forms of the compd B that in embodiment 12, prepares by conventional method between the chart of comparison.
The invention provides the pharmaceutical solid dosage forms for oral administration, its comprise the treatment effective dose micro-embedded in ionic water-insoluble polymers unstable crystal form or the treatment compounds effective of amorphous form. The described treatment compounds effective that has the gel tendency when being exposed to aqueous medium, heating and shearing usually can not be processed to obtain fast, can reproduce by conventional water-based wet granulation process and completely medicine release. By treatment active compound of the present invention is micro-embedded in ionic water-insoluble polymers matrix, treatment active compound of the present invention with gel tendency is converted into amorphous form, and this provides a kind of and have fast, can reproduce and the complete formulation of stripping curve. This amorphous form in ionic water-insoluble polymers matrix, is avoided manufacturing process and ambient influnence to protect it by micro-embedded. Described novel drugs solid dosage forms can repeatedly be made and discharge with consistent stripping curve, minimizes with the bioavilability maximization with variability. This novel drugs solid dosage forms is preferably with the capsule formulation preparation, so that relatively very fast and more reproducible stripping curve to be provided.
As used herein, following term has given implication:
Term " amorphous form " refers to lack long-term orderly packing of molecules and the compound that has the gel tendency when being exposed to aqueous medium, and described gel is because due to their the inherent physical property (as having the tendency that is plastified by water).
Term " ionomer " refers to that molecular weight is 10,000 or larger large molecule, and it is comprised of covalent bond many less molecule (monomer) together. These ionomers in water almost (practically) soluble, but on some pH value or under the solubility that can be ionized and become.
Term " ionomer substrate " is meant an ionomer, its by many often be that the chain that tangles is formed." substrate " also is defined as something, and another something of portion rises or forms within it.
Term " micro-embedded " is meant a kind of method; this method changes the treatment compounds effective of unstable crystal form or amorphous form into amorphous form; and with this chemical compound as in substrate; tight enclosing is avoided the influence of manufacturing process and environment to protect this chemical compound in ionic water-insoluble polymers.
Term " medicinal " is as pharmaceutical carrier, excipient etc., is meant on the pharmacology acceptable and be atoxic basically for the experimenter who is applied particular compound.
Term " pharmaceutical salts " is meant conventional acid-addition salts or base addition salts, and it keeps the biological effectiveness and the character of The compounds of this invention, and is formed by suitable acid of non-toxicity organic or inorganic or organic or inorganic alkali.The example of acid-addition salts comprises derived from mineral acid with derived from those salt of organic acid, described mineral acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, sulfamic acid, phosphoric acid and nitric acid for example, and described organic acid is for example right-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, lactic acid, fumaric acid etc.The example of base addition salts comprises the salt derived from ammonium, potassium, sodium and quaternary ammonium hydroxide, for example tetramethylammonium hydroxide.With medicinal compound (being medicine) chemical modification salify is pharmacists's technique known, in order to physics and chemical stability, hygroscopicity and the dissolubility of the improvement that obtains chemical compound.Referring to for example H.Ansel etc., " pharmaceutical dosage form and drug delivery system " (Pharmaceutical Dosage Forms and Drug Delivery Systems) (nineteen ninety-five the 6th edition), the 196th and the 1456-1457 page or leaf.
Term " prodrug " is meant the chemical compound of experience biotransformation before the pharmacotoxicological effect that shows them.The pharmaceutical chemistry modification is also referred to as " drug latenciation " to overcome the pharmacy problem.Drug latenciation be with the bioactive compound chemical modification to form noval chemical compound, this noval chemical compound enzymatic in vivo will discharge parent compound after attacking.The chemical modification of parent compound makes the variation of physicochemical properties will influence absorption, distribution and enzymatic metabolism.The definition of drug latenciation also has been expanded and has comprised the non-enzymatic regeneration of parent compound.Regeneration as hydrolysis, dissociate (dissociative) and other might not be enzyme mediation reaction the result and take place.The medicine of term prodrug, latentiation and the commutative use of bioreversible derivant.By inferring, latentiation implies element time lag (time lag element) or the time composition (time component) that relates to internal regeneration biological activity parent molecule.The term prodrug is general, because it comprises the medicaments derivative of latentiation and change those materials with the actual contents of receptors bind into after administration.The term prodrug is the generic term of the reagent of experience biotransformation before the pharmacotoxicological effect that shows them.
Term " treatment effective dose " is meant that treatment compounds effective or its pharmaceutical salts effectively treat, prevent, alleviate or improve the amount of disease symptoms.
Term " treatment compounds effective " is meant effective treatment, prevents, alleviates or improves the chemical compound of disease symptoms.Treat compounds effective in the present invention and have and have the tendency of gel with the crystal form of amorphous form or physical instability.
