CN104797240A - Composition for immediate and extended release - Google Patents
Composition for immediate and extended release Download PDFInfo
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- CN104797240A CN104797240A CN201380060349.8A CN201380060349A CN104797240A CN 104797240 A CN104797240 A CN 104797240A CN 201380060349 A CN201380060349 A CN 201380060349A CN 104797240 A CN104797240 A CN 104797240A
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The subject invention relates to fast dissolving pharmaceutical compositions comprising an active ingredient for immediate release and further comprising a controlled release dosage form comprising an active ingredient for controlled release.
Description
Invention field
The present invention relates to fast dissolving pharmaceutical compositions, described pharmaceutical composition comprises the active component for discharging immediately and comprises containing the Co ntrolled release dosage form for the active component of Co ntrolled release, relate to their method of preparation and relate to their in treatment and the purposes of preventing disease in mammal, particularly people.
Background technology
The fast dissolving pharmaceutical dosage form being designed to release of active ingredients immediately is in the oral cavity known and may be used for sending far-ranging medicine (Critical Reviews in Therapeutic Drug CarrierSystems, 21 (6): 433-475 (2004); Seager H. (1998), J.Phar.Pharmacol 50:375-382; The people such as Bandari (January 2008), Asian Journal of Pharmaceutics 2-11).
In rapid-dissolve dosage form, medicine physics remains in by carrier material, such as, and mannitol and fish glue (EP 1 501 534; EP 1 165 053), modified starch (US 6,509,040), with the Pullulan (EP 1 803 446) of combination of amino acids, with the maltodextrin (US 2004/0228919) of sorbitol combinations, in the substrate that levan (WO 2011/120904) or inulin (WO 2011/120903) form.In order to prepare rapid-dissolve dosage form, can the solution of medicine and carrier material, suspension or dispersion liquid be packed in bubble chamber (blister cavities), freezing and lyophilizing subsequently.
The Co ntrolled release bead comprising the active component that will discharge in a controlled fashion is also as known in the art and such as at US 6,911,217, US 2009/0192228, EP 1 781 275, and describes in WO 2007/029087.These Co ntrolled release pearls are typically used in for Orally administered in pharmaceuticals industry Chinese medicine (glutoid) capsule, and can by preparations such as the such as layering of multiple method, extrusion spheronization, granulation, hot-melt extruded, spraying dry.
Some disease and disease need a kind of medicine to cause the mode discharged immediately to be used another kind of medicine with cause extend release mode use.Certainly, if these two kinds of medicines can be used with a single dosage unit, it discharges a kind of medicine with direct mode and discharges another kind in an elongated manner, and this will can be favourable certainly.
summary of the invention
The present invention now provided with a kind of preparation, described preparation not only comprises the first medicine for discharging immediately remained in substrate, and in addition comprising at described Medium Culture the dosage form that another kind retains, described another kind of dosage form is the prolongation release pearl of the second medicine comprised for extending release.
Therefore the present invention provides a kind of single dosage unit pharmaceutical combination product, described product comprise lyophilizing, fusing type, rapid solution or disintegrating preparations, described preparation comprises the first active component for discharging (IR) immediately, wherein said Rapid Dissolution Formulations also comprises prolongation release (ER) bead, and described prolongation release bead comprises will with the second active constituents of medicine of control mode release.Extend release bead physics to retain or embed in the substrate of Rapid Dissolution Formulations.
Described fast-dissolving oral pharmaceutical composition is oral freeze-dried product (also referred to as orally disintegrating tablet or oral molten) typically, and it comprises the first active component for discharging (IR) immediately and comprises prolongation release (ER) bead containing second active constituents of medicine that will discharge in a controlled fashion.
Described prolongation release bead can be prepared by method as known in the art, the such as layering of described method, extrusion spheronization, granulation, hot-melt extruded, spraying dry etc.
Have been found that compositions of the present invention (comprising bead in Rapid Dissolution Formulations), allow to realize much beat all and useful technique effect:
The stable release profiles of the first and second medicines (active component), namely with in IR preparation, only comprise the first medicine respectively and in ER preparation, only comprise those similar, the substantially the same or identical release profiles observed in the compositions of separating of the second medicine;
Compared with the compositions not having bead, relatively high tensile strength (power namely fractureed in three-point bend test needed for tablet);
Pharmacy is acceptable and from the angle of the acceptable composition total weight of consumer;
Be less than the fater disintegration/dissolution time of 30 seconds; With
Described compositions can be prepared by lyophilizing, only has very little to the prolongation release profiles of bead
Impact, essentially no impact or without impact.
Wherein, relatively high tensile strength makes easily to shift out described compositions from its container (typically blister package (blisterpack)), and not disintegrate and not do not damage the risk of dosage form between referring to.Unit dosage forms of the present invention can typically operate in mode like the tablet class suppressed with routine, only with waterborne liquid or when contacting with saliva in mouth, disintegrate occurs.
Although there is such tensile strength, when with aqueous medium or when contacting with saliva, compositions fater disintegration of the present invention, especially when administered orally, described compositions fater disintegration.
Pharmaceutical composition of the present invention can pass through, such as in freezing dry process, from comprising the first active component in the solution, the liquid preparation subliming solvent (such as water) of one or more matrix formers and Co ntrolled release pearl (it also comprises the second other active component) obtains.According to an embodiment, the liquid preparation of unit dose amount is introduced recess and distils subsequently, thus obtaining the pharmaceutical composition of (after distilling) unit dosage forms, described pharmaceutical composition comprises two kinds of active component, and one is used for release immediately and one is used for Co ntrolled release.Described recess can be the recess of open blister package, and then sublimation step (and therefore after recess forms solid unit dosage form of compositions), diaphragm seal or paper tinsel cover recess, form the blister package of sealing.
Especially, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises: the open matrix net containing the first active constituents of medicine; More than one matrix formers; With the Co ntrolled release pearl containing the second active constituents of medicine.
The invention still further relates to a kind of method of pharmaceutical compositions, described method comprises from comprising the first active constituents of medicine, more than one matrix formers, subliming solvent in the Co ntrolled release bead containing the second active constituents of medicine and the liquid preparation of solvent.
The invention still further relates to the method for pharmaceutical compositions, said method comprising the steps of:
A () prepares mixture, described mixture comprises the first active component, Co ntrolled release pearl containing the second active component, more than one matrix formers and solvent;
(b) freezing described solution;
(c) from the solution subliming solvent of described freezing mistake,
Wherein the pharmaceutical composition of acquisition is like this after contacting with standardized aqueous medium, disintegrate in 30 seconds.
The present invention relates to and treat overactive bladder, nocturia or its method combined in the experimenter needing treatment, described method comprises the compositions to described experimenter's administering therapeutic effective dose, and wherein the second active component is antimuscarinic compounds.
The present invention relates to the method for the treatment of benign prostatic hyperplasia in the experimenter needing treatment, described method comprises the compositions to described experimenter's administering therapeutic effective dose, and wherein the second active component is selectivity alpha blocker.
accompanying drawing is sketched
Fig. 1 a is the diagram of single dosage unit pharmaceutical combination product of the present invention, described product comprise lyophilizing, dissolve type, Rapid Dissolution Formulations, described preparation comprises the first active component for discharging immediately, and wherein said Rapid Dissolution Formulations also comprises the prolongation release bead containing second active constituents of medicine that will discharge in a controlled fashion.
Fig. 1 b extends release bead or the diagram of pearl and it comprises for of the present invention:
-1: core
-2: optional inner sealing coating
-3: inner medicated layer
-4: optional outside seal coating
-5: outside rete and
-6: optional other polymeric layer.
Fig. 1 c be for of the present invention extend release bead or pearl diagram and it comprises containing medicine, the core of excipient and optionally Co ntrolled release polymer.Described core can optionally use Co ntrolled release polymer-coated.
Fig. 2 compares
the chart of XL and tolterodine ER pearl (granule) and the stripping curve of lyophilized products in pH 6.8 phosphate buffer according to embodiment 1, uses American Pharmacopeia (USP) instrument 1 (basket), 100rpm.
Fig. 3 is the chart comparing the first active component (Desmopressin) from the dosage form of embodiment 2 and the release of the second active component (tolterodine) in pH 6.8 phosphate buffer, for Desmopressin, use USP instrument 2 (slurry), 50rpm, and for tolterodine, use USP instrument 1 (basket), 100rpm.
Fig. 4 is the chart comparing the first active component (Desmopressin) from the dosage form of embodiment 3 and the release of the second active component (tolterodine) in pH 6.8 phosphate buffer, for Desmopressin, use USP instrument 2 (slurry), 50rpm, and for tolterodine, use USP instrument 1 (basket), 100rpm.
Fig. 5 is the chart comparing the first active component (Desmopressin) from the dosage form of embodiment 4 and the release of the second active component (tolterodine) in pH 6.8 phosphate buffer, for Desmopressin, use USP instrument 2 (slurry), 50rpm, and for tolterodine, use USP instrument 1 (basket), 100rpm.
Fig. 6 compares the chart that the first active component (Desmopressin) and the second active component (tolterodine) from the dosage form of embodiment 5 discharge in pH 6.8 phosphate buffer, for Desmopressin, use USP instrument 2 (slurry), 50rpm, and for tolterodine, use USP instrument 1 (basket), 100rpm.
Fig. 7 compares
the chart of XL and tolterodine ER pearl (granule) and the stripping curve of lyophilized products in pH 6.8 phosphate buffer according to embodiment 6, uses American Pharmacopeia (USP) instrument 1 (basket), 100rpm.
Fig. 8 compares
the chart of XL and tolterodine ER pearl (granule) and the stripping curve of lyophilized products in pH 6.8 phosphate buffer according to embodiment 7, uses American Pharmacopeia (USP) instrument 1 (basket), 100rpm.
Fig. 9 compares
the chart of XL and tolterodine ER pearl (granule) and the stripping curve of lyophilized products in pH 6.8 phosphate buffer according to embodiment 8, uses American Pharmacopeia (USP) instrument 1 (basket), 100rpm.
Figure 10 is the chart comparing the first active component (Desmopressin) from the dosage form of embodiment 9 and the release of the second active component (tolterodine) in pH 6.8 phosphate buffer, for Desmopressin, use USP instrument 2 (slurry), 50rpm, and for tolterodine, use USP instrument 1 (basket), 100rpm.
Figure 11 is the chart comparing the first active component (Desmopressin) from the dosage form of embodiment 10 and the release of the second active component (tolterodine) in pH 6.8 phosphate buffer, for Desmopressin, use USP instrument 2 (slurry), 50rpm, and for tolterodine, use USP instrument 1 (basket), 100rpm.
Figure 12 is the chart comparing the first active component (Desmopressin) from the dosage form of embodiment 11 and the release of the second active component (tolterodine) in pH 6.8 phosphate buffer, for Desmopressin, use USP instrument 2 (slurry), 50rpm, and for tolterodine, use USP instrument 1 (basket), 100rpm.
Figure 13 is the chart comparing the first active component (Desmopressin) from the dosage form of embodiment 12 and the release of the second active component (tolterodine) in pH 6.8 phosphate buffer, for Desmopressin, use USP instrument 2 (slurry), 50rpm, and for tolterodine, use USP instrument 1 (basket), 100rpm.
Figure 14 is the chart comparing the first active component (Desmopressin) from the dosage form of embodiment 13 and the release of the second active component (tolterodine) in pH 6.8 phosphate buffer, for Desmopressin, use USP instrument 2 (slurry), 50rpm, and for tolterodine, use USP instrument 1 (basket), 100rpm.
Figure 15 is the chart comparing the first active component (Desmopressin) from the dosage form of embodiment 14 and the release of the second active component (tolterodine) in pH 6.8 phosphate buffer, for Desmopressin, use USP instrument 2 (slurry), 50rpm, and for tolterodine, use USP instrument 1 (basket), 100rpm.
detailed Description Of The Invention
The object of this invention is to provide a kind of dosage form, described dosage form comprises two kinds of active component, and one of them will discharge in mode immediately and one will discharge in a controlled fashion.
The present invention provides a kind of mouth discrete dosage forms newly now, and described mouth discrete dosage forms comprises two kinds of medicines (active component).A kind of in described medicine discharges in mode immediately, and another kind discharges in a controlled fashion.Described dosage form is rapid-dissolve dosage form, such as, but is not limited to the unit of molten or lyophilizing.The pharmaceutical pack discharged in a controlled fashion is contained in bead (pearl), and described bead (pearl) is included in again in Rapid Dissolution Formulations.Although there is described bead in rapid-dissolve dosage form, described compositions is stable, and the weight of whole compositions is that pharmacy is acceptable and be acceptable from the angle of consumer, and the mouth dissolution time of rapid-dissolve dosage form remains fast.
Term " medicine ", " active component " or " active constituents of medicine " will be used alternatingly in this article.
Term " pharmaceutical composition " and " compositions " are used alternatingly in this article, refer to pharmaceutical composition of the present invention.
Term " Co ntrolled release bead " or " bead " or " Co ntrolled release pearl " or " pearl " or " Co ntrolled release granule " or " granule " will be used alternatingly in this article.
Co ntrolled release pearl can by multiple method preparation as known in the art, such as layering, extrusion spheronization, granulation, hot-melt extruded, spraying dry etc., and wherein the second active component mixes with release control agent and/or is released controlling agent and applies.
When Co ntrolled release pearl is prepared by layering, described Co ntrolled release pearl is typically containing being selected from water-soluble core, the core 1 without pharmaceutically active of the core of water-fast core and water-swellable, described core is coated with the outside rete 5 that inner medicated layer 3 discharges from internal layer with control medicine.
Some Co ntrolled release pearls also comprise " seal coating " 2 be made up of the polymer being selected from water-fast polymer substantially and water-soluble polymer substantially between inertia core 1 and inner medicated layer 3.
Some Co ntrolled release pearls also comprise " seal coating " 4 be made up of the polymer being selected from water-fast polymer substantially and water-soluble polymer substantially between inner medicated layer 3 and outside rete 5.
Described Co ntrolled release pearl can also containing other polymeric layer 6 on outside rete 5.
The object of this invention is to provide Co ntrolled release pearl, its drug release patterns by lyophilizing appreciable impact, does not therefore make it possible in the dosage form of lyophilizing of the present invention, use these pearls.
Described core is typically made up of material that is water-soluble, water-fast or water-swellable, and maybe can be able to be made up of any material being conventionally used as core any other of pearl or bead medicinal, material that is water-soluble, water-fast or water-swellable forms.Such as, described core can be ball (sugared ball NF), sucrose crystal, glass or the microcrystalline Cellulose of sucrose/starch.Especially, described core can be the microcrystalline Cellulose core of water-soluble sugared ball or water-swellable.Such as described core can by extrude excipient such as microcrystalline Cellulose and lactose and then prepared by dry extrudate.
