CN102552161A - Preparation method of medicament solid preparation and obtained medicament solid preparation - Google Patents
Preparation method of medicament solid preparation and obtained medicament solid preparation Download PDFInfo
- Publication number
- CN102552161A CN102552161A CN2010106198836A CN201010619883A CN102552161A CN 102552161 A CN102552161 A CN 102552161A CN 2010106198836 A CN2010106198836 A CN 2010106198836A CN 201010619883 A CN201010619883 A CN 201010619883A CN 102552161 A CN102552161 A CN 102552161A
- Authority
- CN
- China
- Prior art keywords
- water
- insoluble
- basifier
- spraingly
- active component
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a preparation method of a medicament solid preparation. The method comprises the following steps of: dissolving active ingredients of a water-insoluble and/or water-poorly-soluble acid medicament into an alkaline solution containing a basifier to obtain a medicament-containing alkaline liquid; and uniformly mixing auxiliary materials with the medicament-containing alkaline liquid, and performing wet process pelletizing. The invention further discloses a medicament solid preparation prepared with the method. Due to the adoption of the preparation method disclosed by the invention, the defects of severe pollution, large loss and severe potential safety hazard caused by mechanical smashing treatment are overcome, and the effects of reducing the particle sizes of the active ingredients of the water-insoluble and/or water-poorly-soluble acid medicament in a pelletizing process is achieved. The method is easy and convenient to operate, is practicable, has high safety coefficient, and is easily applied to industrial production. The solid preparation prepared with the method has excellent dissolving characteristic, stability and content uniformity.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of method for preparing and gained medical solid preparation of medical solid preparation.
Background technology
In field of pharmaceutical preparations, the particle diameter of active constituents of medicine is closely related with quality to the preparation process of solid preparation, and reducing of particle diameter is the key that improves pharmaceutical preparation dissolution and uniformity of dosage units.In the preparation technology of concrete pharmaceutical preparation,, select the particle diameter of suitable active constituents of medicine usually according to the dissolution characteristics and the biomembrane permeability of medicine.For example, if it is relatively poor to belong to dissolubility, the medicine stripping is the medicine that absorbs the speed limit process, can select smaller particle size, to promote the absorption of medicine.In the preparation technology of medical solid preparation, relate to selection control often to the particle diameter of active constituents of medicine.
At present, mostly through selecting different mechanical crushing method and disintegrating process condition, to realize selection control to the active constituents of medicine particle diameter.Universalpulverizer is a kind ofly to use pulverizer more widely at drug world, and the work that material is pulverized is main in order to impact force, shearing force, is applicable to multiple medium-hard dried material, and the mean diameter after the processing generally reaches about 100 microns.
But problem such as the processing method of mechanical activation comminution exists that dust is many, contaminated environment and loss are big.For some high-activity drugs, also easily in the mechanical activation comminution process, make operator produce untoward reaction, there is serious potential safety hazard.For example, the calming soporific medicine powder that sucks than low dosage can produce hypnotic effect fast, when this type medicine is carried out pulverization process, very easily causes the quick hypnotic untoward reaction of operator, causes security incident.Again for example, when medicines such as some highly active hormones or antitumor are carried out pulverization process, suck or contact a certain amount of drug powder, very easily make operator produce serious drug reaction.
For some insoluble drugs, mean diameter reaches about 100 microns, and the dissolution characteristic of the solid preparation that makes does not still reach requirement.
In the technology that mechanical activation comminution is handled, (, also relate to itself and the blended dispersing uniformity problem of adjuvant like≤5wt%) high-activity drug active component for content in solid preparation is lower.Usually, adopt active constituents of medicine and adjuvant equivalent are diluted the method that progressively enlarges, so that active constituents of medicine is uniformly dispersed in solid preparation.But this method technological operation is loaded down with trivial details, can produce equally that dust is many, contaminated environment, loss is big and there are problems such as potential safety hazard in labor protection.
In addition, the preparation of solid preparation need consider also whether the various performances of product can satisfy the demand.For example, whether can guarantee preferable uniformity of dosage units.Again for example; Stability is the investigation emphasis of solid preparation quality; It is included in solid preparation in storage period, and whether the chemical stability of active constituents of medicine, the content of impurity, solid preparation property stability and stripping stability etc. are in the drug standard limit.
Therefore,, demand seeking a kind of above-mentioned defective that both can avoid the mechanical activation comminution processing method urgently, can guarantee the method for preparing of the various function admirables of solid preparation again to the defective of above-mentioned prior art.
Summary of the invention
Technical problem to be solved by this invention is to select to control the particle diameter of active constituents of medicine through the mode of mechanical activation comminution in order to overcome existing solid preparation method for preparing; Can cause environmental pollution, have serious potential safety hazard, loss is big; And the dissatisfactory defectives such as stripping property of gained solid pharmaceutical preparation; And, provide a kind of operation easier to water-insoluble or spraingly water-soluble acidic drug, pollute littler; Do not have aforementioned potential safety hazard, and can guarantee that prepared solid preparation has the method for preparing and the gained medical solid preparation of the medical solid preparation of excellent dissolution characteristic, stability and uniformity of dosage units.
For solving the problems of the technologies described above, the inventor looks for another way, and unique employing alkaline solution dissolving water-insoluble and/or spraingly water-soluble acidic drug in pelletization, make medicine reply solid state afterwards, thus many defectives of having avoided mechanical activation comminution to handle.And the inventor is also unexpected to find that prepared water-insoluble of this method and/or spraingly water-soluble acidic drug solid preparation have excellent dissolution characteristic, stability and uniformity of dosage units.
The method for preparing of medical solid preparation of the present invention comprises the steps: water-insoluble and/or spraingly water-soluble acidic drug active component are dissolved in the alkaline solution that contains basifier, makes the pastille alkalies; Afterwards, with adjuvant and described pastille alkalies uniform mixing, carry out wet granulation.