Term " crystal form of physical instability " is meant the crystal form of the therapeutical active compound of the following stated: (i) when being exposed to water and/or having the gel tendency when hot; (ii) change amorphous form easily into.The crystal form of physical instability and amorphous form can be distinguished by the X-ray diffraction analysis.
The invention provides the pharmaceutical solid dosage forms that is used for oral administration, it comprises the unstable crystal form for the treatment of effective dose or the treatment compounds effective of amorphous form, this chemical compound by micro-embedded in ionic water-insoluble polymers.Preferably, pharmaceutical dosage form is applied to mammal; More preferably, pharmaceutical dosage form is applied to the people.
The treatment compounds effective of unstable in the present invention crystal form or amorphous form can be selected from extensively various chemical compound and their pharmaceutical salts.Amorphous compound lacks long-term orderly packing of molecules and have the gel tendency when being exposed to aqueous medium.Unstable crystalline compounds is unstable physically and also have a gel tendency.Preferred treatment compounds effective has the glucokinase activating agents chemical compound, it is main indication treatment and following indication impaired fasting glucose (IFG) (impairing fasting glucose that exploitation is used for type 2 diabetes mellitus, IFG) and impaired glucose tolerance (impaired glucosetolerance, chemical compound IGT).Preferred glucokinase activating agents chemical compound is 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta]-N-(pyrazine-2-yl)-propionic acid amide. (compd A) and 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S), 2-dihydroxy ethyl)-pyrazine-2-yl]-propionic acid amide. (compd B).
A kind of preferred glucokinase activating agents chemical compound is 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta]-N-(pyrazine-2-yl)-propionic acid amide. (compd A):
The preparation of compd A (amorphous) is at U.S. Patent number 7,105, and is open in 671, and the content of this United States Patent (USP) is by with reference to being incorporated into this.The preparation of compd A IPA (isopropanol solvent compound) is open in U.S. Provisional Patent Application number 60/791,256, and the content of this U.S. Patent application is by with reference to being incorporated into this.
Another kind of preferred glucokinase activating agents chemical compound is 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S), 2-dihydroxy ethyl)-pyrazine-2-yl]-propionic acid amide. (compd B):
The preparation of compd B is open in U.S. Patent Application Publication No. 2004/0147748, and the content of this U.S. Patent application is incorporated into this by reference.
Ionic water-insoluble polymers can be selected from extensively various chemical compound in the present invention.Ionic water-insoluble polymers can be an anionic or cationic.The selection of ionic water-insoluble polymers for the treatment compounds effective of unstable crystal form or amorphous form micro-embedded in substrate with prevent chemical compound be exposed to create conditions or during dissolution medium gel be crucial.Suitable ionic water-insoluble polymers is that common molecular weight ranges is 60,000-300,000 dalton (D), preferred 65,000-275,000D and 70-250 most preferably, those of 000D.The non-limiting example that exemplifies of useful ionic water-insoluble polymers comprise methacrylic acid and ethyl acrylate copolymer (
L100-55), methacrylic acid and methylmethacrylate copolymer (
L100,
S-100), dimethyl amino ethyl methacrylate and neutral methacrylic acid esters copolymer (
E100), CAP, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate and hydroxypropyl emthylcellulose acetate succinate.
Being used for treatment compounds effective with unstable crystal form or amorphous form changes ionic water-insoluble polymers substrate into and can be undertaken by many methods with the micro-embedded method that the protection chemical compound avoids environmental effect.Exemplary non-limiting micro-embedded method comprises fluidized bed coating, spray drying, and lyophilization, solvent control microdeposit, hot melt is extruded and the shooting flow evacuator body.
In spray drying or freeze-drying method, the treatment compounds effective of physical instability crystal form or amorphous form and ionic water-insoluble polymers be dissolved in commonly have in the lower boiling solvent described solvent such as ethanol, acetone etc.Then with this solution spray drying or lyophilization with evaporating solvent, stay the treatment compounds effective with amorphous form by micro-embedded in ionic water-insoluble polymers.
In solvent control microdeposit method, the treatment compounds effective and the ionic water-insoluble polymers of physical instability crystal form or amorphous form are dissolved in the common solvent, and described solvent is the dimethyl propylene amide for example, dimethyl formamide, ethanol, acetone etc.To treat compounds effective and ionic water-insoluble polymers solution then and add the cold water (2 ℃ to 5 ℃ .) that is adjusted to proper pH value, and make and treat compounds effective microdeposit in polymeric matrix.The required pH of solution depends on used polymer and is to determine easily to those skilled in the art.With the washing of microdeposit use medium for several times, the amount of residual solvent is reduced to for the acceptable scope of this solvent in polymer then." acceptable scope " for every kind of solvent is definite according to international coordination meeting guide (theInternational Conference on Harmonization (ICH) guidelines).