Substantially normally " GI is insoluble " (GI=gastrointestinal) or " GI part is insoluble " film form polymer to the water-fast polymer of the optional seal coating 2 and 4 being arranged between (i) core 1 and inner medicated layer 3 and/or (enter core to control penetration by water) between (ii) inner medicated layer 3 and outside rete 5.The unrestricted example of this polymer is ethyl cellulose, cellulose acetate, acetylbutyrylcellulose, polymethacrylates such as ethyl acrylate/methylmethacrylate copolymer (
nE30D) and ammonio methacrylate copolymer type A and B (
rL 30D and RS 30D), silicone elastomer and two or more mixture thereof.In one particular embodiment, the substantially water-fast polymer of inner sealing coating 2 comprises ethyl cellulose.Sometimes, more than one plasticizers are used together with described polymer.The unrestricted example of plasticizer comprises dibutyl sebacate; propylene glycol, triethyl citrate, tributyl citrate; Oleum Ricini; acetylizad monoglyceride, CitroflexA-2, acetyl tributyl citrate butyl ester; diethyl phthalate; phthalic acid dibutyl ester, glyceryl triacetate, in-chain triglyceride such as fractioned coconut wet goods.
Water-soluble polymer in optional seal coating 2 and 4 can be selected from hydrophilic polymer, such as polyvinylpyrrolidone (PVP), poly alkylene glycol is Polyethylene Glycol such as, gelatin, polyvinyl alcohol, starch and derivant thereof, cellulose derivative, such as hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose, carboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, acrylate copolymer, polymethacrylates and two or more mixture thereof.
Internal layer 3 containing (second) active component can be made up of active component (medicine), is with or without the polymer as binding agent.When deployed, described binding agent normally hydrophilic and can be water-soluble or water-fast.The unrestricted example be used for containing the polymer in the internal layer of active medicine is hydrophilic polymer, such as polyvinylpyrrolidone (PVP), poly alkylene glycol is Polyethylene Glycol such as, gelatin, polyvinyl alcohol, starch and derivant thereof, cellulose derivative, such as hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose, carboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, acrylate copolymer, polymethacrylates and two or more mixture thereof.In one particular embodiment, described inner medicated layer 3 comprises hydroxypropyl emthylcellulose as binding agent.The ratio of internal layer Chinese medicine and hydrophilic polymer is usually in the scope of 1:5 to 10:1 (w/w).
The suitable polymer used in for the outside rete 5 of Drug controlled release can be selected from water-fast polymer or have the polymer of the solubility depending on pH, such as, such as, ethyl cellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, trimellitic acid cellulose acetate, polymethacrylates, or its mixture, described polymer optionally with plasticizer (than as mentioned above those) combine.Optionally, except above-mentioned polymer, described Co ntrolled release layer comprises the another kind of material with different solubilities characteristic, to regulate permeability and thus the rate of release of adjustment the second medicine.Can with such as, the illustrative polymers that ethyl cellulose is used as modifier is together drawn together: HPMC, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, Polyethylene Glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol, there is the polymer of the dissolubility depending on pH, such as cellulose acetate-phthalate or ammonio methacrylate copolymer and methacrylic acid copolymer, or its mixture.Additive is sucrose, lactose such as, and pharmaceutical grade surfactant and two or more mixture thereof also can be included in Co ntrolled release layer.In one particular embodiment, described outside rete 5 comprises the combination of hydroxypropyl emthylcellulose (HPMC) and ethyl cellulose.
Suitable polymer for other polymeric layer 6 optional on outside rete 5 be can provide enteric and/or frozen-dried protective function those and can methacrylic acid copolymer be selected from, cellulose acetate-phthalate, cellulose acetate butyrate, Hydroxypropyl Methylcellulose Phathalate, succinic acid hydroxypropyl methyl cellulose acetate, polyvinyl acetate phthalate, trimellitic acid cellulose acetate, carboxymethylethylcellulose, Lac, cellulose ether (such as, ethyl cellulose, hypromellose, hyprolose), PVP, acrylate polymer (such as,
nE 30D,
rL,
and two or more mixture RS).They can be coated on outside rete 5 with the form of solution or dispersion liquid.Can optionally need frozen-dried protective function to avoid the dissolving of adventitia 5 in freeze-drying process.
Described Co ntrolled release pearl is prepared by following steps:
A) provide substantially water-soluble, core 1 unit of the material of water-fast or water-swellable;
B) optionally the inner sealing coating 2 of polymer is coated in described core 1;
C) internal layer 3 containing (second) active component and optionally polymer adhesive is coated in core 1 or inner sealing coating 2;
D) optionally the outside seal coating 4 of polymer is coated on described internal layer 3;
E) the outside rete 5 effectively controlling active component release is coated in described internal layer 3 or outside seal coating 4; With
F) optionally on described outside rete 5, other polymeric layer 6 is applied.
Layering or coating operation are carried out preferably by the solution of each layer material or dispersion liquid being sprayed in core, such as, at centrifugal application device, and coating pan,
rotor machining, or carry out in fluid bed coater, preferably carry out in fluid bed coater.
After coating seal coating and skin, can usually in fluidized system or in pan dryer system, such as, temperature by being heated to about 30-80 DEG C reaches about 60 minutes by pearl " sclerosis (cure) ".
In one embodiment, the amount of optional inner sealing coating 2 forms about 4% to about 15% (w/w) of final pearl compositions.
In one embodiment, the amount of inner medicated layer 3 forms about 5% to about 25% (w/w) of final pearl compositions.
In one embodiment, the amount of optional outside seal coating 4 forms about 1% to about 25% (w/w) of final pearl compositions.
In one embodiment, the amount of outside rete 5 forms about 25% to about 55% (w/w) of final pearl compositions.
In one embodiment, the amount of optional additional polymer 6 layers forms about 10% to about 35% (w/w) of final pearl compositions.
When obtaining Co ntrolled release bead by hot-melt extruded, known hot-melt extruded equipment is used to extrude (second) active component and Co ntrolled release excipient.The extrudate of generation ground and sieves, obtaining required fraction.Optionally by the granule Co ntrolled release polymer-coated of the drying of required particle diameter.Particle coating can be carried out in suitable coating equipment, described coating equipment such as, centrifugal application device, coating disk,
rotor machining, fluid bed coater etc.
Co ntrolled release excipient for hot-melt extruded can be selected from ethyl cellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, trimellitic acid cellulose acetate, polymethacrylates, HPMC, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, Polyethylene Glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol, carbomer, PLG, polyoxyethylene, glyceryl palmitostearate, behenate and two or more mixture thereof, its optionally with plasticizer (than as mentioned above those) merge.
When obtaining Co ntrolled release pearl by spraying dry, will (second) active component and Co ntrolled release dissolution of polymer or disperse in media as well.By this solution or dispersion liquid spraying dry and optionally the particle drying of generation is sieved, obtain required particle diameter.
Polymer can be selected from for spray-dired Co ntrolled release polymer, such as, such as, ethyl cellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, trimellitic acid cellulose acetate, polymethacrylates, HPMC, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, Polyethylene Glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol and two or more mixture thereof, described polymer optionally with plasticizer (than as mentioned above those) combine.
When obtaining Co ntrolled release pearl by granulating, (second) active component and excipient being dry mixed and using binder solution to granulate.Dried particles also sieves to obtain required fraction.The dried particles of required particle diameter can use Co ntrolled release polymer-coated further.Alternatively, active component and Co ntrolled release excipient be dry mixed and use binder solution to granulate.Then particle drying is sieved, obtain required fraction.Can optionally by the granule Co ntrolled release polymer-coated of the drying of required particle diameter.
Pelletization is carried out in granulator, such as, but is not limited to, quick blunger granulator, planetary stirrer, fluidized bed processor, centrifugal type pelleter etc.The coating of granule can be carried out in suitable coating equipment, and described equipment is centrifugal application device such as, coating disk,
rotor machining, fluid bed coater etc.
Co ntrolled release polymer for granulating can be selected from polymer, such as, such as, ethyl cellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, trimellitic acid cellulose acetate, polymethacrylates, HPMC, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, Polyethylene Glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol and two or more mixture thereof, described polymer optionally with plasticizer (than as mentioned above those) combine.
When obtaining Co ntrolled release pearl by extrusion spheronization; by (second) active component, filler and optionally Co ntrolled release are polymer dry mixed and at granulator such as Fastmixinggranulator, planetary stirrer; fluidized bed processor, granulates in centrifugal type pelleter etc.Then the wet agglomerate obtained is extruded and round as a ball, form spherical particle.Spherical particle is dry and sieve, obtain required fraction.Optionally the granule of the drying of required particle diameter can be used Co ntrolled release polymer-coated further.Alternatively, the particle drying extruded is sieved, obtain required fraction.Optionally the granule of the drying of required particle diameter can be used the polymer-coated controlled further.Being coated in suitable coating equipment of granule is carried out, described equipment such as, centrifugal application device, coating disk,
rotor machining, fluid bed coater etc.
Co ntrolled release polymer for extrusion spheronization can be selected from polymer, such as, such as, ethyl cellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, trimellitic acid cellulose acetate, polymethacrylates, HPMC, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, Polyethylene Glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol and two or more mixture thereof, described polymer optionally with plasticizer (than as mentioned above those) combine.
In one embodiment, the prolongation release profiles for pearl of the present invention has resistance to the freeze-drying process for the preparation of pharmaceutical composition of the present invention, is not namely substantially exposed for the freeze-drying process impact preparing pharmaceutical composition of the present invention.
Term " substrate " should be understood to represent the solid carrier medium for active component.Described substrate comprises more than one excipient.The excipient forming described substrate be also referred to as " matrix formers " in this article and often kind of described chemical agent as " matrix formers ".
Term " open matrix net " should be understood to include the substrate of the carrier material (one or more matrix formers) of water-soluble or water dispersible, and described substrate has the gap disperseed everywhere.Described substrate with aqueous medium or with saliva contacts after fater disintegration.
Unless otherwise defined, the percent in description and claim is based on weight (% by weight or w/w).
Matrix formers in compositions can be any reagent of the substrate of the carrier material that can form water-soluble or water dispersible.The unrestricted example of matrix formers is levan, inulin, Pullulan, sodium alginate, fish glue, β-limit dextrin (BLD), modified starch, maltodextrin (optionally with sorbitol combinations), arabic gum, hydroxypropyl emthylcellulose and/or pectin and combination in any thereof.In one embodiment, described matrix formers is selected from by the following group formed: levan, inulin, Pullulan, arabic gum, maltodextrin, HPMC, sodium alginate and their combination.
Levan is (also referred to as leaven (leaven), levan (levulosan), polyfructosan (polyfructosan), polyfructosan (polyfructose) and polyfructosan (polylevulan)) be fructose, C
6h
12o
6polymer.Levan between fructose ring, has polysaccharide that β-(2->6) connect (wherein numeral describes the carbon atom that connects in fructose ring and β describes stereochemical relationship.Levan has also been described to levan (fructans), and it is β-(2->6) that the major glycosides wherein between D-fructofuranoside monomeric unit connects.Levan is usually manufactured by microorganism and is not present in plant as high-molecular weight compounds.Some have and are less than 100, and the low-molecular-weight levan of 000 daltonian molecular weight may reside in grass.
" levan " used herein should be understood to include the levan being derived from any source, described source is such as but not limited to India's aphelenchoides (Aspergillus indicus), aspergillus versicolor (Aspergilllus versicolor), Acetobacter suboxydans (Acetobacter suboxydans), achromobacter (Achromobacter spp.), actinomycetes (Actinomycenes sp.), actinomyces viscosus (Actinomyces viscosus), aerobacteria (Aerobacter aerogenes), produce aerobacter levans (Aerobacter levanicum), aspergillus sydowi (Aspergillus sydowi), blown-ball Azotobacter (Azotobacter chroococcum), poly-viscosity bacillus (Bacillus polymyxa), Bacillus licheniformis (Bacillus licheniformis), Bacillus macerans (Bacillus macerans), bacillus megaterium (Bacillus megatherium), saccharolytic (Bacillus mesentericus), bacillus subtilis (Bacillussubtilis), the fine bacillus of expectorant saliva (Bacillus vulgates), Ralstonia solanacearum (Corynbacteriumlaevaniformans), ice nucleation active bacteria (Erwinia herbicola), Gluconobacter oxydans (Gluconobacter oxydans), Leuconostoc mesenteroides (Leuconostoc mesenteroides), mucus tooth mycete (Odontomyces viscosus), glass plant bacillus (Phytobacterium vitrosum), peaches and plums plant Zymomonas mobilis (Phytomonas pruni), pseudomonas fluorescens (PsuedomonasFluorescens), pseudomonas syringae (Pseudomonas Syringae), dwell Lee pseudomonas (Pseudomonas prunicola), rothia dentocariosa (Rothis dentocariosa), Ji Lien Serratieae (Serratia kiliensis), bargen's streptococcus (Steptococcus bovis), Streptococcus mutans (Steptococcus mutans), Streptococcus saliva truffles (Steptococcus salivarius), xanthomonas campestris (Xanthomonas campestris), peaches and plums Xanthomonas campestris (Xanthomonaspruni), zymomonas mobilis (Zymomonas mobilis) etc.In a specific embodiment, levan is planted available from fermentation single cell bacterium (Zymomonas) and bacillus (Bacillus).In one more specifically embodiment, levan is available from zymomonas mobilis (Zymomonas mobilis).
Should be appreciated that, the derivant of levan (describing in such as WO 98/03184) also can be used to take alternative levan.
Inulin is fructose, C
6h
12o
6polymer, typically there is terminal glucose.Inulin is between fructose ring, have the polysaccharide that β-(2->1) connect, and wherein numeral describes carbon atom in the fructose ring connected and β describes stereochemical relationship.Inulin is produced by very eurypalynous plant.
Inulin used herein should be understood to include the inulin being derived from any source, described source is such as but not limited to the plant containing high concentration inulin, described plant includes, but are not limited to Radix Inulae (Elecampane) (Inula helenium); Herba Taraxaci (Dandelion) (Taraxacum officinale); Rhizoma Dioscoreae (Wild Yam) (Dioscorea spp.); Jerusalem artichoke (Jerusalem artichokes) (Helianthustuberosus); Herba Cichorii (Chicory) (Cichorium intybus); Pachyrrhyizus erosus (Jicama) (Pachyrhizuserosus); Fructus Arctii (Burdock) (Arctium lappa); Bulbus Allii Cepae (Onion) (Allium cepa); Bulbus Allii (Garlic) (Allium sativum); Folium Agaves variegatae (Agave) (Agave spp.); Yacon (Yac ó n) (Smallanthus sonchifolius spp.); With Karma summer (Camas) (Camassia spp.).In a specific embodiment, inulin is available from Herba Cichorii (Cichorium intybus).
More than one second matrix formers may reside in compositions.As the sugar of the second matrix formers, sugar alcohol, monosaccharide, disaccharide, trisaccharide, polysaccharide, albumen, aminoacid, the unrestricted example of natural gum etc., include but not limited to, mannitol, trehalose, Raffinose, inositol, Pullulan, sucrose, lactose, dextrose, erythritol, xylitol, lactose, maltose alcohol, hydroxyl isomaltulose (isomalt), alanine, arginine, threonine, glycine, cysteine, serine, histidine, valine, proline, lysine, agedoite, glutamine, ribose, glucose, galactose, fructose, maltose, maltotriose, guar gum, xanthan gum, Tragacanth, aluminium-magnesium silicate, microcrystalline Cellulose, sodium carboxymethyl cellulose etc.