Among the present invention, described water-insoluble and/or spraingly water-soluble acidic drug active component are selected from the existing various active constituents of medicine that meets above-mentioned character, comprise the both sexes active constituents of medicine that has acidic-group and basic group simultaneously.In this area, described acidic drug active component mostly is a weak acid class active constituents of medicine.The present invention preferred active water-insoluble or spraingly water-soluble acidic drug active component higher, content lower (be generally below 20%, preferable is below 10%, and better is below 5%, and percentage ratio is mass percent) in solid preparation.More specifically, the present invention is preferred but be not limited to glipizide, folic acid, bumetanide, diclofenamide (dichlorphenamide), isocarboxazid, bendroflumethiazide, paraflutizide, methotrexate, biotin, hexestrol, indapamide, furosemide, the nimble purine of sulfur bird, allopurinol, gliquidone, simvastatin, leflunomide, hydrochlorothiazide or phenobarbital.
According to water-insoluble and/or the customary amount of spraingly water-soluble acidic drug active component in solid preparation, can confirm in the preparation process that water-insoluble and/or spraingly water-soluble acidic drug active component account for the mass percent of wet granulation dry material.As required, except that water-insoluble and/or spraingly water-soluble acidic drug active component, also can add the other drug active component and process compound solid preparation.
Among the present invention, described basifier is meant and can makes water-insoluble and/or spraingly water-soluble acidic drug active component be dissolved in the reagent in the alkaline solution that contains basifier fully.According to this area general knowledge, described basifier should be pharmaceutically acceptable, and with water-insoluble and/or the compatible reagent of spraingly water-soluble acidic drug active component.Among the present invention, described compatibility is meant and can coexists, has no adverse effects.Described basifier can be single basifier; Also can be the compound basifier that two or more one-tenth are grouped into; Can be selected from various alkali; Like inorganic base and/or organic base, highly basic and/or weak base preferable are selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, Sodium ethylate, meglumine, diethanolamine and the triethanolamine one or more.The preferred especially following basifier of the present invention:
When water-insoluble and/or spraingly water-soluble acidic drug active component were indapamide, described basifier was sodium hydroxide, potassium hydroxide or Sodium ethylate, and best is sodium hydroxide.
When water-insoluble and/or spraingly water-soluble acidic drug active component were glipizide, described basifier was sodium hydroxide or potassium hydroxide, and best is sodium hydroxide.
When water-insoluble and/or spraingly water-soluble acidic drug active component were folic acid, described basifier was sodium hydroxide, potassium hydroxide, Sodium ethylate, sodium carbonate or potassium carbonate, and best is sodium hydroxide or sodium carbonate.
When water-insoluble and/or spraingly water-soluble acidic drug active component were methotrexate, described basifier was sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
When water-insoluble and/or spraingly water-soluble acidic drug active component were bendroflumethiazide, described basifier was sodium hydroxide or potassium hydroxide.
The consumption of described basifier is at least and can makes water-insoluble and/or the consoluet minimum of spraingly water-soluble acidic drug active component, 1～1.5 times of preferable minimum for this reason, and best is 1～1.05 times.The amount of the basifier of solubilized water-insoluble and/or spraingly water-soluble acidic drug active component is relevant with many factors, and is relevant like the anion number that can combine with the acid centre of water-insoluble and/or spraingly water-soluble acidic drug active component in basifier kind, solvent species, the basifier and pastille alkalies preparation condition (like temperature, time, charging sequence, alr mode) etc.Wherein, described acid centre be meant in water-insoluble and/or the spraingly water-soluble acidic drug active component can with bonded group of anion or position in the basifier molecule.Therefore; Above-mentioned minimum is meant that under same solvent and pastille alkalies preparation condition as far as certain water-insoluble and/or spraingly water-soluble acidic drug active component, certain basifier can be with its dissolved minimum; Can confirm this minimum through simple conventional method: under same solvent and pastille alkalies preparation condition; Adopt consumption certain water-insoluble of dissolving and/or the spraingly water-soluble acidic drug active component that increase certain basifier gradually, when just dissolving fully, be minimum.The inventor gropes to draw through a large amount of experiments, and particularly, the molar ratio of basifier and water-insoluble and/or spraingly water-soluble acidic drug active component is generally 0.1～2.5, is 0.9～1.5 mostly, the basifier of the preferred especially following dosage of the present invention:
For indapamide, sodium hydroxide or Sodium ethylate that preferred especially its mole is 0.7～1.1 times.
For glipizide, the sodium hydroxide that preferred especially its mole is 0.95～1.1 times.
For folic acid, sodium carbonate or potassium carbonate that the sodium hydroxide that preferred especially its mole is 1.8～2.1 times or its mole are 0.95～1.1 times.
For methotrexate, the sodium carbonate that sodium hydroxide that preferred especially its mole is 1.4～1.6 times or mole are 0.85～1.1 times.
For bendroflumethiazide, the sodium hydroxide that preferred especially its mole is 0.9～1.6 times.
Among the present invention, the solvent in the described alkaline solution that contains basifier can be the mixed liquor of water, organic solvent or water and organic solvent.According to this area general knowledge, the solvent of selection should be the basifier intermediate ion can dissociated solvent.For example, when basifier is inorganic matter, can select the mixed liquor of water or water and organic solvent; When basifier is Organic substance, can be the mixed liquor or the organic solvent of water, water and organic solvent.If active constituents of medicine has the dissolubility that is superior in water in some organic solvent, the preferable selection water and the mixed liquor of this organic solvent are beneficial to the dissolving of active constituents of medicine, reduce the consumption of basifier or solvent, are beneficial to the operation of follow-up granulation step.Described organic solvent is selected in the acceptable solvent of medicament field according to the principle that its dissolubility to water-insoluble and/or spraingly water-soluble acidic drug active component is superior to water; Preferable is can be miscible with water organic solvent; Like medicament field water-soluble alcohol kind solvent commonly used; Like ethanol, propylene glycol, glycerin, acetone, isopropyl alcohol or the tert-butyl alcohol etc., one or more in preferred alcohol, acetone, propylene glycol and the glycerin, special preferred alcohol.In the mixed liquor of water and organic solvent, the concentration of organic solvent can be selected arbitrarily.The consumption of solvent is at least the required granulation liquid minimum of wet granulation to make medicinal soluble separate at least in the described alkaline solution, is generally the mass percent 5～100% of wet granulation dry material, and preferable is 10～50%.