In the hot melt extrusion method, the treatment compounds effective and the ionic water-insoluble polymers of physical instability crystal form or amorphous form are mixed in blender, and be continuously fed into the temperature control extruder, cause treating compounds effective by molecular dispersion in fused ionic water-insoluble polymers.The extrudate that obtains is cooled to room temperature and grinds to form fine powder.Can add plasticizer to reduce the glass transition temperature of polymer, reduce processing temperature.
In the shooting flow evacuator body, the treatment compounds effective and the ionic water-insoluble polymers of physical instability crystal form or amorphous form is dissolved in supercritical fluid such as liquid nitrogen or the liquid carbon dioxide.Then by the evaporative removal supercritical fluid, stay the treatment compounds effective with amorphous form by microdeposit in polymeric matrix.
Fluidized bed coating is the most preferred micro-embedded method that tight contact is provided between amorphous compound and ionic water-insoluble polymers.Fluidized bed coating is the selection technology of the amorphous compound that is used to handle cohesive material, promptly can not handles by conventional aqueous process technology.Amorphous compound is dissolved in ethanol, and after removing ethanol, change stable amorphous form into.
The ratio of treatment compounds effective and ionic water-insoluble polymers was generally 5: 1 to 1: 5 respectively, and preferred 4: 1 to 1: 4, more preferably 3.5: 1 to 1: 3.5, most preferably 3: 1 to 1: 3.
The amount that is present in the treatment compounds effective in the pharmaceutical solid dosage forms by the weight of whole compositionss, is generally 5% to 75%, and is preferred 10% to 60%, and more preferably 25% to 50%, most preferably 20% to 40%.
The amount that is present in the treatment compounds effective of the treatment effective dose in the pharmaceutical solid dosage forms is 5mg to 750mg, preferred 20mg to 500mg, more preferably 50mg to 300mg, and 100mg to 200mg most preferably.
Preferably, pharmaceutical solid dosage forms is deposited on the microcrystalline cellulose spheres and further comprises sealant around pharmaceutical solid dosage forms.
Ionic water-insoluble polymers substrate generally has 100 microns to 1500 microns, preferred 150 microns to 1450 microns, more preferably 175 microns to 1400 microns and 200 microns to 1375 microns particle mean size most preferably.
In a further preferred embodiment, the invention provides the method that is used for the treatment of disease, described method comprises to its experimenter of needs uses the solid pharmaceutical dosage formulation that is used for oral administration, this pharmaceutical dosage form comprises the unstable crystal form for the treatment of effective dose or the treatment compounds effective of amorphous form, in ionic water-insoluble polymers, the ratio of wherein treating compounds effective and ionic water-insoluble polymers is respectively 5: 1 to 1: 5 to this chemical compound by micro-embedded.
Preferably, the invention provides the method for the treatment disease of above definition, wherein said treatment compounds effective is the glucokinase activating agents chemical compound.More preferably; the method of above-mentioned definition is provided; wherein said glucokinase activating agents chemical compound is 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta]-N-(pyrazine-2-yl)-propionic acid amide. or 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S), 2-dihydroxy ethyl)-pyrazine-2-yl]-propionic acid amide..
Preferably, the invention provides the method for the treatment disease of above definition, wherein said treatment compounds effective is to be present in the described pharmaceutical solid dosage forms in the amount by the weight of whole compositionss about 5% to about 50%.More preferably, provide the method for above definition, the described treatment compounds effective of wherein said treatment effective dose is to be present in the described pharmaceutical solid dosage forms to the amount of about 750mg with about 5mg.
Preferably, provide according to method of the present invention, wherein said ionic water-insoluble polymers is selected from the group of being made up of following: methacrylic acid and ethyl acrylate copolymer, methacrylic acid and methylmethacrylate copolymer, dimethyl amino ethyl methacrylate and neutral methacrylic acid esters copolymer, CAP, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate and hydroxypropyl emthylcellulose acetate succinate.In another preferred embodiment that also has, the invention provides the method that a kind of preparation is used for the pharmaceutical solid dosage forms of oral administration, this method comprises: the treatment compounds effective of unstable crystal form or amorphous form is micro-embedded in ionic water-insoluble polymers, and the ratio of wherein said amorphous compound and described ionomer carrier was respectively 5: 1 to 1: 5.
Pharmaceutical solid dosage forms of the present invention prepares by a kind of method, and this method preferably changes the therapeutical active compound of crystal form into micro-embedded amorphous form in ionic water-insoluble polymers substrate.Preferably, the granule of acquisition (that is small bead (beadlet)) mixes or sealing with antitack agent.The percentage ratio that adds to the antitack agent of described spheroid is 1% to 5%.
Pharmaceutical dosage form of the present invention can be according to the embodiment preparation of following elaboration.The purpose that embodiment is provided is the preparation that illustrates rather than limit dosage form of the present invention.