Usually, the remainder (balance) of preparation can be substrate.Therefore the percent of substrate can reach 100%.The weight range of the second matrix formers used according to the invention about 0 to about between 30%.
In one embodiment of the invention, levan is matrix formers main in compositions.In another embodiment, inulin is main matrix formers.In another embodiment, conbined usage levan and inulin are as matrix formers.
In another embodiment, described compositions also comprises mannitol or Raffinose or trehalose or its combination as the second matrix formers in open matrix net.
In one embodiment, levan is matrix formers, forms 10 – 50% of composition total weight.In another embodiment, levan forms the 20-40% of composition total weight.In another embodiment, levan forms the 25-35% of composition total weight.
In other embodiments, mannitol or trehalose or Raffinose or its combination are used as the second matrix formers, form 10 – 40% of composition total weight.In one embodiment, these second matrix formers form the 20-30% of composition total weight.
Therefore, compositions of the present invention can be comprise levan as main matrix forming agent and mannitol or trehalose or Raffinose (or its combination) compositions as the second matrix formers, wherein levan forms 10 – 50% (all % of composition is w/w, mean the weight of the composition mentioned in the weight of all constituents of the compositions of combination), and the second matrix formers forms 10 – 40%, typically 20-30%.
According to the character of active component, the content of the first active component can typically (but by halves) in the scope of 0.01 – 1% of whole compositions, typically in the scope of 0.02-0.2%.According to the character of active component, the content of the second active component can typically (but by halves) in the scope of 1 – 50% of whole compositions, typically in the scope of 3-10%.In one embodiment, active component forms about 4% of composition total weight.In another embodiment, active component forms about 5% of composition total weight.In another embodiment, active component forms about 6% of composition total weight.In other embodiments, active component forms 7% of composition total weight.In other embodiments, active component forms 8% of composition total weight.
Term " disintegrate " refers to according to the condition in aqueous medium, substrate and the dissolving of the first medicine for discharging immediately or " scattering ", and releases or release extends release dosage form, such as bead or pearl, thus makes them start to discharge the second medicine.Disintegrate in standardized aqueous medium, typically being less than in 30 seconds, and more typically being less than in 10 seconds, or is even less than 9,8,7,6,5,4,3, and 2 or even 1 second.
" disintegration time " and " dissolution time " is used alternatingly in this article and should be understood to mean stripping or the time needed for disintegrate compositions of the present invention in standardized aqueous medium.
" oral cavity dissolution time " used herein should be understood to mean the time in the oral cavity needed for the stripping present composition.
" fast/disintegrate/dissolving rapidly " used herein should be understood to include the present composition in standardized aqueous medium in 30 seconds, typically in 20 seconds, preferably in 10 seconds, or even 9,8,7,6,5, disintegrate/dissolving in 4,3,2 or 1 seconds.
The example of aqueous medium used herein is water or buffer (such as potassium dihydrogen phosphate, dipotassium hydrogen phosphate, dibastic sodium phosphate) or by the people such as Morjaria (May 2004), the artificial saliva that Dissolution Technologies 12 – 15 describes.Used herein for determining what " the standardized aqueous medium " of disintegration time defined at experimental section.For determining that the method for disintegration time is as described by experimental section.
Saliva used herein refers to mammal, the saliva especially in human mouth.
" tensile strength " used herein should be understood to destroy the power needed for tablet, it is measured by three-point bend test, under wherein tablet being placed in bending stress (people (2002) such as Mohd, DrugDevelopment and Industrial Pharmacy 28 (7): 809-813).
In one embodiment, pharmaceutical composition of the present invention has about 0.05 to 2N/mm
2the tensile strength of scope.In another embodiment, pharmaceutical composition of the present invention has about 0.05 to 0.3N/mm
2the tensile strength of scope.In another embodiment, pharmaceutical composition of the present invention has about 0.1 – 0.25N/mm
2the tensile strength of scope.In another embodiment, pharmaceutical composition of the present invention has about 0.11 – 0.23N/mm
2the tensile strength of scope.
It is contemplated that pharmaceutical composition of the present invention has such fater disintegration/rate of dissolution, in standardized aqueous medium, described compositions, in 30 seconds, was typically dissolved in 10 seconds.
In one embodiment, pharmaceutical composition of the present invention has about 0.05 – 2N/mm
2the tensile strength of scope and such fater disintegration/rate of dissolution: in standardized aqueous medium, described compositions, in 30 seconds, was typically dissolved in 10 seconds.
In another embodiment, pharmaceutical composition of the present invention has about 0.05 – 0.3N/mm
2the tensile strength of scope and such fater disintegration/rate of dissolution: in standardized aqueous medium, described compositions, in 30 seconds, was typically dissolved in 10 seconds.
In another embodiment, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises the first and second active constituents of medicine, has about 0.05 – 2N/mm
2the tensile strength of scope and such fater disintegration/rate of dissolution: in standardized aqueous medium, described compositions, in 30 seconds, was typically dissolved in 10 seconds.
In another embodiment, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises the first and second active constituents of medicine, has about 0.05 – 0.3N/mm
2the tensile strength of scope and such fater disintegration/rate of dissolution: in standardized aqueous medium, described compositions, in 30 seconds, was typically dissolved in 10 seconds.
Described open matrix net enables liquid enter dosage form by gap and penetrates through its inside.By aqueous medium (such as saliva, water etc.) infiltration, the inside and outside carrier material of dosage form is exposed to the effect of aqueous medium or saliva, thus the fater disintegration/dissolving of carrier material network, thus the first active component and Co ntrolled release bead are discharged in oral cavity.
Open matrix structure is porous and compares with vaginal suppository with the pharmaceutical dosage form of ordinary solid shape such as (granulation with suppress) tablet, pill, capsule, suppository, the disintegrate of enhancing dosage form.Fater disintegration causes the quick release being included in the active component in substrate, and causes the release of the Co ntrolled release pearl swallowing/absorb further, and it will discharge their active component in a controlled fashion.
Can be any active constituents of medicine such as low molecular weight compound for active constituents of medicine of the present invention, peptide, nucleotide, etc.
First and second active component each other can be identical or different.In one embodiment, they are different from each other.
Can be included in open matrix net of the present invention and/or the unrestricted example of medicine (active component) in being included in the bead that contains in open matrix net is analgesic, alpha blocker (alphablockers), antiallergic agent, antasthmatic, (allergic rhinitis, chronic urticaria (chronic uticaria)), anti-inflammatory agent, antacid (antacids), vermifuge (anthelmintics), anti-arrhythmic (anti-arrhythmic agents), anti-arthritic (anti-arthritis), antimicrobial drug, antianxiety drugs, anticoagulant (anti-coagulants), antidepressants, antidiabetic drug, diarrhea (anti-diarrheals), antidiuretic (anti-diuretics), antuepileptic (anti-epileptics), antifungal agent, antigout drug (anti-gout), antihypertensive (anti-hypertensive), anti-incontinence medicine (anti-incontinence), anti-insomnia medicine (anti-insomnia), antimalarial (anti-malarials), antimigraine (anti-migraine), antimuscarinic drug (anti-muscarinic), antineoplastic agent (anti-neoplastic) and immunosuppressant (immunosuppressants), antiprotozoal (anti-protozoal), antirheumatic (anti-rheumatics), anti-rhinitis medicament (anti-rhinitis), spasmolytic (anti-spasmatic), antithyroid drug (anti-thyroid), antiviral agents (antivirals), antianxiety drug (anxiolytics), tranquilizer (sedatives), hypnotic (hypnotics) and stress-reduction agent (neuroleptics), beta-Blocking agent, anti-optimum hyperplasia medicine (anti-benign hyperplasia (BHP)), cardiac inotropic drug (cardiacinotropic), corticosteroid (corticosteroids), antitussive (cough suppressants), cytotoxic agent (cytotoxics), decongestant (decongestants), diabetes gastric retention (diabetic gastricstasis), diuretic (diuretics), enzyme (enzymes), antiparkinsonian drug (anti-parkinsonian), gastrointestinal, histamine receptor antagonists, sterilizing agent (infertility), endometriosis (endometriosis), Hormone Replacement Therapy (hormone replacement therapy), lipid regulating agent (lipid regulating agents), local anaesthetics (local anesthetics), neuromuscular drug (neuromuscular agents), Nitrates and anti-anginal drug (anti-anginal agents), menoxenia (menstrual disorders), motion sickness (motion sickness), anti-pain medicine (anti-pain), antinanseant (anti-nausea), the dyskinesia (movement disorders), nutrient (nutritionalagents), opioid analgesic agent (opioid analgesics), oral vaccine (oral vaccines), protein-based, peptide class and reconstituted drug, Prophylactic chemotherapy brings out and postoperative nausea and vomiting proton pump inhibitor, schizophrenia, gonadal hormone and contraceptive, epilepsy/panic disorder, sexual dysfunction (masculinity and femininity), spermicide (spermicides), analeptic excretory function obstacle, veterinary drug etc.
The concrete limiting examples of these medicines is:
Alpha blocker: Harnal (Tamsulosine)
Analgesic and anti-inflammatory agent: aspirin, aloxiprin (aloxiprin), auranofin (auranofin), azapropazone (azapropazone), benorylate (benorylate), diflunisal (diflunisal), etodolac (etodolac), fenbufen (fenbufen), Fenoprofen (fenoprofen calcium), flurbiprofen (flurbiprofen), ibuprofen (ibuprofen), indomethacin (indomethacin), ketoprofen (ketoprofen), meclofenamic acid (meclofenamic acid), mefenamic acid (mefenamic acid), nabumetone (nabumetone), naproxen (naproxen), oxaprozin (oxaprozin), oxyphenbutazone (oxyphenbutazone), Phenylbutazone (phenylbutazone), piroxicam (piroxicam), sulindac (sulindac), acetaminophen (paracetamol).
Antacid: aluminium hydroxide, magnesium carbonate, magnesium trisilicate, brucite, simethicone.
Vermifuge: albendazole (albendazole), bephenium hydroxynaphthoate (bepheniumhydroxynaphthoate), cambendazole (cambendazole), dichlorophen (dichlorophen), ivermectin (ivermectin), mebendazole (mebendazole), oxamniquine (oxamniquine), oxfendazole (oxfendazole), oxantel (oxantel embonate), praziquantel (praziquantel), pyrantel embonate (pyrantel embonate), thiabendazole (thiabendazole).
Antiallergic agent: Desloratadine (desloratidine), loratadine (loratidine), montelukast (Montelukast), Menglusitena (Montelukast sodium), west is attained (Cetirizin) for profit, fexofenadine (Fexofenadin), ebastine (Ebastine).
Anti-arrhythmic: amiodarone HCl (amiodarone HCl), disopyramide (disopyramide), flecainide acetate (flecainide acetate), quinidine sulfate (quinidine sulphate).
Antibacterium medicine: benethamine penicillin (benethamine penicillin), cinoxacin (cinoxacin), ciprofloxacin HCl (ciprofloxacin HCl), clarithromycin (clarithromycin), clofazimine (clofazimine), cloxacillin (cloxacillin), demeclocycline (demeclocycline), doxycycline (doxycycline), erythromycin (erythromycin), ethionamide (ethionamide), imipenum (imipenem), nalidixan (nalidixic acid), nitrofurantoin (nitrofurantoin), rifampicin (rifampicin), spiramycin (spiramycin), sulfabenzamide (sulphabenzamide), sulfadoxine (sulphadoxine), sulfamethyldiazine (sulphamerazine), sulphacetamide (sulphacetamide), sulfadiazine (sulphadiazine), sulfanilamide is different
azoles (sulphafurazole), sulfalene
azoles (sulphamethoxazole), sulfapyridine (sulphapyridine), tetracycline (tetracycline), trimethoprim (trimethoprim).
Anticoagulant: dicoumarol (dicoumarol), dipyridamole (dipyridamole), acenocoumarol (nicoumalone), phenindione (phenindione).
Antidepressants: amoxapine (amoxapine), ciclazindol (ciclazindol), maprotiline HCl (maprotiline HCl), mianserin HCl (mianserin HCl), nortriptyline HCl (nortriptyline HCl), trazodone HCl (trazodone HCl), trimipramine maleate (trimipramine maleate).
Antidiabetic drug: acetohexamide (acetohexamide), chlorpropamide (chlorpropamide), glibenclamide (glibenclamide), gliclazide (gliclazide), glipizide (glipizide), tolazamide (tolazamide), tolbutamide (tolbutamide).
Diarrhea: atropine sulfate (atropine sulphate), codeine phosphate (codeinephosphate), diphenoxylate+atropine (co-phenotrope), difenoxin (difenoxin), loperamide hydrochloride (loperamide hydrochloride), sulfasalazine (suphasolazine), mesalazine (mesalazine), olsalazine (olsalazine), corticosteroid (corticosteroids), prednisolone (prednisolone).
Antidiuretic: Desmopressin (desmopressin), desmopressin acetate.
Antuepileptic: beclamide (beclamide), carbamazepine (carbamazepine), clonazepam (clonazepam), ethotoin (ethotoin), mephenytoin (methoin), first amber is by (methsuximide), enphenemal (methylphenobarbitone), oxcarbazepine (oxcarbazepine), paramethadione (paramethadione), phenacal (phenacemide), phenobarbitone (phenobarbitone), phenytoin (phenytoin), phensuximide (phensuximide), primidone (primidone), sultiame (sulthiame), valproic acid (valproic acid).
Antifungal agent: amphotericin (amphotericin), Nitric acid butoconazole (butoconazole nitrate), clotrimazole (clotrimazole), econazole nitrate (econazole nitrate), fluconazol (fluconazole), flucytosine (flucytosine), griseofulvin (griseofulvin), itraconazole (itraconazole), ketoconazole (ketoconazole), miconazole (miconazole), natamycin (natamycin), nystatin (nystatin), sulconazole (sulconazole nitrate), terbinafine HCl (terbinafine HCl), terconazole (triaconazole) (terconazole), tioconazole (tioconazole), 9-undecylenic acid (undecenoic acid).
Antigout drug: allopurinol (allopurinol), probenecid (probenecid), sulfinpyrazone (sulphinpyrazone).
Antihypertensive: amlodipine (amlopidine), benidipine (benidipine), darodipine (darodipine), diltiazem HCl (dilitazem HCl), diazoxide (diazoxide), felodipine (felodipine), guanabenz acetate (guanabenz acetate), indoramine (indoramin), isradipine (isradipine), minoxidil (minoxidil), nicardipine HCl (nicardipine HCl), nifedipine (nifedipine), nimodipine (nimodipine), phenoxybenzamine HCl (phenoxybenzamine HCl), prazosin HCl (prazosin HCl), reserpine (reserpine), terazosin HCl (terazosin HCl).