When preparation pastille alkalies, can add some adjuvants, like the water-solubility carrier of binding agent, surfactant, solubilizing agent and solid dispersion etc.Preferable; When being dissolved in water-insoluble and/or spraingly water-soluble acidic drug active component in the alkaline solution that contains basifier and/or afterwards; Also add in the water-solubility carrier of surfactant, solubilizing agent and solid dispersion one or more; Then gained pastille alkalies is carried out subsequent step, promptly, carry out wet granulation with the adjuvant uniform mixing.Wherein, When adding the water-solubility carrier of solid dispersion and water-insoluble and/or spraingly water-soluble acidic drug active component in the alkaline solution that contains basifier simultaneously, the amount of the water-solubility carrier of the solid dispersion that add this moment need be controlled at and can guarantee that water-insoluble and/or spraingly water-soluble acidic drug active component are dissolved in below the amount in the alkaline solution that contains basifier fully; Can also in this solution, add the water-solubility carrier of solid dispersion afterwards again, when addition was big, the acid liquid of gained pastille possibly be suspension or viscous solution form.The present invention especially preferably adds one or more in polyvidone, Polyethylene Glycol (preferred PEG400-8000), sodium lauryl sulphate, poloxamer, polyoxyethylene castor oil, tween (preferred Tween 80), polyoxyethylene stearate 40 esters, lactose, mannitol, sucrose, HP-, beta-schardinger dextrin-and the maltose alcohol.The addition of described surfactant and/or solubilizing agent is preferable is water-insoluble and/or spraingly water-soluble acidic drug active component quality 0.05～5 times, and better is 0.05～2 times.The addition of the water-solubility carrier of described solid dispersion is preferable is water-insoluble and/or spraingly water-soluble acidic drug active component quality 0.5～20 times, and better is 0.5～2 times.Press aforesaid operations and add surfactant and/or solubilizing agent, can increase water-insoluble and/or the dissolubility of spraingly water-soluble acidic drug active component in alkaline solution, reduce solvent load, be beneficial to the operation of follow-up granulation step.It will be further appreciated that press in the water-solubility carrier that aforesaid operations adds surfactant, solubilizing agent and solid dispersion one or more, it is better that especially the water-solubility carrier of solid dispersion can make the dissolution characteristic of gained solid preparation.
Preferable, when preparation pastille alkalies, can be through conventional heating means such as hot baths, the preparation temperature of the pastille alkalies that suitably raises is beneficial to the dissolving of active constituents of medicine.When being solvent with water, preferable is increased to 40～80 ℃.When being solvent with the mixed solution of water and organic solvent, preferable rising is 40～70 ℃.When being solvent with ethanol, preferable rising is 30～50 ℃.
Among the present invention, described adjuvant can be selected from any known and widely used adjuvant in this area, like filler, binding agent, disintegrating agent, adsorbent and lubricant or the like.The content of described adjuvant can be selected according to this area routine or existing knowledge.Wherein, described filler is preferable is in lactose, microcrystalline Cellulose, starch, pregelatinized Starch, mannitol, sucrose and the maltose alcohol one or more.Described binding agent is preferable is in hypromellose, polyvidone, methylcellulose and the hyprolose one or more.Said disintegrating agent is preferable is in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone and the cross-linking sodium carboxymethyl cellulose one or more.What described lubricant was preferable is magnesium stearate, micropowder silica gel (colloidal silica), Pulvis Talci or sodium stearyl fumarate.
With adjuvant and described pastille alkalies uniform mixing, when carrying out the step of wet granulation, also can add acidulant, the alkalescence of the mixed liquor of acidulant and pastille alkalies is reduced with respect to the alkalescence of pastille alkalies.
According to this area general knowledge, it is pharmaceutically acceptable that said acidulant all should be, and with water-insoluble and/or the compatible reagent of spraingly water-soluble acidic drug active component.Preferable, the basifier of the preferred following type of the present invention and the combination of acidulant: described basifier is inorganic strong alkali, organic alkali or inorganic middle highly basic, and described acidulant is inorganic acid (example hydrochloric acid).
The amount of described acidulant is the alkalescence of the mixed liquor that can make acidulant and the pastille alkalies at least amount with respect to the alkalescence reduction of pastille alkalies.Preferable, the consumption of basifier and acidulant satisfies following relation: formula 1 income value is 0.01～1.5, and preferable is 0.2～1.1, and better is 0.9～1.1.
(acidulant molal quantity * A)/(formula 1 of basifier molal quantity * B) wherein, A is the hydrion number in the acidulant molecule, and B is the total valence state number of basifier molecular anion.
Special preferred formula 1 value of the present invention is 0.9～1.1 the following basifier and the combination of acidulant: sodium hydroxide and hydrochloric acid, potassium hydroxide and hydrochloric acid, Sodium ethylate and hydrochloric acid, sodium carbonate and hydrochloric acid and potassium carbonate and hydrochloric acid.
For some water-insoluble and/or spraingly water-soluble acidic drug active component, add acidulant, can more help the stability of solid preparation.And for some water-insoluble and/or spraingly water-soluble acidic drug active component; In prescription, do not add under acidulant or the acidulant consumption situation seldom; Solid preparation still can have preferable stability; But under the prerequisite that does not influence preparation stability, suitably increase the acidulant consumption and reduce alkalescence, can help relaxing the PH of solid preparation.