Embodiment
Provide the following example to illustrate pharmaceutical solid dosage forms, this pharmaceutical solid dosage forms utilizes the amorphous compound and the ionic water-insoluble polymers of (i) different ratios; (ii) dissimilar polymer (that is ionic water-insoluble polymers vs non-ionic water-soluble polymer); (iii) as the crystal form of raw-material different physical instability.
Embodiment 1
In the present embodiment; prepare amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta]-pharmaceutical solid dosage forms of N-(pyrazine-2-yl)-propionic acid amide. (compd A), wherein that described amorphous drug is micro-embedded in ionic water-insoluble polymers.Compd A IPA is the isopropyl alcohol solvate, and it is the crystal form as raw-material physical instability, and changes amorphous form into by micro-embedded method.
Fig. 1 is the diagram that illustrates a kind of preferred micro-embedded method, and the alcoholic solution that this method uses the fluid bed spreader will treat compounds effective and ionic water-insoluble polymers is deposited on the microcrystalline cellulose spheres.
The excipient that is used for example of formulations is as described below:
L100 and
L100-55 (producer-Rohm Pharma-Degussa).
The Kollidon VA 64 (vinylpyrrolidone-vinyl acetate co-polymer of producer-BASF), copolymerization of ethylene ketopyrrolidine (copolyvidone), copolyvidone (copovidone), VP/Vac copolymer 60/40, l-vinyl-2-pyrrolidone and vinylacetate be the copolymer of 6: 4 ratios by mass.
Amorphous silicic acid calcium (Zeopharm 600)-producer: Mutchler.
The granularity specification:
Altalc-500 (producer: be Talcum Luzenac America), the impalpable powder final stage.
Corn starch (producer: national starch (National Starch)).
Polyvidone (povidone) K30 (producer: BASF).
Preparation is formed
Be filled in the hard gelatin capsule
*Be equivalent to the 100mg amorphous form after during processing, removing IPA.
The micro-embedded step of medicine
Preparation medicine layer suspension
In tarry rustless steel container, compd A IPA is added dehydrated alcohol (ethyl alcohol200proof), use the propeller mixer middling speed to mix simultaneously.Continue to mix and dissolve fully until compd A IPA.Slowly polymer is added above-mentioned solution, middling speed is mixed simultaneously.Continue to mix and dissolve fully until polymer.Corn starch (or in prescription specified Altalc-500) is added above-mentioned solution, use the propeller mixer middling speed to mix simultaneously.Continue to mix at least 1 hour or until obtaining uniform medicine layer suspension dispersion.
The medicine layer suspension is applied to spheroid
Microcrystalline cellulose spheres (Cellets 200) is put into the fluid bed spreader with Wurster HS plug-in unit (insert).With warm at least 2 minutes of microcrystalline cellulose spheres, the intake air temperature was 50 ± 15 ℃, provided enough air volume with the fluidisation spheroid.To be coated on the microcrystalline cellulose spheres from above medicine layer suspension, wherein utilize following processing conditions to use the propeller mixer middling speed to mix continuously:
50 ± 15 ℃ of inlet temperatures
40 ± 10 ℃ of target product temperature
Jet hole 1.0 ± 0.5mm
Spray pressure 3.0 ± 1.0 crust
Use enough air volumes to be used for the fluidisation ball.
The dry stratified ball of medicine (drug layered spheres) that obtains at least 1 hour is used the sealing coating process afterwards.
The sealing application step
Preparation sealing coating suspension
In rustless steel container, 30 POVIDONE K 30 BP/USP 30 (polyvinylpyrrolidone) is added dehydrated alcohol, use the propeller mixer middling speed to mix simultaneously.Continue to mix and dissolve fully until 30 POVIDONE K 30 BP/USP 30.Amorphous silicic acid calcium (Zeopharm 600) is added above-mentioned solution, use the propeller mixer middling speed to mix 30 minutes or be coated with the dispersion of suspension at least simultaneously until acquisition sealing uniformly.
To seal the coating suspension and be applied to the stratified ball of medicine
To wherein utilize following processing conditions to use the propeller mixer middling speed to mix continuously from above sealing coating suspension spray extremely from the stratified ball of above medicine:
50 ± 15 ℃ of intake air temperature
40 ± 10 ℃ of target product temperature
Jet hole 1.0 ± 0.5mm
Spray pressure 3.0 ± 1.0 crust
Use enough air volumes to be used for the fluidisation ball.
Use 40 ± 15 ℃ intake air temperature, will be coated with the ball drying at least 30 minutes from above sealing.By turning off plant air heating, coolant seal coating ball is to obtain 30 ± 5 ℃ product temperature.Sealing coating ball is discharged in the double-layer polyethylene bag in opaque high-density polyethylene drum.In the opaque high-density polyethylene drum of sealing, in the double-layer polyethylene bag, transport the ball of the sealing coating of finishing, between Polythene Bag, have two silica gel bags in order to encapsulation.