Anti-insomnia medicine: zolpidem (Zolpidem).
Antimalarial drug: amodiaquine (amodiaquine), chloroquine (chloroquine), chlorproguanil HCl (chloroproguanil HCl), halofantrine HCl (halofantrine HCl), mefloquine HCl (mefloquine HCl), proguanil HCl (proguanil HCl), pyrimethamine (pyrimethamine), quinine sulfate (quinine sulphate).
Anti-migraine medicine: rizatriptan (rizatriptan), dihydroergotamine mesylate (dihydroergotamine mesylate), ergotamine tartrate (ergotamine tartrate), desernil (methysergide maleate), maleic acid benzene pyrimidine (pizotifen maleate), Sumatriptan Succinate (sumatriptan succinate), caffeine (caffeine).
Antimuscarinic drug: tolterodine (tolterodin), Tolterodine tartrate, former times cloth woods (oxybutinin) difficult to understand, atropine (atropine), benzhexol HCl (benzhexol HCl), biperiden (biperiden), profenamine HCl (ethopropazine HCl), scopolamine butyl bromide (hyoscinebutyl bromide), hyoscyamine (hyoscyamine), mepenzolate bromide (mepenzolate bromide), orphenadrine (orphenadrine), oxyphencyclimine HCl (oxyphencylcimine HCl), tropicamide (tropicamide).
Antineoplastic agent and immunosuppressant: aminoglutethimide (aminoglutethimide), amsacrine (amsacrine), imuran (azathioprene), busulfan (busulphan), chlorambucil (chlorambucil), ciclosporin (cyclosporin), dacarbazine (dacarbazine), estramustine (estramustine), etoposide (etoposide), lomustine (lomustine), melphalan (melphalan), mercaptopurine (mercaptopurine), methotrexate (methotrexate), mitomycin (mitomycin), mitotane (mitotane), mitoxantrone (mitozantrone), procarbazine HCl (procarbazine HCl), Tamoxifen Citrate (tamoxifen citrate), testolactone (testolactone).
Antiprotozoal: benznidazole (benznidazole), clioquinol (clioquinol), decoquinate (decoquinate), diiodohydroxyquinoline (Iodoquinol) (diiodohydroxyquinoline), diloxanide (diloxanidefurcate), dinitolmide (dinitolmide), furazolidone (furzolidone), metronidazole (metronidazole), nimorazole (nimorazole), nitrofurazone (nitrofurazone), ornidazole (ornidazole), tinidazole (tinidazole).
Antirheumatic: ibuprofen (ibuprofen), aceclofenac (aceclofenac), acemetacin (acemetacin), azapropazone (azapropazone), diclofenac sodium (diclofenac sodium), diflunisal (diflunisal), etodolac (etodolac), ketoprofen (ketoprofen), indomethacin (indomethacin), mefenamic acid (mefenamic acid), naproxen (naproxen), piroxicam (piroxicam), aspirin, benorylate (benorylate), auranofin (auranofin), penicillamine (penicillamine).
Anti-rhinitis medicament, anti-urticaria drug: west is attained for profit, fexofenadine, ebastine, loratadine, montelukast
Spasmolytic: phloroglucinol dehydrate (phloroglucinol anhydre)
Antithyroid drug: carbimazole (carbimazole), propylthiouracil (propylthiouracil).
Antiviral agents: acyclovir (acyclovir), amantadine hydrochloride (amantadinehydrochloride), famciclovir (famciclovir), zidovudine (zidovadine), didanosine (didanosine), prick his guest (zalcitabine) of former times, foscarnet sodium (foscarnet sodium).
Antianxiety drugs, tranquilizer, sleeping pill and stress-reduction agent: alprazolam (alprazolam), amobarbital (amylobarbitone), barbital (barbitone), bentazepam (bentazepam), bromazepam (bromazepam), bromperidol (bromperidol), brotizolam (brotizolam), neonal (butobarbitone), carbromal (carbromal), chlordiazepoxide (chlordiazepoxide), chlorphenamine (Chlorpheniramine), clomethiazole (chlormethiazole), chlorpromazine (chlorpromazine), clobazam (clobazam), clonazepam (clonazepan), clotiazepam (clotiazepam), clozapine (clozapine), diazepam (diazepam), droperidol (droperidol), ethinamate (ethinamate), fluanisone (flunanisone), flunitrazepam (flunitrazepam), fluorine promazine (fluopromazine), Flupentixol Decanoate (flupenthixol decanoate), Fluphenazine (fluphenazine decanoate), flurazepam (flurazepam), haloperidol (haloperidol), lorazepam (lorazepam), lormetazepam (lormetazepam), medazepam (medazepam), meprobamate (meprobamate), methaqualone (methaqualone), midazolam (midazolam), nitrazepam (nitrazepam), oxazepam (oxazepam), pentobarbital (pentobarbitone), perphenazine (perphenazine) phenylephrine (phenylephrine), pimozide (pimozide), prochlorperazine (prochlorperazine), isoephedrine HCl (pseudoephedrine HCL), sulpiride (sulpride), temazepam (temazepam), thioridazine (thioridazine), triazolam (triazolam), zopiclone (zopiclone).
Beta-Blocking agent: acebutolol (acebutolol), alprenolol (alprenolol), atenolol (atenolol), labetalol (labetalol), metoprolol (metoprolol), nadolol (nadolol), oxprenolol (oxprenolol), pindolol (pindolol), propranolol (propanolol).
Cardiac inotropic drug: amrinone (amrinone), digitophyllin (digitoxin), digoxin (digoxin), enoximone (enoximone), lanatoside C (lanatoside C), medigoxin (medigoxin).
Corticosteroid: beclometasone (beclomethasone), betamethasone (betamethasone), budesonide (budesonide), cortisone acetate (cortisone acetate), deoxidation meter Sai Song (desoxymethasone), dexamethasone (dexamethasone), fludrocortisone acetate (fludrocortisone acetate), flunisolide (flunisolide), fluocortolone (flucortolone), fluticasone propionate (fluticasone propionate), hydrocortisone (hydrocortisone), methylprednisolone (methylprednisolone), prednisolone (prednisolone), prednisone (prednisone), triamcinolone (triamcinolone).
Cough medicine: codeine phosphate (codeine phosphate), dextromethorphan (dexomethorphan), guaifenesin (guaifenesin), pholcodine (pholcodine), diamorphine (diamorphine), methadone (methadone).
Cytotoxic agent: ifosfamide (ifosfamide), chlorambucil (chlorambucil), melphalan (melphalan), busulfan, cytotoxic antibody, doxorubicin (doxorubicin), epirubicin (epirubicin), primycin (plicamycin), bleomycin (bleomycin), methotrexate (methotrexate), cytosine arabinoside (cytarabine), fludarabine (fludarabine), gemcitabine (gencitabine), fluorouracil (fluorouracil), mercaptopurine (mercaptopurine), thioguanine (thioguanine), vincristine (vincristine), vinblastine (vinblastine), vindesine (vindesine), etoposide (etoposide).
Decongestant: pseudoephedrine hydrochloride (pseudoephedrine hydrochloride).
Diuretic: acetazolamide (acetazolamide), amiloride (amiloride), benzyl fluorine piperazine (bendrofluazide), bumetanide (bumetanide), chlorothiazide (chlorothiazide), chlortalidone (chlorthalidone), etacrynic acid (ethacrynic acid), furosemide (frusemide), metolazone (metolazone), spironolactone (spironolactone), triamterene (triamterene).
Enzyme: pancreatin (pancreatin), pepsin (pepsin), lipase.
Epilepsy: gabapentin (Gabapentin)
Antiparkinsonian drug: bromocriptine methanesulfonate (bromocriptine mesylate), lisuride maleate (lysuride maleate), Selegiline (selegiline), to fluorine Selegiline (para-fluoroselegiline), lazabemide (lazabemide), rasagiline (rasagiline), 2-BUMP [N-(2-butyl)-N-methyl propargylamine], M-2-PP [N-methyl-N-(2-amyl group)-propargylamine], MDL-72145 [β-(fluorine methylene)-3, 4-dimethoxy-phenethylamine], mofegiline (mofegiline), apomorphine (apomorphine), N-N-propylnoraporphine (N-propylnoraporphine), cabergoline (cabergoline), metergoline (metergoline), naxagolide (naxagolide), pergolide (pergolide), piribedil (piribedil), ropinirole (ropinirole), terguride (terguride), quinagolide (quinagolide).
Gastrointestinal agents: bisacodyl (bisacodyl), cimetidine (cimetidine), cisapride (cisapride), diphenoxylate HCl (diphenoxylate HCl), domperidone (domperidone), metoclopramide (metoclopramide), famotidine (famotidine), loperamide (loperamide), mesalazine (mesalazine), nizatidine (nizatidine), esomeprazole (esomeprazole), metopimazine (metopimazine), pantoprazole (pantoprazole), ondansetron HCl (ondansetron HCl), granisetron (Granisetron), tropisetron (tropisetron), dolasetron (dolasetron), ranitidine HCl (ranitidine HCl), sulfasalazine (sulphasalazine), lansoprazole (Lanzoprazole),
Histamine receptor antagonists: acrivastine (acrivastine), astemizole (astemizole), cinnarizine (cinnarizine), cyclizine (cyclizine), Cyproheptadine HCl (cyproheptadine HCl), dimenhydrinate (dimenhydrinate), flunarizine HCl (flunarizine HCl), loratadine, meclizine HCl (meclozine HCl), oxatomide (oxatomide), terfenadine (terfenadine), triprolidine (triprolidine).
Hormone Replacement Therapy: dydrogesterone (dydrogesterone)
Hypertension: enalapril (Enalapril)
Lactogenic: oxytocin (Oxytocin), oxytocin agonists
Lipid regulating agent: bezafibrate (bezafibrate), clofibrate (clofibrate), fenofibrate (fenofibrate), gemfibrozil (gemfibrozil), probucol (probucol).
Local anaesthetics: tetracaine (amethocaine), amylocaine (amylocaine), benzocaine (benzocaine), bucricaine (bucricaine), bupivacaine (bupivacaine), butacaine (butacaine), butanilicaine (butanilicaine), 2-diethylaminoethyl p-butoxybenzoate. (butoxycaine), butyl aminobenzoate (butyl aminobenzoate), carticaine (carticaine), chloroprocaine (chloroprocaine), cinchocaine (cinchocaine), clibucaine (clibucaine), clormecaine (clormecaine), Folium Cocoe (coca), cocaine (cocaine), cyclomethycaine (cyclomethycaine), quotane (dimethisoquin), diperodon (diperodon), dyclonine (dyclocaine), ethyl chloride, to piperidines and acetyl-amino ethyl benzoate (ethylp-piperidinoacetylaminobenzoate), etidocaine (etidocaine), hexylcaine (hexylcaine), isobutamben (isobutamben), ketocaine (ketocaine), lignocaine (lignocaine), mepivacaine (mepivacaine), meprylcaine (meprylcaine), Myrtecaine (myrtecaine), octacaine (octacaine), oxetacaine (oxethazaine), oxybuprocaine (oxybuprocaine), parethoxycaine (parethoxycaine), Pramoxine (pramoxine), prilocaine (prilocaine), procaine (procaine), proparacaine (propranocaine), propoxycaine (propoxycaine), proparacaine (proxymetacaine), ropivacaine (ropivacaine), tolycaine (tolycaine), tricaine (tricaine), trimecaine (trimecaine), vadocaine (vadocaine).
Motion sickness: diphenhydramine (diphenhydramine)
Neuromuscular drug: pyridostigmine (pyridostigmine).
Nitrates and other anti-anginal drugs: amyl nitrite (amyl nitrate), glyceryl trinitrate (glyceryl trinitrate), sorbide nitrate (isosorbide dinitrate), isosorbide mononitrate (isosorbide mononitrate), four nitric acid five erithritol esters.
Nutrient: bata-carotene (betacarotene), vitamin, as vitamin A, vitamin B
2, vitamin D, vitamin E, vitamin K, mineral.
Opium kind analgesics: codeine (codeine), dextropropoxyphene (dextropropyoxyphene), diamorphine (diamorphine), dihydrocodeine (dihydrocodeine), meptazinol (meptazinol), methadone (methadone), morphine (morphine), nalbuphine (nalbuphine), pentazocine (pentazocine).
Oral vaccine: for preventing or reduce the symptom of disease, described disease is as influenza, pulmonary tuberculosis (Tuberculosis), meningitis (Meningitis), hepatitis (Hepatitis), pertussis (WhoopingCough), poliomyelitis (Polio), tetanus (Tetanus), diphtheria (Diphtheria), malaria (Malaria), cholera (Cholera), herpes (Herpes), typhoid fever (Typhoid), HIV, AIDS, measles (Measles), Lyme disease (Lyme disease), traveler's diarrhea (Traveller's Diarrhea), first, second and hepatitis C, otitis media (Otitis Media), dengue fever (Dengue Fever), rabies (Rabies), parainfluenza (Parainfluenza), rubella (Rubella), yellow fever (Yellow Fever), dysentery (Dysentery), legionnaires disease (Legionnaires Disease), toxoplasmosis (Toxoplasmosis), Q heat (Q-Fever), hemorrhagic fever (Haemorrhegic Fever), Argentinian hemorrhagic fever (ArgentinaHaemorrhegic Fever), dental caries (Caries), Chagas disease (Chagas Disease), the urinary tract infection caused by escherichia coli, pneumoccoccosis (Pneumococcal Disease), parotitis (Mumps), Chikungunya fever (Chikungunya), pollinosis (Hayfever), asthma (Asthma), rheumatic arthritis, cancer, coccidiosis (Coccidiosis), newcastle (Newcastle Disease), enzootic pneumonia (Enzootic pneumonia), feline leukemia (Feline leukemia), atrophic rhinitis (Atrophic rhinitis), erysipelas (Erysipelas), foot and mouth disease and hyopneumoniae, or for preventing or reduce the symptom of the disease caused by following species: Vibrio species (Vibrio species), salmonella species (Salmonella species), special fungus kind (Bordetella species) of Boulder, influenzae species (Haemophilus species), toxoplasmosis (Toxoplasmosis gondii), cytomegalovirus (Cytomegalovirus), Chiamydia species (Chlamydia species), Streptococcus spp (Streptococcal species), Norwalk virus (Norwalk Virus), escherichia coli (Escherischiacoli), helicobacter pylori (Helicobacter pylori), rotavirus (Rotavirus), gonococcus (Neisseria gonorrhae), the scorching diplococcus (Neisseria meningiditis) of neisseria meningitis, adenovirus, Epstein-Barr virus (Epstein Barr Virus), Japanese encephalitis virus (Japanese Encephalitis Virus), Pneumocystis carinii (Pneumocystis carini), herpes simplex (Herpes simplex), clostridial species (Clostridia species), respiratory syncytial virus (Respiratory SyncytialVirus), klebsiella species (Klebsiella species), shigella species (Shigellaspecies), Pseudomonas aeruginosa (Pseudomonas aeruginosa), parvovirus (Parvovirus), Campylobacter spp species (Campylobacter species), rickettsia species (Rickettsia species), varicella zoster (Varicella zoster), Yersinia spp (Yersinia species), ross river virus (Ross River Virus), J.C. virus (J.C.Virus), Rhodococcus equi (Rhodococcus equi), Moraxella catarrhalis (Moraxella catarrhalis), Borrelia burgdoyferi (Borrelia burgdorferi) and haemolysis Pasteurella (Pasteurella haemolytica).