Among the present invention; Described wet granulation can be undertaken by conventional steps and condition that this area belongs to the various method of granulating of wet granulation category, granulates (like wobbler extruding, screw extrusion or rotation extrusion etc.), stirs granulation, fluidized-bed spray granulation or centrifugal spray granulation etc. like extruding.For dosage in solid preparation big (generally greater than 10%); Or dissolubility is less in containing the alkaline solution of basifier; Need more a large amount of alkaline solution ability solubilized water-insoluble and/or spraingly water-soluble acidic drug active component completely; Can select the little wet granulation technology of granulation solution amount restriction is granulated like fluidized-bed spray granulation or centrifugal spray.
When using acidulant, preferable by in the following mode any carries out concrete operations: mode (1) is with acidulant or contain solution and the adjuvant uniform mixing of acidulant, again with pastille alkalies uniform mixing, pushes and granulates or stir granulation; Mode (2) is mixed pastille alkalies and, acidulant or the solution that contains acidulant uniformly, granulation liquid, again this granulation liquid and adjuvant are pushed granulation, stirring granulation, fluidized-bed spray granulation or centrifugal spray granulation etc. afterwards; Mode (3) is mixed the pastille alkalies with adjuvant uniformly, mixes uniformly with the solution that contains acidulant more afterwards, pushes and granulates or the stirring granulation; Mode (4) with the pastille alkalies with; Adjuvant below 1/3, and acidulant or the solution that contains acidulant mix uniformly, and (concrete operations can be: earlier with adjuvant below 1/3 and acidulant or contain the solution uniform mixing of acidulant, the gained mixture is mixed with the pastille alkalies again; Perhaps; Earlier adjuvant 1/3 below and pastille alkalies are mixed, again with acidulant or contain the solution uniform mixing of acidulant), mixes with the residue adjuvant more afterwards and pushes granulation or stirring granulation.What the adjuvant in the described adjuvant below 1/3 was preferable is water soluble adjuvant.Describedly can be below 1/4～1/10 usually below 1/3.The described solution that contains acidulant is meant, by this area routine operation, with the solution of little solvent dissolving acidulant gained, conveniently to carry out the mixing step; Described solvent can be the mixed liquor of water, organic solvent or water and organic solvent.Described organic solvent is with aforementioned.
Wet granulation can directly obtain solid particle preparation after accomplishing, and also can be used as the preparation intermediate, through further conventional steps, makes other forms of solid preparations such as tablet or capsule.
Further, the invention still further relates to the solid preparation that makes by said method.
Among the present invention, above-mentioned each optimum condition, can be on the basis that meets this area general knowledge combination in any, get final product each preferred embodiments of the present invention.
Among the present invention, agents useful for same and raw material can get through commercially available.
Positive progressive effect of the present invention is: the defective that method for preparing of the present invention has been avoided mechanical activation comminution to handle being brought is seriously polluted, loss is big and potential safety hazard is serious promptly reaches the effect that reduces water-insoluble and/or spraingly water-soluble acidic drug active component particle diameter in pelletization.This method is easy to operation, and safety coefficient is high, is prone to be applied to suitability for industrialized production.Solid preparation Chinese medicine active component particle diameter of the present invention is little, has excellent dissolution characteristic, and bioavailability is high, and individual variation is little, and also has preferable stability and uniformity of dosage units.
The specific embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.The dosage form specification like the 2mg/ sheet, is meant every middle drug active component 2mg in active constituents of medicine content.
Consumption unit is gram, and percentage ratio is mass percent.
The mass percent of active constituents of medicine and solvent is the mass percent that accounts for the wet granulation dry material.Wherein, the consumption of solvent comprises the water in the aqueous solution of acidulant and basifier.
Coating material is gastric solubleness coating material premix material-Opadry.
Comparative example 1 and embodiment 1 indapamide granular recipe and method for preparing (indapamide molecular weight: 365.83)
Embodiment 2～3 indapamide granular recipe and method for preparinies
Embodiment 4 indapamide granular recipe and method for preparinies
Embodiment 5 indapamide sheets (2.5mg/ sheet) prescription and method for preparing
Comparative example 2 and embodiment 6 indapamide sheets (2.5mg/ sheet) prescription and method for preparing
Embodiment 7 indapamide sheets (2.5mg/ sheet) prescription and method for preparing
Embodiment 8 indapamide sheets (2.5mg/ sheet) prescription and method for preparing
Embodiment 9 indapamide capsules (2.5mg/ grain) prescription and method for preparing
Embodiment 10 indapamide capsules (2.5mg/ grain) prescription and method for preparing
Get the preceding granule of embodiment 6 tablettings and cross 30 mesh sieves, encapsulated behind the mix homogeneously.
Comparative example's 3 glipizide granular recipes and method for preparing (glipizide molecular weight 445.54)
Embodiment 11～12 glipizide granular recipe and method for preparinies
Comparative example 4 and embodiment 13 glipizide tablets (2.5mg/ sheet) prescription and method for preparing
Embodiment 14 glipizide tablets (2.5mg/ sheet) prescription and method for preparing
Embodiment 15 glipizide tablets (5mg/ sheet) prescription and method for preparing
Embodiment 16 glipizide capsules (2.5mg/ grain) prescription and method for preparing
Get the preceding granule of embodiment 14 tablettings and cross 30 mesh sieves, encapsulated behind the mix homogeneously.