Encapsulated
Use capsule filling machine, will pack in the White-opalescent hard gelatin capsule with the target weight of regulation from above sealing coating ball.As required with the dedusting of White-opalescent hard gelatin capsule.In airtight opaque high-density polyethylene drum, in the double-layer polyethylene bag, store the White-opalescent hard gelatin capsule of finishing, between Polythene Bag, have two silica gel bags.
Embodiment 2
In the present embodiment; prepare amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta]-pharmaceutical solid dosage forms of N-(pyrazine-2-yl)-propionic acid amide. (compd A), wherein that amorphous compound is micro-embedded in non-ionic water-soluble polymer.Compd A IPA is the isopropanol solvent compound, and it is the crystal form as raw-material physical instability, and changes amorphous form into by micro-embedded method.
Preparation is formed
The hard gelatin capsule of packing into
*During processing, after removing IPA, be equivalent to the 100mg anhydrous form
Preparation method
Prepare capsule to be similar to embodiment 1 described mode, difference is Altalc-500 is substituted corn starch as antitack agent.Replace the sealing application step with blend step, the stratified ball of medicine that obtains was mixed in the Turbula blender 5 minutes with amorphous silicic acid calcium (Zeopharm 600).
Embodiment 3
In the present embodiment; prepare amorphous 2 (R) of the present invention-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta with the drug load that increases]-N-(pyrazine-2-yl)-propionic acid amide. (compd A) preparation, wherein that amorphous drug is micro-embedded in ionic water-insoluble polymers.Compd A IPA is the isopropanol solvent compound, and it is the crystal form as raw-material physical instability, and changes amorphous form into by micro-embedded method.
Preparation is formed
Be filled in the hard gelatin capsule
*Be equivalent to the 100mg anhydrous form after during processing, removing IPA
Prepare capsule to be similar to embodiment 1 described mode.
Fig. 2 illustrates with compd A isopropanol solvent compound to compare; amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta]-chart of the powder X-ray-ray pattern of the pharmaceutical solid dosage forms (embodiment 3) of N-(pyrazine-2-yl)-propionic acid amide. (compd A); described isopropanol solvent compound is the crystal form as raw-material a kind of physical instability, and the selected micro-embedded method of this graph shows preferentially changes crystal form into amorphous form.
Fig. 9 is illustrated in amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta after 3 months the storage]-chart of the powder X-ray-ray pattern of the pharmaceutical solid dosage forms (embodiment 3) of N-(pyrazine-2-yl)-propionic acid amide. (compd A); the described chemical compound of this graph shows remains amorphous form, and the condition of described storage is under acceleration environment (40 ℃/75%RH) have in the opaque high-density polyethylene bottle of induction insulating (induction-sealed) of vinyl cover.
Embodiment 4-7
In these embodiments; amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta]-solid dosage forms of N-(pyrazine-2-yl)-propionic acid amide. (compd A), wherein in embodiment 4-5 or embodiment 6-7 amorphous compound respectively by micro-embedded in ionic water-insoluble polymers or in the non-ionic water-soluble polymer.Prepare these compositionss to illustrate the influence of polymer for the dosage form stripping curve.Compd A IPA is the isopropanol solvent compound, and it is the crystal form as raw-material physical instability, and changes amorphous form into by micro-embedded method.
Preparation is formed
Be filled in the hard gelatin capsule
*Be equivalent to the 100mg anhydrous form after during processing, removing IPA
Prepare capsule to be similar to embodiment 1 described mode, difference is pointed out to be, substitutes corn starch, and Altalc-500 is used as antitack agent.Replace the sealing application step with blend step, the stratified ball of medicine that obtains was mixed in the Turbula blender 5 minutes with amorphous silicic acid calcium (Zeopharm 600).
Embodiment 8
In the present embodiment; prepare amorphous 2 (R) of the present invention-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S); the 2-dihydroxy ethyl)-pyrazine-2-yl]-propionic acid amide. (compd B) preparation, wherein that amorphous drug is micro-embedded in ionic water-insoluble polymers.Compd B is the crystal form as raw-material physical instability, and changes amorphous form into by micro-embedded method.
Preparation is formed
Be filled in the hard gelatin capsule
Prepare capsule to be similar to embodiment 1 described mode.
Fig. 3 illustrates with the compd B as raw-material physical instability crystal form to compare; amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S); the 2-dihydroxy ethyl)-pyrazine-2-yl]-chart of the powder X-ray-ray pattern of the pharmaceutical solid dosage forms (embodiment 8) of propionic acid amide. (compd B), the selected micro-embedded method of this graph shows preferentially changes crystal form into amorphous form.
Figure 10 is illustrated in amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S) after 6 months the storage; the 2-dihydroxy ethyl)-pyrazine-2-yl]-chart of the powder X-ray-ray pattern of the pharmaceutical solid dosage forms (embodiment 8) of propionic acid amide. (compd B); the described chemical compound of this graph shows remains amorphous form, and the condition of described storage is under acceleration environment (40 ℃/75%RH) have in the insulating opaque high-density polyethylene bottle of induction of vinyl cover.