Excretory function obstacle: tamsulosin (Tamsulosine), trospium chloride (trospium chloride), tolterodine (tolterodine), former times cloth woods (oxybutinin) difficult to understand
Protein, peptide and restructuring medicine: recombinant hormone and different hormone, recombinant cytokine, restructuring plasminogen (recombinant plasminogens), TNF receptor fusion protein, monoclonal antibody, nucleic acid, antisense oligonucleotide, oligonucleotide, glycoprotein and adhesion molecule.
Beast rhinitis: tepoxalin (Tepoxalin)
Gonadal hormone and contraceptive: citric acid clomiphene citrate (clomiphene citrate), danazol (danazol), desogestrel (desogestrel), ethinylestradiol (ethinyloestradiol), etynodiol (ethynodiol), ethynodiol diacetate (ethynodiol diacetate), levonorgestrel (levonorgestrel), medroxyprogesterone acetate (medroxyprogesterone acetate), mestranol (mestranol), methyltestosterone (methyltestosterone), norethindrone (norethisterone), norethisterone enanthate (norethisteroneenanthate), norgestrel (norgestrel), estradiol (estradiol), conjugated estrogen class (conjugated estrogens), dydrogesterone (dydrogesterone), progesterone (progesterone), stanozolol (stanozolol), diethylstilbestrol (stilboestrol), testosterone (testosterone), tibolone (tibolone).
Schizophrenia: olanzapine (Olanzapine), nicergoline (Nicergoline)
Sexual dysfunction: cabergoline (Cabergolin), oxytocin, tadanafil (tadalafil), sldenafil (sildenafil), Vardenafil (vardenafil).
Spermaticide: nonoxinol 9 (nonoxynol 9).
Analeptic: amphetamines (amphetamine), dextroamphetamine (dexamphetamine), dexfenfluramine (dexfenfluramine), fenfluramine (fenfluramine), Mazindol (mazindol), pemoline (pemoline).
In one embodiment, described first active component is Desmopressin or its pharmaceutical salts, particularly desmopressin acetate.
In one embodiment, the second active component (being included in described Co ntrolled release pearl) is antimuscarinic compounds.In another embodiment, second active component is selected from tolterodine ((R)-N, N-diisopropyl-3-(2-hydroxy-5-methyl base phenyl)-3-phenylpropylamine), 5-form hydroxy methyl metabolite ((R)-N of tolterodine, N-diisopropyl-3-(2-hydroxyl-5-hydroxymethyl phenyl)-3-phenylpropylamine), (S)-enantiomer ((S)-N of tolterodine, N-diisopropyl-3-(2-hydroxy-5-methyl base phenyl)-3-phenylpropylamine), 5-form hydroxy methyl metabolite ((S)-N of (the S)-enantiomer of tolterodine, N-diisopropyl-3-(2-hydroxyl-5-hydroxymethyl phenyl)-3-phenylpropylamine), the racemate ((R of tolterodine, S)-N, N-diisopropyl-3-(2-hydroxy-5-methyl base phenyl)-3-phenylpropylamine), its prodrug forms and pharmaceutical salts thereof.In a specific embodiment, described active component is tolterodine or its pharmaceutical salts.In special embodiment, active component is Tolterodine tartrate.
Concrete at one, in non-limiting embodiments, the first active component comprised in open matrix net is Desmopressin or its pharmaceutical salts, particularly desmopressin acetate, and the second active component comprised in Co ntrolled release pearl is tolterodine or its pharmaceutical salts, particularly Tolterodine tartrate.Desmopressin acetate and Tolterodine tartrate are particularly preferred respectively as the combination of the first and second active component.In this embodiment, described compositions may be used for treatment urinary organs disease, such as, but is not limited to, the overactive bladder especially in women or the overactive bladder with nocturia.
Overactive bladder causes frequent micturition, urge incontinence and/or urge incontinence (urgeincontinence).Overactive bladder can also comprise nocturia, namely wakes up night and urinates.When overactive bladder is usually relevant to detrusor instability (di), bladder dysfunction also due to the neuropathy of central nervous system (detrusor overactivity), may comprise spinal cord and brain injury, such as multiple sclerosis and apoplexy.Overactive bladder symptom can also be caused by the following, such as, male bladder outlet blocks (male bladder outlet obstruction) (usually due to prostate hyperplasia (prostatic hypertrophy)), interstitial cystitis (interstitial cystitis), the local edema caused due to focal bladder cancer and pain, due to the radiocystitis caused pelvic irradiation, and cystitis.
In one embodiment, in compositions, the amount of desmopressin acetate forms 0.01 – 1%w/w and the amount of compositions mesotartaric acid tolterodine formation 3 to 10%w/w.In another embodiment, in compositions, the amount of desmopressin acetate forms 0.02-0.2%w/w and the amount of compositions mesotartaric acid tolterodine formation 3 to 6%w/w.
When tolterodine is the active component in Co ntrolled release pearl, the active component part (fraction) of release in vitro is preferably not more than about 40% after 1h, and after 3 hours from about 35 to about 85%, and be not less than about 65% after 7 hours.
When tolterodine is the active component in Co ntrolled release pearl, tolterodine will be DETRUSITOL XL with commercially available brand name from the release profiles (although it is present in Medium Culture) of pearl
tMthe release profiles of tolterodine hard capsule similar or even identical.
In one embodiment, the second active component (being included in Co ntrolled release pearl) is selectivity alpha block agent.In another embodiment, second active component is tamsulosin ((R)-5-(2-{ [2-(2-ethoxy phenoxy) ethyl] amino } propyl group)-2-methoxybenzene-1-sulfonamide), its prodrug forms and pharmaceutical salts thereof.In a specific embodiment, the second active component is tamsulosin hydrochloride.
Concrete at one, in non-limiting embodiments, the first active component be included in described open matrix net is Desmopressin or its pharmaceutical salts, particularly desmopressin acetate, and the second active component be included in described Co ntrolled release pearl is tamsulosin, or its pharmaceutical salts, particularly tamsulosin hydrochloride.Desmopressin acetate and tamsulosin hydrochloride are particularly preferred respectively as the combination of the first and second active component.In these embodiments, described compositions may be used for treating the benign prostatic hyperplasia (BPH) in male.
Pharmaceutical dosage form of the present invention, in contacting with fluid (aqueous medium or saliva) disintegrate afterwards, discharges described active component and described Co ntrolled release pearl thus.
Typically, pharmaceutical dosage form of the present invention is a mouthful dispersion medicine dosage form, and in mouth, they are in 30 seconds, typically 20 seconds or shorter, preferably 15 seconds or shorter, more preferably 10 seconds or shorter and even more preferably disintegrate in 9,8,7,6,5,4,3,2 or 1 seconds.
Term used herein " mouth dispersion " should be understood to include and work as according to Ph.Eur.1997, and 2.9.1 saves, when measuring in water for 37 DEG C ± 0.5 DEG C, and the solid dosage forms of disintegrate or dissolving in (at the most) 30 seconds inherent water.
The suitable route of administration of dosage form of the present invention is oral administration, includes but not limited to buccal and sublingual administration.In a specific embodiment, described dosage form sublingual administration.Dosage form of the present invention also can be placed on tongue, Sublingual or against cheek or gums.
Pharmaceutical dosage form of the present invention is suitable for the first active component and described Co ntrolled release pearl to be provided to such as oral cavity.Described first active component can be absorbed, described mucosa such as hypoglossis mucous membrane through the mucosa at medicine-feeding part place, and/or when oral administration, from oral cavity (such as through buccal mucosa and/or gingival mucosa) and/or gastrointestinal tract distribution whole body.
The exact dose of described dosage administration and scheme must depend on the curative effect that will realize and can along with given activity composition, route of administration and the age of individual subject and the changed condition that give medicine.Sometimes the patient's unit dosage forms that can be taken two or any other quantity by instruction in single-dose or in single-dose, sometimes only take unit dosage forms a part as half or 1/4th.
Dosage form of the present invention achieves the balance of performance: tensile strength, stability, homogeneity and fater disintegration.It can be produced by known freeze drying technology.It can store (and packaging) in bubble-cap but due to its tensile strength, also can to store and/or be packaged in bottle or in bulk.The present invention realizes these results in single procedure of processing, and does not need to take multiple step to comprise granulation.
Except the composition discussed before; described substrate can also comprise other excipient (auxiliary agent, auxiliary reagent) as but be not limited to filler, thickening agent, binding agent, diluent, lubricant, pH adjusting agent, protective agent, viscosifier, wicking agent (wicking agents), non-gas-producing disintegrant, gas-producing disintegrant, surfactant, antioxidant, wetting agent, coloring agent, flavoring agent, odor mask, sweetener, antiseptic etc.
In one embodiment, compositions of the present invention is by from comprising the first active component, one or more matrix formers in a solvent, and in the liquid preparation of Co ntrolled release bead and optionally one or more the second matrix formers, subliming solvent obtains.Usually, this liquid preparation is placed in such as mould, to make after distillation, in this mould, usually forms solid composite with dosage unit.Described mould can be open blister packaging, and this solid dosage unit is formed in the depression of this blister package sealed by diaphragm seal or paper tinsel afterwards thus.
In one embodiment, described method comprises in the depression described preparation of unit dose amount being incorporated into open blister packaging; Then described preparation is distilled to obtain solid dosage forms in described depression.
Described distillation can by lyophilization comprise in a solvent the first active component, one or more matrix formers, Co ntrolled release pearl and optionally one or more the second matrix formers liquid preparation carry out.In one embodiment, described solvent is water.
Therefore the present invention discloses a kind of method preparing fast dispersing dosage form, described method comprises the solution of the first active component, one or more matrix formers, Co ntrolled release pearl and the optionally combination of one or more the second matrix formers by lyophilizing, suspension, dispersion liquid or emulsion carry out.Described fast dispersing dosage form contains the network of the first active component, one or more matrix formers, Co ntrolled release pearl and optionally one or more the second matrix formers, and described network is by obtaining from the liquid preparation subliming solvent containing these components.
Typically, preparation comprises the preliminary preparation of the first active component, one or more matrix formers, Co ntrolled release pearl and optionally one or more the second matrix formers in a solvent, then distils.Described distillation can be undertaken by preparation described in lyophilization.In the process preparing fast dispersing dosage form, the early stage dissolving of the second active component or release can be prevented by the time of contact reduced between liquid component and Co ntrolled release pearl, the described time such as being not more than 45,35,25,20,15, or 10 minutes, or be not more than the period of 5 minutes.
In lyophilization step, with to comprise in a solvent the first active component, one or more matrix formers, Co ntrolled release pearl and other one or more optional matrix formers arbitrarily preparation (liquid form) fill mould.Each mould typically contains the pearl of this kind of preparation of limited amount and the first active component of limited amount and limited amount.In alternate embodiment, Co ntrolled release pearl is filled with mould with aequum pre-fill and optionally cooling freezing, and subsequently the preparation comprising the remaining ingredient of described fast dispersing dosage form of liquid form is added in mould.Then such as by by gas cooling medium by mould by freezing for the preparation in mould.After described preparation is frozen, solvent is therefrom distilled.Described distillation is carried out in freeze dryer.As a result, form one or more matrix formers thus and optionally to comprise the open matrix net (carrying the first active component and pearl) together with one or more other matrix formers in the formulation.
Described preparation holds in a mold to produce the solid form of any intended shape during freeze drying process.Before lyophilizing, this mould can be cooled and freezing (such as in quick freezing pipeline or on the shelf of freeze dryer), such as, use liquid nitrogen or drikold.In one embodiment, freezing rate is 0.1 to 2 DEG C/min.In another embodiment, freezing rate is 0.5 to 1.5 DEG C/min.In another embodiment also had, freezing rate is 10 to 260 DEG C/min.In another embodiment, freezing rate is 20 to 260 DEG C/min.In another embodiment, freezing rate is 20 to 160 DEG C/min.
After freeze drying, if this cryodesiccated compositions needs to shift out from mould or to store within it until used afterwards.Usually, each mould is designed to the unit dosage forms of production combination thing.The compositions of acquisition like this after contacting with fluid at the most in 30 seconds, usually being less than rapid dispersion and disintegrate in 10 seconds.
For the preparation of the solvent water typically of the present composition, but optionally can also comprise cosolvent (such as the alcohol such as tert-butyl alcohol).
Prepare the present composition from liquid preparation can containing pH adjusting agent to regulate its pH in the scope of 2 to 10, typically in the scope of 3.5 to 9.5 or 4.5 to 8.Citric acid and sodium citrate can be used as pH adjusting agent, but also can use other, comprise sodium hydroxide, sodium carbonate, hydrochloric acid and malic acid.To nonvolatile pH adjusting agent do not removed by lyophilization or other sublimation process and therefore may be present in final compositions.
Described mould can comprise the depression of a series of cylindrical shape or other shapes within it, and each size corresponds to the desired size of the dosage form that will be formed.
In one embodiment, described mould is the depression in the sheet material of film material.This film material can comprise the depression more than.This film material can be similar to for packing the film material adopted in the conventional blister package of oral tablet and similar medication form.Such as, this film material can be made up of the thermoplastic with the depression formed by thermoforming or cold forming.Polychloroethylene film can be used as film material.Also the lamilated body of film material can be used.
Embodiment
Describe the present invention in the examples below further, described embodiment is intended to the scope of the present invention required by restriction never in any form.
Method
The method of test matrix falls apart time
Present composition disintegration time is in an aqueous medium determined in this test, and it is also the indication of its disintegration time in saliva.
Equipment: Electrolab, model ED2SAPO
Step: this method is carried out according to USP 31-NF 26 (general rules, <701> disintegrate) and Ph Eur.1997 (disintegrate of 2.9.1. Tablet and Capsula).Water to be loaded in beaker and to use water-bath to maintain 37 DEG C ± 0.5 DEG C.Dosage form is placed in and is about 0.5mm (± 0.05mm) by the thread diameter of copper and length is about the sinker of 15mm.Then sinker is placed in the basket of basket frame assembly, and starts instrument.Disintegration time is recorded with second.
Test the dissolving-out method that the first active component discharges immediately
This test determines the first active component in an aqueous medium from the stripping (%) of the present composition, and it is the indication of the release profiles of the first active component.
Equipment: Varian, model VK7025
Step: the method is carried out according to USP 32-NF 27 (general rules, <711> stripping).Dissolution medium (0.1N HCl, phosphate buffer pH 6.8, acetate buffer pH 4.5 or water in 0.5%SLS (dodecyl sodium sulfate)) is selected based on the active component in compositions.Fill stripping bowl based on the active component in compositions with suitable medium volume (500mL or 900mL) and use water-bath that the temperature of medium is maintained 37 DEG C ± 0.5 DEG C.The instrument used is USP Type II (slurry) and is set to 50rpm.Sample is taken out at 5min, 10min, 15min and 30min.Analyze sample through chromatograph or by UV as one sees fit, and calculate % release.