Embodiment 17 folic acid granular recipes and method for preparing (folate molecule amount 441.4)
Comparative example 5 and embodiment 18 folic acid granular recipes and method for preparing (folate molecule amount 441.4)
Embodiment 19 folic acid granular recipe and method for preparinies
Comparative example's 6 YESUAN PIAN (5mg/ sheet) prescription and method for preparing
Embodiment 20 YESUAN PIAN (5mg/ sheet) prescription and method for preparing
Embodiment 21 YESUAN PIAN (5mg/ sheet) prescription and method for preparing
Embodiment 22 YESUAN PIAN (5mg/ sheet) prescription and method for preparing
Embodiment 26 methotrexate granular recipe and method for preparinies
Embodiment 27 methotrexate sheets (2.5mg/ sheet) prescription and method for preparing
Embodiment 28 methotrexate sheets (2.5mg/ sheet) prescription and method for preparing
Embodiment 29 bendroflumethiazide sheets (2.5mg/ sheet) prescription and method for preparing (bendroflumethiazide molecular weight: 421.41)
Embodiment 23 folic acid capsules (5mg/ grain) prescription and method for preparing
Get the preceding granule of embodiment 21 tablettings and cross 30 mesh sieves, encapsulated behind the mix homogeneously.
Embodiment 24 YESUAN PIAN (5mg/ sheet) prescription and method for preparing
Embodiment 25 methotrexate granular recipes and method for preparing (methotrexate molecular weight 454.45)
Embodiment 30 indapamide sheets (2.5mg/ sheet) prescription and method for preparing
Embodiment 31 indapamide sheets (2.5mg/ sheet) prescription and method for preparing
Embodiment 32 glipizide tablets (5mg/ sheet) prescription and method for preparing
Embodiment 33 glipizide tablets (2.5mg/ sheet) prescription and method for preparing
Embodiment 34 YESUAN PIAN (5mg/ sheet) prescription and method for preparing
Embodiment 35 YESUAN PIAN (5mg/ sheet) prescription and method for preparing
Embodiment 36 methotrexate slice prescription and method for preparinies
Embodiment 37 bendroflumethiazide sheets (2.5mg/ sheet) prescription and method for preparing
Embodiment 38 bendroflumethiazide granular recipe and method for preparinies
Embodiment 39 bendroflumethiazide sheets (5mg/ sheet) prescription and method for preparing
Embodiment 40 indapamide sheets (2.5mg/ sheet) prescription and method for preparing
Effect embodiment 1 particle diameter comparative test
Test instrunment: BT-9300S laser particle size distribution instrument; BT-800 Automatic Cycle sampling system.
Test condition: the medium in the circulation sampling system is a water, and volume is about 570ml, and the centrifugal pump rotating speed is 1600rpm.
Method of testing: get the about 2g of granule, add the circulation sampling system, the system absorbance of making reaches about 15%, opens ultra-sonic dispersion 3 minutes, and continuous 6 sampling tests obtain the particle diameter meansigma methods.D10, D50 and D90 are respectively that the cumulative particle sizes percentile reaches 10%, 50% and 90% o'clock pairing particle diameter.
1) indapamide particle diameter contrast:
Visible by above-mentioned data, adopt that the indapamide volume average particle size is decreased to 8.5～21.8% of crude drug particle diameter in the indapamide granule that method of the present invention makes, reach 4.78～12.25 microns.
2) glipizide particle diameter contrast:
Visible by above-mentioned data, 8.8～8.5% of the crude drug particle diameter that adopts glipizide volume average particle size in the glipizide granule that method of the present invention makes to be decreased to handle through micropowder reaches 0.62～0.60 micron.
3) folic acid particle diameter contrast:
Visible by above-mentioned data, 15.9～34.6% of the crude drug particle diameter that adopts folic acid volume average particle size in the folic acid granule that method of the present invention makes to be decreased to handle through micropowder reaches 0.89～1.94 micron.
4) methotrexate particle diameter:
Visible by above-mentioned data, adopt the methotrexate volume average particle size in the methotrexate granule that method of the present invention makes to be decreased to 5.2～10.9% of crude drug particle diameter, reach 4.43～9.37 microns.
4) bendroflumethiazide particle diameter:
Visible by above-mentioned data, adopt the bendroflumethiazide volume average particle size in the bendroflumethiazide granule that method of the present invention makes to be decreased to 8.9% of crude drug particle diameter, reach 6.43 microns.
Effect embodiment 2 dissolution comparative tests
1) indapamide sheet dissolution test
Dissolution determination method: sample thief, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2010 C, second method), dissolution fluid 900ml; Get 0.2mol/l potassium dihydrogen phosphate 250ml; Add 0.2mol/ sodium hydroxide solution 118m thin up to 1000ml, regulate pH to 6.8, rotating speed is that per minute 100 changes; Operation in accordance with the law, and preparation contrast solution.According to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2010), measure trap in the wavelength of 240nm, calculate every stripping quantity.
2) glipizide tablet dissolution test
Dissolution determination method (1): sample thief, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2010 C, second method), dissolution fluid is phosphate buffer (pH7.4) 500ml, rotating speed is that per minute 100 changes, operation in accordance with the law, and preparation contrast solution.According to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2010), measure trap in the wavelength of 222nm, calculate every stripping quantity.
Dissolution determination method (2): sample thief, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2010 C, second method), dissolution fluid is water 500ml, rotating speed is that per minute 100 changes, operation in accordance with the law, and preparation contrast solution.According to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2010), measure trap in the wavelength of 222nm, calculate every stripping quantity.
3) YESUAN PIAN dissolution test
Dissolution determination method (1): sample thief, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2010 C, second method), dissolution fluid is phosphate buffer (pH6.8) buffer 900ml, rotating speed is that per minute 100 changes, operation in accordance with the law, and preparation contrast solution.According to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2010), measure trap in the wavelength of 281nm, calculate every stripping quantity.
Dissolution determination method (2): sample thief, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2010 C, second method), dissolution fluid is water 900ml, rotating speed is that per minute 100 changes, operation in accordance with the law, and preparation contrast solution.According to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2010), measure trap in the wavelength of 281nm, calculate every stripping quantity.
Effect embodiment 3 stable comparative tests
1) indapamide
Test specimen is put respectively in the high-density polyethylene plastics bottle, and sealing is put into and quicken to be investigated case, and in 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% condition is carried out the stability of relevant item and measured after carrying out 3 months accelerated test.