Embodiment 9
In the present embodiment; prepare amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S); the 2-dihydroxy ethyl)-pyrazine-2-yl]-propionic acid amide. (compd B) preparation, wherein that amorphous drug is micro-embedded in non-ionic water-soluble polymer.Compd B is the crystal form as raw-material physical instability, and changes amorphous form into by micro-embedded method.
Preparation is formed
Be filled in the hard gelatin capsule
Prepare capsule to be similar to embodiment 1 described mode, difference is, replaces the sealing application step with blend step, and the ball that obtains was mixed in the Turbula blender 5 minutes with amorphous silicic acid calcium (Zeopharm 600).
Embodiment 10-11
(control sample)
In these embodiments, prepare amorphous 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta in a usual manner]-N-(pyrazine-2-yl)-propionic acid amide. (compd A).With compd A and ionic water-insoluble polymers (i.e.Eudragit (r) L100-55, Eudragit (r) L100) or non-ionic water-soluble polymer (being 30 POVIDONE K 30 BP/USP 30, Klucel LF) physical mixed.That compd A is not micro-embedded in these polymer.
Preparation is formed
| Embodiment 10 | Embodiment 11 | |
| Composition | The mg/ capsule ＊ | The mg/ capsule ＊ |
| Compd A, spray-dried powders | ?100.00 | ?100.00 |
| ?Eudragit?L100-55 | ?66.67 | ?-- |
| ?Eudragit?L100 | ?-- | ?66.67 |
| 30 POVIDONE K 30 BP/USP 30 | ?-- | ?-- |
| ?Klucel?LF | ?-- | ?-- |
| ?Altalc-500 | ?29.412 | ?29.412 |
| Amorphous silicic acid calcium (Zeopharm 600) | ?3.398 | ?3.398 |
| Filling weight ＊ | ?199.48 | ?199.48 |
Be filled in the hard gelatin capsule
By the spray-dired compd A powder of weighing, polymer, Talcum and Zeopharm 600, and they are put into blender, the preparation capsule.Mixture was mixed 10 minutes.By #30 mesh sieve sieve mixture of powders, and in blender remix 5 minutes.The mixture of powders of some 199.48mg is filled in the hard gelatin capsule of #0 size.
Figure 11 is illustrated in to use ionic water-insoluble polymers by the pharmaceutical solid dosage forms of the present invention of the compd A of micro-embedded method preparation with by conventional method (physical mixed among the embodiment 4-5; Non-micro-embedded method) chart of the comparison between the stripping curve of the solid dosage forms of the compd A that in embodiment 10-11, prepares.
This embodiment illustrated with the micro-embedded method in ionic water-insoluble polymers of the chemical compound of unstable crystal form provide relatively comparatively fast, stripping curve completely.Contrast therewith, conventional formulation (physical mixed; Non-micro-embedded method) provides relatively poor stripping curve.
Embodiment 12
(control sample)
In the present embodiment, prepare unstable crystal 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S), 2-dihydroxy ethyl)-pyrazine-2-yl in a usual manner]-propionic acid amide. (compd B).With compd B with
The L100-55 physical mixed.That compd B is not micro-embedded in ionic water-insoluble polymers.
Preparation is formed
| Composition | The mg/ capsule ＊ |
| Compd B, micronized powder | ??100.00 |
| ?Eudragit?L100-55 | ??66.67 |
| Corn starch | ??18.50 |
| Amorphous silicic acid calcium (Zeopharm 600) | ??4.65 |
| 30 POVIDONE K 30 BP/USP 30 | ??0.50 |
| Filling weight ＊ | ??190.32 |
Be filled in the hard gelatin capsule
By the micronized compd B powder of weighing, Eudragit L-100-55 and corn starch, and they are put into blender, the preparation capsule.Mixture was mixed 5 minutes.Then Zeopharm600 and PVP K30 are added blender, mixture was further mixed 2 minutes.The mixture of powders of some 190.32mg is filled in the hard gelatin capsule of #0 size.
Figure 12 is illustrated in to use ionic water-insoluble polymers by the pharmaceutical solid dosage forms of the present invention of the compd B of micro-embedded method preparation with by conventional method (physical mixed among the embodiment 8; Non-micro-embedded method) chart of the comparison between the stripping curve of the solid dosage forms of the compd B of preparation in embodiment 12.
Figure 11-12 illustrated with the micro-embedded method in ionic water-insoluble polymers of the chemical compound of unstable crystal form or amorphous form provide relatively comparatively fast, stripping curve completely.Contrast therewith, conventional formulation (physical mixed; Non-micro-embedded method) provides relatively poor stripping curve.