The dissolving-out method of release is extended for testing the second active component
This test determines the second active component in an aqueous medium from the stripping (%) of the present composition, and it is the indication of the second active component release profiles.
Equipment: Varian, model VK7025
Step: the method is carried out according to USP 32-NF 27 (general rules, <711> stripping).Dissolution medium (0.1N HCl, phosphate buffer pH 6.8, acetate buffer pH 4.5 or water in 0.5%SLS) is selected based on the active component in compositions.Fill stripping bowl based on the active component in compositions with suitable medium volume (900mL) and use water-bath that medium temperature is maintained 37 DEG C ± 0.5 DEG C.The instrument used is USP type i (basket) and is set to 100rpm.At 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, within 9 hours and 12 hours, take out sample.Analyze sample through chromatograph or by UV as one sees fit, and calculate % release.
For the method for the particle diameter of measurement core
This test uses standard screen (BSS, ASTM) to determine the particle diameter of core.The method is according to USP35-NF 30 (general rules, <786> is by analyzing the particle size distribution evaluation of screening).Sieve in institute's research range is stacking in top of each other with the roughness risen, and core bead/pearl/granule is placed on the sieve of top.The stirring that nest (nest) carries out standard duration will be sieved, and accurately determine subsequently to be retained in the material weight on each sieve.
embodiment 1
Tolterodine ER granule
| Composition | Mg/ unit |
| Sugar ball 1 (150-180 μm) | 8.00 |
| Seal coating 2 | |
| Eudragit NE 30D | 1.60 |
| Talcum | 0.80 |
| Pure water | In right amount |
| Medicine layer 3 | |
| Tolterodine L-TARTARIC ACID salt | 4.00 |
| HPMC 5cps | 0.80 |
| Pure water | In right amount |
| ER coating 5 | |
| Eudragit NE 30D | 4.00 |
| HPMC 5cps | 0.25 |
| Talcum | 1.83 |
| Pure water | In right amount |
| Gross weight | 21.28 |
Concise and to the point preparation process:
Tolterodine ER granule is prepared in fluidized bed processor (Wurster coating procedure).Different component/the preparation process of ER granule is:
A. inertia core 1: select the sugared ball (Pharm-a-spheresUSP/NF, EP) of size range 150-180 μm for seal coating, medicine layer and ER layer.
B. seal coating 2: the Eudragit NE 30D (Colorcon) being diluted to 20%w/w concentration is insoluble to water layer for first.Be sprayed on sugared ball by Eudragit NE 30D dispersion liquid (polymer: the ratio of Talcum is 1:0.5), the weight obtaining 30%w/w increases.
C. medicine layer 3: the target weight to ~ 46%w/w on the sugared ball that the aqueous solution of medicine and binding agent is sprayed on seal coating increases.Tolterodine tartrate: the ratio of HPMC 5cps is 5:1.
D. releasing layer 5 is extended: this layer is the combination of Eudragit NE 30D+HPMC 5cps+ Talcum; By Eudragit NE 30D+HPMC 5cps ~ (ratio of Eudragit NE30D:HPMC 5cps is 94.34:5.66 to 20%w/w aqueous dispersions; Talcum: polymer content ~ 43.1%) be sprayed on and scribble on the granule of medicine, the weight obtaining 40%w/w increases.
E. the sclerosis of tolterodine ER granule: by tolterodine ER granule 40 DEG C of sclerosis 12 hours.
Lyophilized products compositions:
| Composition | Mg/ lyophilized products |
| Tolterodine ER granule | 22.72 |
| Levan | 26.00 |
| Mannitol | 21.94 |
| Avicel RC 591 | 8.00 |
| Citric acid (anhydrous) | Be adjusted to pH 4.5 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 78.66mg |
The concise and to the point preparation process of lyophilized products:
1. all excipient are dissolved in pure water, produce base composition.Add to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level
3. the matrix solution of step 1 is loaded the bubble chamber containing tolterodine ER granule
4. the bubble of freezing filling in liquid nitrogen passage
5. bubble is remained on below cryogenic temperature, until whole batch is frozen
6. freezing bubble is loaded in freezer dryer and is used for lyophilization
7. by pressure buildup tests monitoring lyophilization terminal
8. unload dry bubble from freezer dryer.
9. sealing bubble, then impresses.
Tolterodine in pH 6.8 phosphate buffer from the drug release (stripping curve) of the tolterodine ER granule of embodiment 1 and lyophilized products and for the drug release from Detrusitol XL (stripping curve) display of comparing in fig. 2.
embodiment 2
Tolterodine ER granule
| Composition | Mg/ unit |
| Sugar ball 1 (150-180 μ) | 8.00 |
| Seal coating 2 | |
| Surelease E-7-19010 | 2.40 |
| Pure water | In right amount |
| Medicine layer 3 | |
| Tolterodine L-TARTARIC ACID salt | 4.00 |
| HPMC 5cps | 0.80 |
| Pure water | In right amount |
| ER coating 5 | |
| Surelease E-7-19010 | 12.76 |
| HPMC 5cps | 2.44 |
| Pure water | In right amount |
| Gross weight | 30.40 |
Concise and to the point preparation process:
Tolterodine ER granule (Wurster coating procedure) is prepared in fluidized bed processor.
Different component/the preparation process of ER granule is:
A. inertia core 1: select the sugared ball (Pharm-a-spheres USP/NF, EP) of size range 150-180 μm for seal coating, medicine layer and ER layer.
B. seal coating 2: the Surelease (Colorcon) being diluted to 15%w/w concentration is insoluble to water layer for first.Be sprayed on by Surelease dispersion liquid on sugared ball, the weight obtaining 30%w/w increases.
C. medicine layer 3: the target weight to ~ 46%w/w on the sugared ball aqueous solution of medicine and binding agent being sprayed on seal coating increases.Tolterodine tartrate: the ratio of HPMC 5cps is 5:1.
D. releasing layer 5 is extended: this layer is the combination of Surelease+HPMC 5cps.By Surelease+HPMC 5cps ~ 15%w/w aqueous dispersions (ratio of Surelease:HPMC 5cps is: 84:16) is sprayed on the granule of medication coat, obtain 100%w/w weight increase.
E. the sclerosis of tolterodine ER granule: by tolterodine ER granule 70 DEG C of sclerosis 3 hours.
Lyophilized products compositions:
| Composition | Mg/ lyophilized products |
| Tolterodine ER granule | 31.49 |
| Desmopressin | 0.12 |
| Levan | 26.00 |
| Mannitol | 21.94 |
| Citric acid (anhydrous) | Be adjusted to pH 4.5 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 79.55mg |
The concise and to the point preparation process of lyophilized products:
1. all excipient are dissolved in pure water.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level
3. in the bubble chamber containing tolterodine ER granule, load Desmopressin dispersion liquid.
4. the bubble of freezing filling in liquid nitrogen passage
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen
6. freezing bubble is loaded in freezer dryer and is used for lyophilization
7. monitor dry terminal by pressure buildup tests
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble, then impresses.
In pH 6.8 phosphate buffer, active component shows in figure 3 from the release of the dosage form of embodiment 2.
embodiment 3
Tolterodine ER granule
| Composition | Mg/ unit |
| Sugar ball 1 (150-180 μ) | 8.00 |
| Seal coating 2 | |
| Surelease E-7-19010 | 2.40 |
| Pure water | In right amount |
| Medicine layer 3 |
| Tolterodine L-TARTARIC ACID salt | 4.00 |
| HPMC 5cps | 0.80 |
| Pure water | In right amount |
| ER coating 5 | |
| Surelease E-7-19010 | 12.76 |
| HPMC 5cps | 2.44 |
| Pure water | In right amount |
| Gross weight | 30.40 |
Concise and to the point preparation process:
Tolterodine ER granule (Wurster coating procedure) is prepared in fluidized bed processor.
Different component/the preparation process of ER granule is:
A. inertia core 1: select the sugared ball (Pharm-a-spheres USP/NF, EP) of size range 150-180 μm for seal coating, medicine layer and ER layer.
B. seal coating 2: the Surelease (Colorcon) being diluted to 15%w/w concentration is insoluble to water layer for first.Be sprayed on by Surelease dispersion liquid on sugared ball, the weight obtaining 30%w/w increases.
C. medicine layer 3: the target weight to ~ 46%w/w on the sugared ball aqueous solution of medicine and binding agent being sprayed on seal coating increases.Tolterodine tartrate: the ratio of HPMC 5cps is 5:1.
D. releasing layer 5 is extended: this layer is the combination of Surelease+HPMC 5cps.By Surelease+HPMC 5cps ~ 15%w/w aqueous dispersions (ratio of Surelease:HPMC 5cps is: 84:16) is sprayed on the granule of medication coat, obtain 100%w/w weight increase.
E. the sclerosis of tolterodine ER granule: by tolterodine ER granule 70 DEG C of sclerosis 3 hours.
Lyophilized products compositions:
| Composition | Mg/ lyophilization thing |
| Tolterodine ER granule | 31.49 |
| Desmopressin | 0.12 |
| Levan | 26.00 |
| Mannitol | 21.94 |
| Avicel RC 591 | 4.00 |
| Citric acid (anhydrous) | Be adjusted to pH 4.5 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 83.55 mg |
The concise and to the point preparation process of lyophilized products:
1. all excipient are dissolved in pure water.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level
3. in the bubble chamber containing tolterodine ER granule, fill Desmopressin dispersion liquid.
4. the bubble of freezing filling in liquid nitrogen passage
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen
6. freezing bubble is loaded in freezer dryer and is used for lyophilization
7. monitor dry terminal by pressure buildup tests
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble also then impresses.
In pH 6.8 phosphate buffer, active component shows in the diagram from the release of the dosage form of embodiment 3.
embodiment 4
Tolterodine ER granule
| Composition | Mg/ unit |
| Sugar ball 1 (150-180 μ) | 8.00 |
| Seal coating 2 | |
| Surelease E-7-19010 | 2.40 |
| Pure water | In right amount |
| Medicine layer 3 | |
| Tolterodine L-TARTARIC ACID salt | 4.00 |
| HPMC 5 cps | 0.80 |
| Pure water | In right amount |
| ER coating 5 | |
| Surelease E-7-19010 | 12.76 |
| HPMC 5cps | 2.44 |
| Pure water | In right amount |
| Gross weight | 30.40 |
Concise and to the point preparation process:
Tolterodine ER granule (Wurster coating procedure) is prepared in fluidized bed processor.
Different component/the preparation process of ER granule is:
A. inertia core 1: select the sugared ball (Pharm-a-spheres USP/NF, EP) of size range 150-180 μm for seal coating, medicine layer and ER layer.
B. seal coating 2: the Surelease (Colorcon) being diluted to 15%w/w concentration is insoluble to water layer for first.Be sprayed on by Surelease dispersion liquid on sugared ball, the weight obtaining 30%w/w increases.
C. medicine layer 3: the target weight to ~ 46%w/w on the sugared ball aqueous solution of medicine and binding agent being sprayed on seal coating increases.Tolterodine tartrate: the ratio of HPMC 5cps is 5:1.
D. releasing layer 5 is extended: this layer is the combination of Surelease+HPMC 5cps.By Surelease+HPMC 5cps ~ 15%w/w aqueous dispersions (ratio of Surelease:HPMC 5cps is: 84:16) is sprayed on the granule of medication coat, obtain 100%w/w weight increase.
E. the sclerosis of tolterodine ER granule: by tolterodine ER granule 70 DEG C of sclerosis 3 hours.
Lyophilized products compositions:
| Composition | Mg/ lyophilized products |
| Tolterodine ER granule | 31.49 |
| Desmopressin | 0.075 |
| Levan | 26.00 |
| Mannitol | 21.94 |
| Pullulan | 16.00 |
| Citric acid (anhydrous) | Be adjusted to pH 4.5 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 95.505mg |
The concise and to the point preparation process of lyophilized products:
1. all excipient are dissolved in pure water.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level
3. in the bubble chamber containing tolterodine ER granule, fill Desmopressin dispersion liquid.
4. the bubble of freezing filling in liquid nitrogen passage
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen
6. freezing bubble is loaded in freezer dryer and is used for lyophilization
7. monitor dry terminal by pressure buildup tests
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble, then impresses.
In pH 6.8 phosphate buffer, active component shows in Figure 5 from the release of the dosage form of embodiment 4.
embodiment 5
Tolterodine ER granule
| Composition | Mg/ unit |
| Sugar ball 1 (150-180 μ) | 8.00 |
| Seal coating 2 | |
| Surelease E-7-19010 | 2.40 |
| Pure water | In right amount |
| Medicine layer 3 | |
| Tolterodine L-TARTARIC ACID salt | 4.00 |
| HPMC 5 cps | 0.80 |
| Pure water | In right amount |
| ER coating 5 |
| Surelease E-7-19010 | 12.76 |
| HPMC 5cps | 2.44 |
| Pure water | In right amount |
| Gross weight | 30.40 |
Concise and to the point preparation process:
Tolterodine ER granule (Wurster coating procedure) is prepared in fluidized bed processor.
Different component/the preparation process of ER granule is:
A. inertia core 1: select the sugared ball (Pharm-a-spheres USP/NF, EP) of size range 150-180 μm for seal coating, medicine layer and ER layer.
B. seal coating 2: the Surelease (Colorcon) being diluted to 15%w/w concentration is insoluble to water layer for first.Be sprayed on by Surelease dispersion liquid on sugared ball, the weight obtaining 30%w/w increases.
C. medicine layer 3: the target weight to ~ 46%w/w on the sugared ball aqueous solution of drug-binder being sprayed on seal coating increases.Tolterodine tartrate: the ratio of HPMC 5cps is 5:1.
D. releasing layer 5 is extended: this layer is the combination of Surelease+HPMC 5cps.By Surelease+HPMC 5cps ~ 15%w/w aqueous dispersions (ratio of Surelease:HPMC 5cps is: 84:16) is sprayed on the granule of medication coat, obtain 100%w/w weight increase
E. the sclerosis of tolterodine ER granule: by tolterodine ER granule 70 DEG C of sclerosis 3 hours.
Lyophilized products compositions:
| Composition | Mg/ lyophilized products |
| Tolterodine ER granule | 31.49 |
| Desmopressin | 0.075 |
| Levan | 26.00 |
| Mannitol | 21.94 |
| Arabic gum | 10.00 |
| Citric acid (anhydrous) | Be adjusted to pH 4.5 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 89.505mg |
The concise and to the point preparation process of lyophilized products:
1. all excipient are dissolved in pure water.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level
3. in the bubble chamber containing tolterodine ER granule, fill Desmopressin dispersion liquid.
4. the bubble of freezing filling in liquid nitrogen passage
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen
6. freezing bubble is loaded in freezer dryer and is used for lyophilization
7. monitor dry terminal by pressure buildup tests
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble also then impresses.