Method for determination related substances: lucifuge operation.These article of getting fine powder is an amount of, and it is an amount of to add mobile phase, puts in the hot bath jolting 5 minutes, makes the indapamide dissolving, processes the solution that contains indapamide 0.5mg among every 1ml approximately with the mobile phase dilution, filters, and gets subsequent filtrate as test sample.According to HPLC (two appendix V of Chinese Pharmacopoeia version in 2010 D), use octadecylsilane chemically bonded silica to be filler, measure respectively.The long-pending normalization method of showing up calculates.
The dissolution test method is with effect embodiment 2.
Effect embodiment 4 uniformity of dosage units comparative experimentss
1) indapamide sheet
The assay method of uniformity of dosage units: get 1 of these article, put in the mortar, it is an amount of to add ethanol, grinds; And be transferred in the 100ml measuring bottle with the ethanol gradation, jolting makes the indapamide dissolving, adds ethanol dilution to scale; Shake up, filter, precision is measured subsequent filtrate 10ml, puts in the 50ml measuring bottle; Add ethanol dilution to scale, shake up, get the reference substance solution under this solution and the assay item; According to ultraviolet visible spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2010), measure trap in the wavelength of 242nm, calculate.
2) glipizide tablet
The assay method of uniformity of dosage units: get 1 of these article, porphyrize adds an amount of grinding of phosphate buffer (pH7.4), and is transferred in the 200ml measuring bottle with phosphate buffer (pH7.4) gradation, shakes up, and filters, and gets subsequent filtrate as need testing solution; It is an amount of that other gets the glipizide reference substance, processes the solution that contains 25 μ g among every 1ml approximately with method, as reference substance solution.Get above-mentioned two kinds of solution, measure absorbance respectively, calculate in the wavelength of 275nm.
3) YESUAN PIAN
The assay method of uniformity of dosage units: get 1 of these article, put in the 25ml measuring bottle, add the about 15ml of 0.5% ammonia solution, put in the hot bath and heated 20 minutes; Jolting constantly makes folic acid dissolving, puts coldly, is diluted with water to scale; Shake up, filter, get subsequent filtrate as need testing solution; According to HPLC (two appendix V of Chinese Pharmacopoeia version in 2010 D), use octadecylsilane chemically bonded silica to be filler, the record chromatogram; Other gets the folic acid reference substance, measures with method, with calculated by peak area content, should meet (two appendix X of Chinese Pharmacopoeia version in 2010 E) by external standard method.
4) bendroflumethiazide sheet
The Determination of Content Uniformity method: get 1 of these article, put in the mortar, porphyrize, it is an amount of to add 0.4% sodium hydroxide solution; Grind, and be transferred in the 25ml measuring bottle with 0.4% sodium hydroxide solution gradation, shake well makes the bendroflumethiazide dissolving, adds 0.4% sodium hydroxide solution and is diluted to scale; Shake up, filter, precision is measured subsequent filtrate 2ml, puts in the 25ml measuring bottle; Thin up shakes up to scale, according to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2010), measures absorbance in the wavelength of 274nm; Precision takes by weighing the bendroflumethiazide reference substance in addition, adds the also quantitative dilution of 0.01mol/L caustic lye of soda dissolving and processes the solution that contains 15 μ g among every 1ml approximately, measures absorbance with method, calculates.
Claims (18)
1. the method for preparing of a medical solid preparation is characterized in that it comprises the steps: water-insoluble and/or spraingly water-soluble acidic drug active component are dissolved in the alkaline solution that contains basifier, makes the pastille alkalies; Afterwards, with adjuvant and described pastille alkalies uniform mixing, carry out wet granulation.
2. the method for claim 1; It is characterized in that: described water-insoluble and/or spraingly water-soluble acidic drug active component are content below 20% in solid preparation; Preferable is below 10%, and better is water-insoluble or the spraingly water-soluble acidic drug active component below 5%; Percentage ratio is mass percent.
3. the method for claim 1 is characterized in that: described water-insoluble and/or slightly water-soluble alkalescent medicine active component are glipizide, folic acid, bumetanide, diclofenamide (dichlorphenamide), isocarboxazid, bendroflumethiazide, paraflutizide, methotrexate, biotin, hexestrol, indapamide, furosemide, the nimble purine of sulfur bird, allopurinol, gliquidone, simvastatin, leflunomide, hydrochlorothiazide or phenobarbital.
4. like each described method of claim 1～3; It is characterized in that: described basifier is inorganic base and/or organic base; Perhaps highly basic and/or weak base preferable are selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, Sodium ethylate, meglumine, diethanolamine and the triethanolamine one or more.
5. the method for claim 1 is characterized in that:
When described water-insoluble and/or spraingly water-soluble acidic drug active component were indapamide, described basifier was sodium hydroxide, potassium hydroxide or Sodium ethylate;
When described water-insoluble and/or spraingly water-soluble acidic drug active component were glipizide, described basifier was sodium hydroxide or potassium hydroxide;
When described water-insoluble and/or spraingly water-soluble acidic drug active component were folic acid, described basifier was sodium hydroxide, potassium hydroxide, Sodium ethylate, sodium carbonate or potassium carbonate;
When described water-insoluble and/or spraingly water-soluble acidic drug active component were methotrexate, described basifier was sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate;
When described water-insoluble and/or spraingly water-soluble acidic drug active component were bendroflumethiazide, described basifier was sodium hydroxide or potassium hydroxide.
6. like claim 1,4 or 5 described methods, it is characterized in that: the consumption of described basifier is for making water-insoluble and/or the consoluet minimum of spraingly water-soluble acidic drug active component 1～1.5 times, and better is 1～1.05 times.
7. like claim 1,4 or 5 described methods, it is characterized in that: the molar ratio of described basifier and water-insoluble and/or spraingly water-soluble acidic drug active component is 0.1～2.5, and better is 0.9～1.5.