Dissolution test
Use USP device (basket (basket) or blade method (paddle method)) under fixing speed, in the dissolution medium of 900mL, to assess the stripping of the peroral dosage form that contains compd A (embodiment 1-7 and 10-11) and compd B (embodiment 8-9 and 12).In different time interval acquiring sample aliquot, and by UV or HPLC analysis.Result and medium, method and the speed of stripping research are set forth in Fig. 4-8.
Wherein amorphous drug (compd A or compd B) is provided faster stripping curve (embodiment 1,3,4,5 and 8) completely by micro-embedded preparation of the present invention in ionic water-insoluble polymers.Ionic water-insoluble polymers prevents the gel of amorphous drug when being exposed to dissolution medium really.Contrast therewith, wherein amorphous drug (compd A or compd B) is provided slower incomplete stripping curve (embodiment 2,6,7 and 9) by micro-embedded conventional formulation in non-ionic water-soluble polymer.This data show non-ionic water-soluble polymer does not prevent amorphous drug gel when being exposed to dissolution medium.Pharmaceutical solid dosage forms protection amorphous drug of the present invention is avoided the influence of microenvironment, even also keep the dissolution characteristic of dosage form thus under (stressed) storage requirement of strengthening (i.e. was at 3-6 under the 40 ℃/75%RH month).
Although a plurality of embodiment of the present invention is provided, obviously can changes essential structure and utilize other embodiment of the present invention under the spirit and scope of the present invention situation to be provided at not deviate from.All these improvements and changes are intended to comprise that within the scope of the invention scope of the present invention is limited by appended claim rather than by the specific embodiments that provides by by way of example.
Claims (25)
1. pharmaceutical solid dosage forms that is used for oral administration, its comprise the treatment effective dose micro-embedded in ionic water-insoluble polymers the physical instability crystal form or the treatment compounds effective of amorphous form, the ratio of wherein said treatment compounds effective and described ionic water-insoluble polymers was respectively 5: 1 to 1: 5.
2. according to the dosage form of claim 1, wherein said treatment compounds effective is the glucokinase activating agents chemical compound.
3. according to the dosage form of claim 2; wherein said glucokinase activating agents chemical compound is 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta]-N-(pyrazine-2-yl)-propionic acid amide. or 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S), 2-dihydroxy ethyl)-pyrazine-2-yl]-propionic acid amide..
4. according to the dosage form of claim 3, wherein said glucokinase activating agents chemical compound is 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S), 2-dihydroxy ethyl)-pyrazine-2-yl]-propionic acid amide..
5. according to the dosage form of claim 1, wherein said treatment compounds effective is to be present in the described pharmaceutical solid dosage forms in the amount by the weight 5% to 75% of whole compositionss.
6. according to the dosage form of claim 1, the described treatment compounds effective of wherein said treatment effective dose is that the amount with 5mg to 750mg is present in the described pharmaceutical solid dosage forms.
7. according to the dosage form of claim 6, the described treatment compounds effective of wherein said treatment effective dose is that the amount with 100mg to 200mg is present in the described pharmaceutical solid dosage forms.
8. according to the dosage form of claim 1, wherein said ionic water-insoluble polymers has 60,000 to 300,000 daltonian molecular weight.
9. according to the dosage form of claim 1, wherein said ionic water-insoluble polymers is selected from the group of being made up of following: methacrylic acid and ethyl acrylate copolymer, methacrylic acid and methylmethacrylate copolymer, dimethyl amino ethyl methacrylate and neutral methacrylic acid esters copolymer, CAP, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate and hydroxypropyl emthylcellulose acetate succinate.
10. according to the dosage form of claim 9, wherein said ionic water-insoluble polymers is methacrylic acid and methylmethacrylate copolymer or methacrylic acid and ethyl acrylate copolymer.
11. according to the dosage form of claim 10, wherein said ionic water-insoluble polymers is methacrylic acid and ethyl acrylate copolymer.
12. according to the dosage form of claim 1, wherein said pharmaceutical solid dosage forms is deposited on the microcrystalline cellulose spheres.
13. according to the dosage form of claim 1, it also comprises the sealant around described pharmaceutical solid dosage forms.
14. according to the dosage form of claim 1 to 13, it is used for the treatment of disease.
15. according to the dosage form of claim 1 to 13, it is used for the treatment of type ii diabetes.
16. method for preparing the pharmaceutical solid dosage forms that is used for oral administration, described method comprises: will treat the micro-embedded in ionic water-insoluble polymers of the unstable crystal form of effective dose or amorphous form, the ratio of wherein said treatment compounds effective and described ionomer carrier was respectively 5: 1 to 1: 5.
17. according to the method for claim 16, wherein said treatment compounds effective is the glucokinase activating agents chemical compound.