In pH 6.8 phosphate buffer, active component shows in figure 6 from the release of the dosage form of embodiment 5.
embodiment 6
Tolterodine ER granule
| Composition | Mg/ unit |
| Sugar ball 1 (106-125 μ) | 8.00 |
| Seal coating 2 | |
| Surelease E-7-19010 | 2.40 |
| Pure water | In right amount |
| Hermetic coating bead | 10.40 |
| Medicine layer 3 | |
| Tolterodine L-TARTARIC ACID salt | 4.00 |
| HPMC 5cps | 0.80 |
| Pure water | In right amount |
| Gross weight | 15.20 |
| ER coating 5 |
| Surelease E-7-19010 | 15.32 |
| HPMC 5cps | 2.92 |
| Pure water | In right amount |
| Gross weight | 33.44 |
| Coating 6 | |
| Surelease E-7-19010 | 7.47 |
| Eudragit L100 | 0.912 |
| HPMC 5cps | 0.729 |
| Pure water | In right amount |
| Gross weight | 42.55 |
Concise and to the point preparation process:
Tolterodine ER granule (Wurster coating procedure) is prepared in fluidized bed processor.
Different component/the preparation process of ER granule is:
A. inertia core 1: select the sugared ball (Pharm-a-spheres USP/NF, EP) of size range 106-125 μm for seal coating, medicine layer and ER layer.
B. seal coating 2: the Surelease (Colorcon) being diluted to 15%w/w concentration is insoluble to water layer for first.Be sprayed on by Surelease dispersion liquid on sugared ball, the weight obtaining 30%w/w increases.
C. medicine layer 3: the target weight to ~ 46%w/w on the sugared ball aqueous solution of medicine and binding agent being sprayed on seal coating increases.Tolterodine tartrate: the ratio of HPMC 5cps is 5:1.
D. releasing layer 5 is extended: this layer is the combination of Surelease+HPMC 5cps.By Surelease+HPMC 5cps ~ 15%w/w aqueous dispersions (ratio of Surelease:HPMC 5cps is: 84:16) is sprayed on the granule of medication coat, obtain 120%w/w weight increase.
E. the sclerosis of tolterodine ER granule: by tolterodine ER granule 70 DEG C of sclerosis 3 hours.
F. coating 6: this layer is the combination of Surelease+HPMC 5cps+Eudragit L100.By Surelease:Eudragit L100:HPMC 5cps 82:10:8 ~ 15%w/w aqueous dispersions is sprayed on tolterodine ER granule, obtain 60%w/w weight increase.
G. the sclerosis of tolterodine granule: by the granule of coating 70 DEG C of sclerosis 3 hours.
Lyophilized products compositions:
| Composition | Mg/ unit |
| Tolterodine granule | 43.95 |
| Levan | 26.00 |
| Mannitol | 21.94 |
| Avicel RC 591 | 8.00 |
| Citric acid (anhydrous) | Be adjusted to pH 4.5 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 99.89 |
The concise and to the point preparation process of lyophilized products:
1. all excipient are dissolved in pure water, produce base composition.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine of exact level.
3. the matrix solution of filling step 1 in the bubble chamber containing tolterodine granule.
4. the bubble of freezing filling in liquid nitrogen passage
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen
6. freezing bubble is loaded in freezer dryer and is used for lyophilization
7. monitor dry terminal by pressure buildup tests
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble is also then packed.
In pH 6.8 phosphate buffer, tolterodine from the drug release (stripping curve) of the tolterodine ER granule of embodiment 6 and lyophilized products and for the drug release from Detrusitol XL (stripping curve) display of comparing in the figure 7.
embodiment 7
Tolterodine ER granule
Concise and to the point preparation process:
Tolterodine ER granule (Wurster coating procedure) is prepared in fluidized bed processor.
Different component/the preparation process of ER granule is:
A. inertia core 1: select the microcrystalline cellulose spheres (Cellets 175) of size range 150-200 μm for medicine layer and ER layer.
B. medicine layer 3: the target weight be sprayed on by the aqueous dispersions of binder solution Chinese medicine and Talcum to ~ 27%w/w in core increases.Tolterodine tartrate: the ratio of HPMC 5cps is 5:1.
C. releasing layer 5 is extended: this layer is Eudragit NE 30D, the combination of HPMC 5cps and Talcum.By Eudragit NE 30D, the target weight to ~ 20%w/w on the granule that the aqueous dispersions of HPMC 5cps and Talcum is sprayed on medication coat increases.
D. the sclerosis of tolterodine ER granule: by tolterodine ER granule 40 DEG C of sclerosis 24 hours.
Lyophilized products compositions:
| Composition | Per unit (mg) |
| Tolterodine ER bead | 32.77 |
| Levan | 26.00 |
| Mannitol (Perlitol 160C) | 21.94 |
| Avicel RC 591 | 8.00 |
| Citric acid solution (5%w/v) | Appropriate to pH 4.5 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 88.71mg |
The concise and to the point preparation process of lyophilized products:
1. all excipient are dissolved in pure water.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level
3. the matrix solution of step 1 is filled in the bubble chamber containing tolterodine ER granule.
4. the bubble of freezing filling in liquid nitrogen passage
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen
6. freezing bubble is loaded in freezer dryer and is used for lyophilization
7. by pressure buildup tests monitoring lyophilization terminal
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble also then impresses.
In pH 6.8 phosphate buffer, tolterodine from the drug release (stripping curve) of the tolterodine ER granule of embodiment 7 and lyophilized products and for the drug release from Detrusitol XL (stripping curve) display of comparing in fig. 8.
embodiment 8
Tolterodine ER granule
Concise and to the point preparation process:
Tolterodine granule (Wurster coating procedure) is prepared in fluidized bed processor.
Different component/the preparation process of described granule is:
A. inertia core 1: select the microcrystalline cellulose spheres (Cellets 175) of size range 150-200 μm for medicine layer and ER layer.
B. medicine layer 3: the aqueous dispersions in binder solution is sprayed on the target weight increase of extremely ~ 27%w/w in core by medicine and Talcum.Tolterodine tartrate: the ratio of HPMC 5cps is 5:1.
C. releasing layer 5 is extended: this layer is Eudragit NE 30D, the combination of HPMC 5cps and Talcum.By Eudragit NE 30D, the granule that the aqueous dispersions of HPMC 5cps and Talcum is sprayed on medication coat increases 20%w/w to target weight.
D. the sclerosis of tolterodine ER granule: by tolterodine ER granule 40 DEG C of sclerosis 24 hours.
E. coating 6: this layer is Eudragit L 30D-55, the combination of Talcum and triethyl citrate.By Eudragit L 30D-55, to target weight increase ~ 20%w/w on the granule that the aqueous dispersions of Talcum and triethyl citrate is sprayed on the coating extending release.
F. the sclerosis of granule: the granule applied by tolterodine was 40 DEG C of sclerosis 2 hours.
Lyophilized products compositions:
| Composition | Per unit (mg) |
| Tolterodine ER bead | 38.94 |
| Levan | 26.00 |
| Mannitol (Perlitol 160C) | 21.94 |
| Avicel RC 591 | 8.00 |
| Citric acid solution (5%w/v) | Appropriate to pH 4.5 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 94.88mg |
The concise and to the point preparation process of lyophilized products:
1. all excipient are dissolved in pure water.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level
3. the matrix solution of step 1 is filled in the bubble chamber containing tolterodine ER granule.
4. the bubble of freezing filling in liquid nitrogen passage
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen
6. freezing bubble is loaded in freezer dryer and is used for lyophilization
7. by pressure buildup tests monitoring lyophilization terminal
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble also then impresses.
In pH 6.8 phosphate buffer, tolterodine from the drug release (stripping curve) of the tolterodine ER granule of embodiment 8 and lyophilized products and for the drug release from Detrusitol XL (stripping curve) display of comparing in fig .9.
embodiment 9
Tolterodine ER granule
| Composition | Mg/ unit |
| Sugar ball 1 (150-180 μ) | 8.00 |
| Seal coating 2 | |
| Surelease E-7-19010 | 2.40 |
| Pure water | In right amount |
| Medicine layer 3 | |
| Tolterodine L-TARTARIC ACID salt | 4.00 |
| HPMC 5cps | 0.80 |
| Pure water | In right amount |
| Outside (barrier) seal coating 4 | |
| HPMC 5cps | 1.52 |
| Pure water | In right amount |
| ER coating 5 | |
| Eudragit NE30D | 4.49 |
| HPMC 5cps | 0.26 |
| Talcum | 1.93 |
| Pure water | In right amount |
| Outer 6 | |
| Eudragit NE30D | 5.85 |
| Talcum | 5.85 |
| Pure water | In right amount |
| Gross weight | 35.1 |
Concise and to the point preparation process:
Tolterodine ER granule (Wruster coating procedure) is prepared in fluidized bed processor.
Different component/the preparation process of ER granule is:
A. inertia core 1: select the sugared ball (Pharm-a-spheres USP/NF, EP) of size range 150-180 μm for seal coating, medicine layer, barrier layer, ER layer and skin.
B. seal coating 2: the Surelease (Colorcon) being diluted to 15%w/w concentration is insoluble to water layer for first.Be sprayed on by Surelease dispersion liquid on sugared ball, the weight obtaining 30%w/w increases.
C. medicine layer 3: the target weight to ~ 46%w/w on the sugared ball aqueous solution of drug-binder being sprayed on seal coating increases.Tolterodine tartrate: the ratio of HPMC 5cps is 5:1.
D. outside (barrier) seal coating 4: the target weight to ~ 10%w/w on the sugared ball aqueous solution of HPMC 5cps (5%w/v) being sprayed on medication coat and seal coating increases.
E. releasing layer 5 is extended: this layer is the combination of Eudragit NE30D+HPMC 5cps+ Talcum.By Eudragit NE30D+HPMC 5cps+ Talcum ~ (ratio of EudragitNE30D:HPMC 5cps is 20%w/w aqueous dispersions; 94.34:5.66 and Talcum is 43.1% of polymer content) be sprayed on the granule of barrier coatings, obtain 40%w/w weight increase.
F. skin 6: this layer is the combination of Eudragit NE30D+ Talcum.By Eudragit NE30D+ Talcum ~ 20%w/w aqueous dispersions (Eudragit NE30D: the ratio of Talcum is; 50:50) be sprayed on the granule of ER coating, the weight obtaining 50%w/w increases.
G. the sclerosis of tolterodine ER granule: by tolterodine ER granule 40 DEG C of sclerosis 12 hours.
Lyophilization compositions:
| Composition | Mg/ unit |
| Tolterodine ER granule | 36.69* |
| Desmopressin | 0.12 |
| Levan | 26.00 |
| Mannitol | 21.94 |
| Avicel RC 591 | 8.00 |
| Citric acid (anhydrous) | Be adjusted to pH 4.50 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 92.75mg |
The concise and to the point preparation process of lyophilization thing:
1. all excipient are dissolved or dispersed in pure water.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level.
3. in the bubble chamber containing tolterodine ER granule, fill Desmopressin dispersion liquid.
4. the bubble of freezing filling in liquid nitrogen passage
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen.
6. freezing bubble is loaded in freezer dryer and is used for lyophilization.
7. monitor dry terminal by pressure buildup tests.
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble also then impresses.
In pH 6.8 phosphate buffer, active component shows in Fig. 10 from the release of the lyophilization agent type of embodiment 9.
Embodiment 10
Lyophilization compositions:
| Composition | Mg/ unit |
| The tolterodine ER granule of embodiment 9 | 36.69* |
| Desmopressin | 0.12 |
| Inulin | 48.00 |
| Mannitol | 20.00 |
| Sodium alginate (Keltone LVCR) | 4.00 |
| Citrate buffer | Appropriate to pH 4.30 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 108.81mg |
The concise and to the point preparation process of lyophilization thing:
1. all excipient are dissolved in pure water.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level.
3. in the bubble chamber containing tolterodine ER granule, fill Desmopressin dispersion liquid.
4. the bubble of freezing filling in liquid nitrogen passage.
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen.
6. freezing bubble is loaded in freezer dryer and is used for lyophilization.
7. monitor dry terminal by pressure buildup tests.
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble also then impresses.
In pH 6.8 phosphate buffer, active component shows in fig. 11 from the release of the lyophilized products dosage form of embodiment 10.
Embodiment 11
Lyophilization compositions:
| Composition | Mg/ unit |
| Tolterodine ER granule (embodiment 9) | 36.69* |
| Desmopressin | 0.12 |
| Inulin | 48.00 |
| Mannitol | 20.00 |
| HPMC 3cps | 2.00 |
| Citrate buffer | Appropriate to pH 4.30 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 106.81mg |
The concise and to the point preparation process of lyophilization thing:
1. all excipient are dissolved in pure water.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level.
3. in the bubble chamber containing tolterodine ER granule, fill Desmopressin dispersion liquid.
4. the bubble of freezing filling in liquid nitrogen passage.
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen.
6. freezing bubble is loaded in freezer dryer and is used for lyophilization.
7. monitor dry terminal by pressure buildup tests.
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble also then impresses.
In pH 6.8 phosphate buffer, active component shows in fig. 12 from the release of the lyophilized products dosage form of embodiment 11.
Embodiment 12
Lyophilization compositions:
| Composition | Mg/ unit |
| The tolterodine ER granule of embodiment 9 | 36.69* |
| Desmopressin | 0.12 |
| Inulin | 48.00 |
| Mannitol | 20.00 |
| Citrate buffer | Appropriate to pH 4.30 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 104.81mg |
The concise and to the point preparation process of lyophilization thing:
1. all excipient are dissolved in pure water.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level.
3. in the bubble chamber containing tolterodine ER granule, fill Desmopressin dispersion liquid.
4. the bubble of freezing filling in liquid nitrogen passage.
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen.
6. freezing bubble is loaded in freezer dryer and is used for lyophilization.
7. monitor dry terminal by pressure buildup tests.
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble also then impresses.
In pH 6.8 phosphate buffer, active component shows in fig. 13 from the release of the lyophilized products dosage form of embodiment 12.
Embodiment 13
Tolterodine ER granule
Concise and to the point preparation process:
Tolterodine ER granule (Wurster coating procedure) is prepared in fluidized bed processor.
Different component/the preparation process of ER granule is:
1. inertia core 1: select the MCC bead (Cellets 175) of size range 150-200 μm to be then the parent material of ER layer as medicine layer.
2. medicine layer 3: the target weight aqueous dispersions of drug-binder being sprayed on extremely ~ 26.58%w/w on MCC bead increases.Tolterodine tartrate: the ratio of HPMC 5cps is 5:1.
3. extend releasing layer 5: this layer is the combination of Eudragit NE30D+HPMC 5cps+ Talcum.By Eudragit NE30D+HPMC 5cps+ Talcum ~ (ratio of Eudragit NE30D:HPMC 5cps is 20%w/w aqueous dispersions; 94.34:5.66 and Talcum is 43.1% of polymer content) be sprayed on the granule of medication coat, obtain 20%w/w weight increase.
4. skin 6: this layer is the combination of Eudragit L30D55+TEC+ Talcum.By EudragitL30D55+TEC+ Talcum ~ 20%w/w aqueous dispersions (Eudragit L30D55: Talcum is 1:0.5, and TEC is 10% of actual Eudragit polymer content) is sprayed on ER granule, obtain 20%w/w weight increase.
5. the sclerosis of tolterodine ER granule: after mixing with 2% Talcum as foreign minister, by tolterodine ER granule 40 DEG C of sclerosis 24 hours.
Lyophilization compositions:
| Composition | Mg/ unit |
| Tolterodine ER granule | 38.94 |
| Desmopressin | 0.12 |
| Levan | 26.00 |
| Mannitol | 21.94 |
| Citric acid (anhydrous) | Be adjusted to pH 4.5 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 87.00 |
The concise and to the point preparation process of lyophilization thing:
1. all excipient are dissolved in pure water.Add to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level.
3. in the bubble chamber containing tolterodine ER granule, fill Desmopressin dispersion liquid.
4. the bubble of freezing filling in liquid nitrogen passage.
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen.
6. freezing bubble is loaded in freezer dryer and is used for lyophilization.
7. monitor dry terminal by pressure buildup tests.
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble also then impresses.
In pH 6.8 phosphate buffer, active component shows in fig. 14 from the release of the lyophilized products dosage form of embodiment 13.
Embodiment 14
Tolterodine ER granule
Concise and to the point preparation process:
Tolterodine ER granule (Wurster coating procedure) is prepared in fluidized bed processor.
Different component/the preparation process of ER granule is:
1. inertia core 1: select the MCC bead (Cellets 175) of size range 150-200 μm to be then the parent material of ER layer as medicine layer.
2. medicine layer 3: the aqueous dispersions of drug-binder is sprayed on MCC bead, target is ~ weight of 26.58%w/w increases.Tolterodine tartrate: the ratio of HPMC 5cps is 5:1.
3. extend releasing layer 5: this layer is the combination of Eudragit NE30D+HPMC 5cps+ Talcum.By Eudragit NE30D+HPMC 5cps+ Talcum ~ (ratio of Eudragit NE30D:HPMC 5cps is 20%w/w aqueous dispersions; 94.34:5.66 and Talcum is 43.1% of polymer content) be sprayed on medication coat granule, obtain 20%w/w weight increase.
4. the sclerosis of tolterodine ER granule: after mixing with 2% Talcum as foreign minister, by tolterodine ER granule 40 DEG C of sclerosis 24 hours.
Lyophilization compositions:
| Composition | Mg/ unit |
| Tolterodine ER granule | 32.77 |
| Desmopressin | 0.12 |
| Levan | 26.00 |
| Mannitol | 21.94 |
| Maltodextrin | 30.00 |
| Citric acid (anhydrous) | Be adjusted to pH 4.5 |
| Pure water | Appropriate to 400 μ l |
| Gross weight | 110.83 |
The concise and to the point preparation process of lyophilization thing:
1. all excipient are dissolved in pure water.Be supplemented to final volume with pure water and use 5%w/v citric acid solution by pH regulator to pH 4.5.
2. with the particles filled prefabricated bubble chamber of tolterodine ER of exact level.
3. in the bubble chamber containing tolterodine ER granule, fill Desmopressin dispersion liquid.
4. the bubble of freezing filling in liquid nitrogen passage.
5. bubble is remained on lower than cryogenic temperature until whole batch is frozen.
6. freezing bubble is loaded in freezer dryer and is used for lyophilization.
7. monitor dry terminal by pressure buildup tests.
8. from the bubble that freezer dryer unloading is dry.
9. sealing bubble also then impresses.
In pH 6.8 phosphate buffer, active component shows in fig .15 from the release of the lyophilized products dosage form of embodiment 14.
Claims (40)
1. a pharmaceutical composition, described pharmaceutical composition comprises: the open matrix net containing the first active constituents of medicine; More than one matrix formers; With the Co ntrolled release pearl containing the second active constituents of medicine.
2. pharmaceutical composition according to claim 1, more than one matrix formers wherein said are selected from by the following group formed: levan, inulin, Pullulan, HPMC, maltodextrin, arabic gum, sodium alginate and their combination.
3. pharmaceutical composition according to claim 1 and 2, wherein said open matrix net also comprises mannitol, trehalose and/or Raffinose.
4. the pharmaceutical composition according to any one of claims 1 to 3, described pharmaceutical composition was dissolved in standardized aqueous medium in 30 seconds.
5. pharmaceutical composition according to claim 4, described pharmaceutical composition was dissolved in standardized aqueous medium in 10 seconds.
6. the pharmaceutical composition according to any one of claim 1 to 5, wherein said first active constituents of medicine is desmopressin acetate.
7. the pharmaceutical composition according to any one of claim 1 to 6, wherein said Co ntrolled release pearl comprises the core (1) of the inert material of water-soluble, water-fast or water-swellable, and described core has
The upper optional inner sealing coating (2) that is substantially water-fast or water-soluble polymer substantially of (i) described core (1);
(ii) inner medicated layer (3), described inner medicated layer (3) covers described core (1) or inner sealing coating (2) and containing the second active component; With
(iii) the polymer outer rete (5) on described inner medicated layer (3), described rete (5) is effective to the Co ntrolled release of described second active component from described inner medicated layer (3).
8. pharmaceutical composition according to claim 7, wherein said core (1) is water-soluble sugared ball.
9. pharmaceutical composition according to claim 7, wherein said core (1) is the microcrystalline Cellulose core of water-swellable.
10. the pharmaceutical composition according to any one of claim 7 to 9, the amount of wherein said inner sealing coating (2) forms about 4 to about 15% (w/w) of described Co ntrolled release pearl.
11. pharmaceutical compositions according to any one of claim 7 to 10, the amount of wherein said inner medicated layer (3) forms about 5 to about 25% (w/w) of described Co ntrolled release pearl.
12. pharmaceutical compositions according to any one of claim 7 to 11, the amount of wherein said outside rete (5) forms about 25 to about 55% (w/w) of described Co ntrolled release pearl.
13. pharmaceutical compositions according to any one of claim 7 to 12, wherein said outside rete (5) is had by other infiltrative polymer coating (6) coating relying on pH.
14. pharmaceutical compositions according to any one of claim 7 to 13, the described water-fast polymer substantially of wherein said inner sealing coating (2) comprises ethyl cellulose.
15. pharmaceutical compositions according to any one of claim 7 to 14, wherein said inner medicated layer (3) comprises hydroxypropyl emthylcellulose as binding agent.
16. pharmaceutical compositions according to any one of claim 7 to 15, the described outside rete (5) being wherein effective to the Co ntrolled release of described second active component comprises the combination of hydroxypropyl emthylcellulose and ethyl cellulose.
17. pharmaceutical compositions according to any one of claim 1 to 16, wherein said second active component is antimuscarinic compounds.
18. pharmaceutical compositions according to claim 17, wherein said antimuscarinic compounds is selected from tolterodine, the 5-form hydroxy methyl metabolite of tolterodine, (the S)-enantiomer of tolterodine, the 5-form hydroxy methyl metabolite of (the S)-enantiomer of tolterodine, the racemate of tolterodine, its prodrug forms and pharmaceutical salts thereof.
19. pharmaceutical compositions according to claim 18, wherein said antimuscarinic compounds is tolterodine or its pharmaceutical salts.
20. pharmaceutical compositions according to claim 19, wherein said antimuscarinic compounds is Tolterodine tartrate.
21. pharmaceutical compositions according to claim 20, the Tolterodine tartrate part wherein discharged in vitro is no more than about 40% after 1h, and after 3 hours from about 35 to about 85%, and be no less than about 65% after 7 hours.
22. according to claim 17 to the pharmaceutical composition described in 21 any one, and described pharmaceutical composition is used for the treatment of overactive bladder.
23. according to claim 17 to the pharmaceutical composition described in 21 any one, and described pharmaceutical composition is used for the treatment of the overactive bladder with nocturia.
24. according to claim 17 to the pharmaceutical composition described in 21 any one, and described pharmaceutical composition is used for the treatment of the overactive bladder with nocturia in women.
25. pharmaceutical compositions according to any one of claim 1 to 16, wherein said second active component is selectivity alpha block agent.
26. pharmaceutical compositions according to claim 25, wherein said selectivity alpha block agent is tamsulosin, its prodrug forms or its pharmaceutical salts.
27. pharmaceutical compositions according to any one of claim 1 to 26, described pharmaceutical composition is oral dosage form.
28. pharmaceutical compositions according to claim 27, described pharmaceutical composition is suitable for sublingual administration.
29. pharmaceutical compositions according to any one of claim 1 to 28, described pharmaceutical composition obtains by following steps:
I described Co ntrolled release pearl mixes with the liquid preparation containing described first active component and more than one matrix formers by () in a solvent, form mixture;
(ii) described solvent is distilled from described mixture.
30. pharmaceutical compositions according to claim 29, wherein said distillation is undertaken by preparation described in lyophilization.
The method of 31. 1 kinds of pharmaceutical compositions, described method comprises from liquid preparation subliming solvent, and described liquid preparation comprises the first active constituents of medicine, more than one matrix formers, the Co ntrolled release bead comprising the second active constituents of medicine and solvent.
32. methods according to claim 31, wherein said distillation is undertaken by liquid preparation described in lyophilization.
33. methods according to claim 31 or 32, wherein said solvent is water.
The method of 34. 1 kinds of pharmaceutical compositions, said method comprising the steps of:
A () prepares mixture, described mixture comprises: the first active component, the Co ntrolled release pearl containing the second active component, more than one matrix formers and solvent;
(b) freezing described solution;
C () to distil described solvent from described freezing solution,
Wherein the pharmaceutical composition of acquisition is like this after contacting with standardized aqueous medium, disintegrate in 30 seconds.
35. methods according to claim 33, wherein said compositions after contacting with standardized aqueous medium, disintegrate in 10 seconds.
36. methods according to any one of claim 31 to 35, wherein said compositions is the compositions according to any one of claim 1 to 28.
37. 1 kinds of methods for the treatment of overactive bladder, nocturia or their combination in the experimenter having this to need, described method comprises the compositions according to any one of claim 17-21 to described experimenter's administering therapeutic effective dose.
38. according to method according to claim 37, and wherein said experimenter is female subjects.
39. methods for the treatment of benign prostatic hyperplasia in the experimenter having this to need, described method comprises the compositions according to any one of claim 25-26 to described experimenter's administering therapeutic effective dose.
40. according to method according to claim 39, and wherein said experimenter is male subject.
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| IN3575DE2012 | 2012-11-21 | ||
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| IN3947DE2012 | 2012-12-20 | ||
| PCT/EP2013/074373 WO2014079922A1 (en) | 2012-11-21 | 2013-11-21 | Composition for immediate and extended release |
Publications (1)
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| CN104797240A true CN104797240A (en) | 2015-07-22 |
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| CN201380060349.8A Pending CN104797240A (en) | 2012-11-21 | 2013-11-21 | Composition for immediate and extended release |
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| EP (1) | EP2922525A1 (en) |
| JP (1) | JP2016500088A (en) |
| KR (1) | KR20150085826A (en) |
| CN (1) | CN104797240A (en) |
| AR (1) | AR093585A1 (en) |
| AU (1) | AU2013349682A1 (en) |
| BR (1) | BR112015011430A2 (en) |
| CA (1) | CA2891365A1 (en) |
| EA (1) | EA201590805A1 (en) |
| HK (1) | HK1213779A1 (en) |
| IL (1) | IL238648A0 (en) |
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| MX (1) | MX2015006399A (en) |
| PH (1) | PH12015501096A1 (en) |
| SG (2) | SG10201703388TA (en) |
| TW (1) | TW201422254A (en) |
| WO (1) | WO2014079922A1 (en) |
| ZA (1) | ZA201503603B (en) |
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| CN108289891A (en) * | 2015-11-23 | 2018-07-17 | 韦尔斯利医药有限公司 | Alleviate the composition of frequent micturition, manufacturing method and application |
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| CN108430465A (en) * | 2015-09-30 | 2018-08-21 | 韦尔斯利医药有限公司 | Composition, its manufacturing method and purposes for alleviating frequent micturition |
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| CN110049757A (en) * | 2017-01-11 | 2019-07-23 | 辉凌公司 | Quickly disintegrated pharmaceutical composition |
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| EP3024474B1 (en) | 2013-07-23 | 2022-01-05 | Serenity Pharmaceuticals LLC | Compositions comprising desmopressin in combination with a beta-3 adrenergic receptor agonist |
| KR20150144209A (en) * | 2014-06-16 | 2015-12-24 | 훼링 비.브이. | Pharmaceutical composition comprising stabilized desmopressin or pharmaceutically acceptable salt thereof |
| CN106999538A (en) * | 2014-11-20 | 2017-08-01 | 阿勒根公司 | Method and composition comprising minirin Yu alpha-2 adrenoceptor antagonist-combination |
| JP2018504454A (en) | 2015-01-12 | 2018-02-15 | ナノ ファーマシューティカル ラボラトリーズ エルエルシーＮａｎｏ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｌａｂｏｒａｔｏｒｉｅｓ ＬＬＣ | Laminated sustained-release microbeads and method for producing the same |
| WO2016174664A1 (en) | 2015-04-29 | 2016-11-03 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
| EP3445343A1 (en) | 2016-04-21 | 2019-02-27 | Valcuria AB | Composition and method for pretreating cancer |
| US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
| KR20190021180A (en) * | 2017-08-22 | 2019-03-05 | 아주대학교산학협력단 | Pharmaceutical complex formulations for treating neurodegenerative diseases |
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- 2013-11-21 BR BR112015011430A patent/BR112015011430A2/en not_active Application Discontinuation
- 2013-11-21 CN CN201380060349.8A patent/CN104797240A/en active Pending
- 2013-11-21 EP EP13792703.4A patent/EP2922525A1/en not_active Withdrawn
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Also Published As
| Publication number | Publication date |
|---|---|
| AR093585A1 (en) | 2015-06-10 |
| TW201422254A (en) | 2014-06-16 |
| SG10201703388TA (en) | 2017-05-30 |
| ZA201503603B (en) | 2016-01-27 |
| WO2014079922A1 (en) | 2014-05-30 |
| EA201590805A1 (en) | 2015-11-30 |
| HK1213779A1 (en) | 2016-07-15 |
| KR20150085826A (en) | 2015-07-24 |
| CA2891365A1 (en) | 2014-05-30 |
| SG11201503913TA (en) | 2015-06-29 |
| AU2013349682A1 (en) | 2015-06-04 |
| BR112015011430A2 (en) | 2017-07-11 |
| MX2015006399A (en) | 2015-07-21 |
| JP2016500088A (en) | 2016-01-07 |
| PH12015501096A1 (en) | 2015-07-27 |
| EP2922525A1 (en) | 2015-09-30 |
| IN2015DN03984A (en) | 2015-10-02 |
| IL238648A0 (en) | 2015-06-30 |
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