8. the method for claim 1 is characterized in that:
When described water-insoluble and/or spraingly water-soluble acidic drug active component were indapamide, described basifier was the sodium hydroxide or the Sodium ethylate of 0.7～1.1 times of indapamide mole;
When described water-insoluble and/or spraingly water-soluble acidic drug active component were glipizide, described basifier was the sodium hydroxide of 0.95～1.1 times of glipizide mole;
Described water-insoluble and/or spraingly water-soluble acidic drug active component are folic acid, and described basifier is the sodium carbonate or the potassium carbonate of 0.95～1.1 times of sodium hydroxide or its mole of 1.8～2.1 times of folic acid moles;
Described water-insoluble and/or spraingly water-soluble acidic drug active component are methotrexate, and described basifier is the sodium carbonate of 0.85～1.1 times of sodium hydroxide or the mole of 1.4～1.6 times of methotrexate moles;
Described water-insoluble and/or spraingly water-soluble acidic drug active component are bendroflumethiazide, and described basifier is the sodium hydroxide of 0.9～1.6 times of bendroflumethiazide mole.
9. the method for claim 1 is characterized in that: the solvent in the described alkaline solution that contains basifier is the mixed liquor of water, organic solvent or water and organic solvent, and the basifier intermediate ion can dissociate in this solvent;
Described organic solvent is for being superior to the medicament field acceptable solvent of water to the dissolubility of water-insoluble and/or spraingly water-soluble acidic drug active component; Preferable is water soluble alcohols or ketones solvent, one or more that better is in ethanol, acetone, propylene glycol and the glycerin.
10. like claim 1 or 9 described methods, it is characterized in that: the consumption of solvent is the mass percent 5～100% of wet granulation dry material in the described alkaline solution, and preferable is 10～50%.
11. the method for claim 1; It is characterized in that: described be dissolved in water-insoluble and/or spraingly water-soluble acidic drug active component in the alkaline solution that contains basifier in and/or afterwards; Also add in the water-solubility carrier of surfactant, solubilizing agent and solid dispersion one or more; Then gained pastille alkalies is carried out subsequent step, promptly, carry out wet granulation with the adjuvant uniform mixing;
When being dissolved in water-insoluble and/or spraingly water-soluble acidic drug active component in the alkaline solution that contains basifier; When also adding the water-solubility carrier of solid dispersion, the amount of the water-solubility carrier of described solid dispersion is controlled at and can guarantees that water-insoluble and/or spraingly water-soluble acidic drug active component are dissolved in below the amount in the alkaline solution that contains basifier fully;
In the water-solubility carrier of described surfactant, solubilizing agent and solid dispersion one or more are preferable is in polyvidone, PEG400-8000, sodium lauryl sulphate, poloxamer, polyoxyethylene castor oil, Tween 80, polyoxyethylene stearate 40 esters, lactose, mannitol, sucrose, HP-, beta-schardinger dextrin-and the maltose alcohol one or more;
The addition of described surfactant and/or solubilizing agent is preferable is water-insoluble and/or spraingly water-soluble acidic drug active component quality 0.05～5 times, and better is 0.05～2 times;
The addition of the water-solubility carrier of described solid dispersion is preferable is water-insoluble and/or spraingly water-soluble acidic drug active component quality 0.5～20 times, and better is 0.5～2 times.
12. the method for claim 1 is characterized in that: when the described pastille alkalies of preparation, carry out the solution preparation according to following operation: when being solvent, be warming up to 40～80 ℃ with water; When the mixed solution with water and organic solvent is solvent, be warming up to 40～70 ℃; When being solvent, be warming up to 30～50 ℃ with ethanol.
13. like each described method of claim 1～12; It is characterized in that: carry out described with adjuvant and described pastille alkalies uniform mixing; When carrying out the step of wet granulation; Also add acidulant, the alkalescence of the mixed liquor of acidulant and pastille alkalies is reduced with respect to the alkalescence of pastille alkalies.
14. method as claimed in claim 13 is characterized in that: said basifier is inorganic strong alkali, organic alkali or inorganic middle highly basic, and described acidulant is an inorganic acid;
Better, described basifier and acidulant are combinations: sodium hydroxide and hydrochloric acid, potassium hydroxide and hydrochloric acid, Sodium ethylate and hydrochloric acid, sodium carbonate and hydrochloric acid and potassium carbonate and hydrochloric acid.
15. like claim 13 or 14 described methods, it is characterized in that: the consumption of described basifier and acidulant satisfies following relation: formula 1 income value is 0.01～1.5, preferable is 0.2～1.1, and better is 0.9～1.1;
(acidulant molal quantity * A)/(the formula 1 of basifier molal quantity * B)
Wherein, A is the hydrion number in the acidulant molecule, and B is the total valence state number of basifier molecular anion.
16. method as claimed in claim 13 is characterized in that: carry out concrete operations by in the following mode any:
Mode (1) is with acidulant or contain the solution and the adjuvant uniform mixing of acidulant, again with pastille alkalies uniform mixing, pushes and granulates or stir and granulate;
Mode (2) is mixed pastille alkalies and, acidulant or the solution that contains acidulant uniformly, granulation liquid, again this granulation liquid and adjuvant are pushed granulation, stirring granulation, fluidized-bed spray granulation or centrifugal spray granulation etc. afterwards;
Mode (3) is mixed the pastille alkalies with adjuvant uniformly, mixes uniformly with the solution that contains acidulant more afterwards, pushes and granulates or the stirring granulation;
Mode (4) is pastille alkalies and, the adjuvant 1/3 below, and acidulant or the solution that contains acidulant mixes uniformly, mixes with the residue adjuvant to push again afterwards and granulates or the stirring granulation; What the adjuvant in the described adjuvant below 1/3 was preferable is water soluble adjuvant.