18. method according to claim 17; wherein said glucokinase activating agents chemical compound is 2 (R)-(3-chloro-4-mesyl-phenyl)-3-[1 (R)-3-oxo-cyclopenta]-N-(pyrazine-2-yl)-propionic acid amide. or 2 (R)-(3-chloro-4-mesyl-phenyl)-3-cyclopenta-N-[5-(1 (S), 2-dihydroxy ethyl)-pyrazine-2-yl]-propionic acid amide..
19. according to the method for claim 16, wherein said treatment compounds effective is to be present in the described pharmaceutical solid dosage forms in the amount by the weight 5% to 50% of whole compositionss.
20. according to the method for claim 16, the described treatment compounds effective of wherein said treatment effective dose is that the amount with 5mg to 750mg is present in the described pharmaceutical solid dosage forms.
21. method according to claim 16, wherein said ionic water-insoluble polymers is selected from the group of being made up of following: methacrylic acid and ethyl acrylate copolymer, methacrylic acid and methylmethacrylate copolymer, dimethyl amino ethyl methacrylate and neutral methacrylic acid esters copolymer, CAP, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate and hydroxypropyl emthylcellulose acetate succinate.
22. according to the method for claim 16, the wherein said micro-embedded group that is selected from following composition: fluidized bed coating, spray drying, lyophilization, solvent control microdeposit, hot melt is extruded and the shooting flow evacuator body.
23. according to the method for claim 22, wherein said micro-embedded be fluidized bed coating.
24. according to the method for claim 16, the treatment active compound of wherein said micro-embedded crystal form with physical instability changes amorphous form into.
25. aforesaid the present invention.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US85185206P | 2006-10-13 | 2006-10-13 | |
| US60/851,852 | 2006-10-13 | ||
| US60/954,401 | 2007-08-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101641083A true CN101641083A (en) | 2010-02-03 |
Family
ID=41615702
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200780037684A Pending CN101641083A (en) | 2006-10-13 | 2007-10-04 | The pharmaceutical solid dosage forms that comprises micro-embedded chemical compound in ionic water-insoluble polymers |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101641083A (en) |
| ZA (1) | ZA200902498B (en) |
-
2007
- 2007-10-04 CN CN200780037684A patent/CN101641083A/en active Pending
-
2009
- 2009-04-09 ZA ZA200902498A patent/ZA200902498B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200902498B (en) | 2010-03-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20080107725A1 (en) | Pharmaceutical Solid Dosage Forms Comprising Amorphous Compounds Micro-Embedded in Ionic Water-Insoluble Polymers | |
| ES2254274T3 (en) | HYDROGEL HETERODISPERSOS SYSTEMS OF SUSTAINED LIBERATION FOR INSOLUBLE PHARMACOS. | |
| EP1748764B1 (en) | An amine drug-containing slow-release granule preparation based on particles with a coating layer and the corresponding method of production | |
| KR20010082251A (en) | Sustained-release particles | |
| CN106102716A (en) | The solid composite medicament of androgen receptor antagonists | |
| JP2002523443A (en) | Omeprazole preparation | |
| BRPI0812064B1 (en) | pharmaceutical formulation in the form of agglomerates, tablets, and process for producing a pharmaceutical formulation | |
| JP6148252B2 (en) | New formulation | |
| CN101977593A (en) | Drug delivery systems comprising weakly basic drugs and organic acids | |
| HU204201B (en) | Coating materialdetermining delivery of active components from pharmaceutical compositions, and process for producing phrmaceutical compositions containing this coating material | |
| US9833436B2 (en) | Method of preparing drug agglomerate | |
| US20040175427A1 (en) | Omeprazole formulation | |
| EP2533766B1 (en) | Pharmaceutical mini-tablets for sustained release of flecainide acetate | |
| ES2285538T3 (en) | GRANULES CONTAINING VENLAFAXINE CHLORHYDRATE. | |
| EP2665466B1 (en) | Solid molecular dispersion of fesoterodine | |
| TR202016210A2 (en) | Pharmaceutical form containing acidic substance | |
| US20120027822A1 (en) | Process for Producing Rapidly Disintegrating Spheroids (Pellets), Granules and/or Mixtures Thereof | |
| AU1543702A (en) | Multiparticulate formulations of lithium salts for oral administration suitable for-a-day administration | |
| ES2376095B1 (en) | ENERGY PELLETS OF DULOXETINE. | |
| CN101641083A (en) | The pharmaceutical solid dosage forms that comprises micro-embedded chemical compound in ionic water-insoluble polymers | |
| EP3628311B1 (en) | A process for the preparation of a modified release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride | |
| WO2020111089A1 (en) | Pharmaceutical composition | |
| EP4125825B1 (en) | A modified release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride and a process for its preparation | |
| CN113476420B (en) | Metformin hydrochloride sustained-release tablet and preparation method thereof | |
| US20230310401A1 (en) | Pharmaceutical Composition Containing Dabigatran Etexilate And Preparation Method Thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20100203 |