17. the method for claim 1 is characterized in that: the solid particle with the method for claim 1 makes through further conventional steps, makes tablet or capsule.
18. the medical solid preparation that makes like each described method of claim 1～17.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010619883.6A CN102552161B (en) | 2010-12-28 | 2010-12-28 | The preparation method of a kind of pharmaceutical solid preparation and gained pharmaceutical solid preparation |
| PCT/CN2011/083285 WO2012088992A1 (en) | 2010-12-28 | 2011-12-01 | Process for preparing solid medicine preparation and solid medicine preparation therefrom |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010619883.6A CN102552161B (en) | 2010-12-28 | 2010-12-28 | The preparation method of a kind of pharmaceutical solid preparation and gained pharmaceutical solid preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102552161A true CN102552161A (en) | 2012-07-11 |
| CN102552161B CN102552161B (en) | 2016-06-22 |
Family
ID=46382289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010619883.6A Active CN102552161B (en) | 2010-12-28 | 2010-12-28 | The preparation method of a kind of pharmaceutical solid preparation and gained pharmaceutical solid preparation |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102552161B (en) |
| WO (1) | WO2012088992A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103462918A (en) * | 2013-09-22 | 2013-12-25 | 南京正亮医药科技有限公司 | Valaciclovir hydrochloride tablet and preparation method thereof |
| CN103520122A (en) * | 2013-10-25 | 2014-01-22 | 海南通用康力制药有限公司 | Bumetanide freeze-dried powder preparation for injection and preparation method thereof |
| CN107714653A (en) * | 2017-11-27 | 2018-02-23 | 济南新科医药科技有限公司 | A kind of soluble methotrexate (MTX) granule of stabilization |
| CN107823160A (en) * | 2017-12-02 | 2018-03-23 | 广东世信药业有限公司 | A kind of solid dispersed formulation for antigout and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1854454T3 (en) * | 2002-01-16 | 2014-01-13 | Boehringer Ingelheim Pharma | Process for the preparation of amorphous telmisartan |
| EP1417958A1 (en) * | 2002-11-08 | 2004-05-12 | Pari GmbH | Wet granulation process |
| AU2002350719A1 (en) * | 2002-11-29 | 2004-06-23 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base |
| JP2009515956A (en) * | 2005-11-22 | 2009-04-16 | テバ ファーマシューティカル インダストリーズ リミティド | Telmisartan pharmaceutical composition |
-
2010
- 2010-12-28 CN CN201010619883.6A patent/CN102552161B/en active Active
-
2011
- 2011-12-01 WO PCT/CN2011/083285 patent/WO2012088992A1/en active Application Filing
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103462918A (en) * | 2013-09-22 | 2013-12-25 | 南京正亮医药科技有限公司 | Valaciclovir hydrochloride tablet and preparation method thereof |
| CN103520122A (en) * | 2013-10-25 | 2014-01-22 | 海南通用康力制药有限公司 | Bumetanide freeze-dried powder preparation for injection and preparation method thereof |
| CN107714653A (en) * | 2017-11-27 | 2018-02-23 | 济南新科医药科技有限公司 | A kind of soluble methotrexate (MTX) granule of stabilization |
| CN107714653B (en) * | 2017-11-27 | 2022-01-28 | 济南新科医药科技有限公司 | Stable soluble methotrexate granules |
| CN107823160A (en) * | 2017-12-02 | 2018-03-23 | 广东世信药业有限公司 | A kind of solid dispersed formulation for antigout and preparation method thereof |
| CN107823160B (en) * | 2017-12-02 | 2020-04-14 | 广东世信药业有限公司 | Solid dispersion preparation for resisting gout and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012088992A1 (en) | 2012-07-05 |
| CN102552161B (en) | 2016-06-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102106807B (en) | Method for preparing solid preparation and solid preparation | |
| CN102106806B (en) | Method for preparing solid preparation and solid preparation | |
| CN102846543B (en) | Aripiprazole pharmaceutic preparation and preparation method thereof | |
| CN102552161A (en) | Preparation method of medicament solid preparation and obtained medicament solid preparation | |
| CN104352464B (en) | A kind of Gefitinib pharmaceutical composition without surfactant and preparation method thereof | |
| CN105982870A (en) | Apixaban tablet | |
| CN104306344A (en) | Azilsartan tablets and preparation process thereof | |
| CN102106826A (en) | Aripiprazole solid preparation and preparation method thereof | |
| CN102106824B (en) | Eszopiclone solid preparation and preparation method thereof | |
| CN110604722B (en) | Solid dispersion method of celecoxib and preparation method of celecoxib capsules | |
| Sharma et al. | Review on Moisture activated Dry Granulation Process | |
| CN106265557A (en) | Pharmaceutical composition containing ticagrelor | |
| CN114681404B (en) | Repaglinide granule pharmaceutical composition and preparation method thereof | |
| CN114288259B (en) | Quick-release preparation of vitamin B2 and preparation method thereof | |
| CN102106805B (en) | Cymipristone solid preparation and preparation methods thereof | |
| CN102499909B (en) | Itraconazole dispersible tablets and preparation method thereof | |
| CN103919780B (en) | Calming soporific preparation, its compound preparation, preparation method and pharmaceutical composition | |
| CN102106825B (en) | Solid zopiclone preparation and preparation method thereof | |
| CN102106808B (en) | Solid preparation and preparation method thereof | |
| CN112263554B (en) | Lopinavir ritonavir compound tablet and preparation method thereof | |
| CN104398513A (en) | Medicinal composition for increasing dissolution rate of racanisodamine and preparation method thereof | |
| CN106913547A (en) | A kind of pazopanib tablet and preparation method thereof | |
| CN106913545B (en) | Glimepiride tablet and preparation method thereof | |
| CN115317455A (en) | Rosuvastatin calcium tablet with uniform tablet content and easy dissolution and preparation method thereof | |
| CN107007562B (en) | Gefitinib tablet and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |