CN102552161B - The preparation method of a kind of pharmaceutical solid preparation and gained pharmaceutical solid preparation - Google Patents
The preparation method of a kind of pharmaceutical solid preparation and gained pharmaceutical solid preparation Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
The preparation method that the invention discloses a kind of pharmaceutical solid preparation, it comprises the steps: to be dissolved in the alkaline solution containing basifier by water-insoluble and/or spraingly water-soluble acidic drug active component, prepares pastille alkalies；Afterwards, by adjuvant and described pastille alkalies Homogeneous phase mixing, wet granulation is carried out。The invention also discloses the pharmaceutical solid preparation that said method prepares。The preparation method of the present invention avoids mechanical activation comminution and processes seriously polluted, loss is big and potential safety hazard the is serious defect brought, namely reaches to reduce the effect of water-insoluble and/or spraingly water-soluble acidic drug active component particle diameter in pelletization。The method is easy to operation, and safety coefficient is high, is easily applied to industrialized production。The solid preparation that the method prepares has the dissolution characteristic of excellence, stability and uniformity of dosage units。
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to preparation method and the gained pharmaceutical solid preparation of a kind of pharmaceutical 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 the reduction of particle diameter is the key improving pharmaceutical preparation dissolution and uniformity of dosage units。In the preparation technology of concrete pharmaceutical preparation, generally according to the dissolution characteristics of medicine and biomembrane permeability, select the particle diameter of suitable active constituents of medicine。Such as, if it is poor to belong to dissolubility, drug-eluting is the medicine absorbing speed limit process, and optional less particle diameter, to promote the absorption of medicine。In the preparation technology of pharmaceutical solid preparation, the selection often relating to the particle diameter to active constituents of medicine controls。
At present, mostly by selecting different mechanical crushing methods and disintegrating process condition, to realize the selection of active constituents of medicine particle diameter is controlled。Universalpulverizer is a kind of at the drug world wide pulverizer of application, to the effect of crushing material based on impact force, shearing force, it is adaptable to multiple medium-hard dried material, the mean diameter after process commonly reaches 100 microns。
But, the processing method of mechanical activation comminution exists that dust is many, contaminated environment and the problem such as loss is big。For some high-activity drugs, it is also easy in mechanical milling processes, makes operator produce untoward reaction, there is serious potential safety hazard。Such as, the calming soporific medicine powder sucking relatively low-dose can quickly produce hypnotic effect, when this kind of medicine is carried out pulverization process, very easily causes the untoward reaction of the quick hypnosis of operator, causes security incident。Again such as, when some medicines such as highly active hormone 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 100 microns, and the dissolution characteristic of prepared solid preparation does not still reach requirement。
In the technique that mechanical activation comminution processes, for the high-activity drug active component of content in solid preparation relatively low (such as≤5wt%), further relate to its sex chromosome mosaicism that is uniformly dispersed mixed with adjuvant。Generally, adopt and active constituents of medicine is diluted, with adjuvant equivalent, the method progressively expanded, so that active constituents of medicine is uniformly dispersed in solid preparation。But the method technological operation is loaded down with trivial details, can produce that dust is many equally, contaminated environment, loss be big and labor protection exists the problems such as potential safety hazard。
Additionally, the preparation of solid preparation also needs whether the various performances considering product can meet needs。Such as, if can guarantee that preferably uniformity of dosage units。Again such as, stability is the investigation emphasis of solid preparation quality, it includes within solid preparation storage period, the chemical stability of active constituents of medicine, the content of impurity, solid preparation property stability and dissolution stability etc., if be in drug standard limit。
Therefore, for the defect of above-mentioned prior art, it would be highly desirable to seek a kind of drawbacks described above that both can avoid mechanical activation comminution processing method, the preparation method ensuring that the various function admirable of solid preparation。
Summary of the invention
The technical problem to be solved is to overcome existing solid preparation preparation method to select to control the particle diameter of active constituents of medicine by the mode of mechanical activation comminution, environmental pollution can be caused, there is serious potential safety hazard, loss is big, and the dissatisfactory defect such as the stripping property of gained solid pharmaceutical preparation, and for water-insoluble or spraingly water-soluble acidic drug, there is provided one operation easier, pollute less, there is no previous security hidden danger, and can guarantee that obtained solid preparation has the dissolution characteristic of excellence, the preparation method of the pharmaceutical solid preparation of stability and uniformity of dosage units and gained pharmaceutical solid preparation。
For solving above-mentioned technical problem, the present inventor looks for another way, and unique employing alkaline solution dissolves water-insoluble and/or spraingly water-soluble acidic drug, afterwards in pelletization, makes medicine reply solid state, thus avoiding many defects that mechanical activation comminution processes。Further, the present inventor it have surprisingly been found that, water-insoluble obtained by the method and/or spraingly water-soluble acidic drug solid preparation have the dissolution characteristic of excellence, stability and uniformity of dosage units。
The preparation method of the pharmaceutical solid preparation of the present invention comprises the steps: to be dissolved in the alkaline solution containing basifier by water-insoluble and/or spraingly water-soluble acidic drug active component, prepares pastille alkalies；Afterwards, by adjuvant and described pastille alkalies Homogeneous phase mixing, wet granulation is carried out。
In 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 meeting above-mentioned character, including the both sexes active constituents of medicine with acidic-group and basic group。In this area, described acidic drug active component is mostly weak acid class active constituents of medicine。The present invention preferably activity is higher, in solid preparation content relatively low (be generally less than 20%, it is advantageous to be less than 10%, more preferably be less than 5%, percentage ratio is mass percent) water-insoluble or spraingly water-soluble acidic drug active component。More specifically, the present invention is preferably but 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。
The customary amount in solid preparation according to water-insoluble and/or spraingly water-soluble acidic drug active component, namely can determine that in preparation process, water-insoluble and/or spraingly water-soluble acidic drug active component account for the mass percent of wet granulation dry material。As required, outside dewater insoluble and/or spraingly water-soluble acidic drug active component, also can add other drug active component and make compound solid preparation。
In the present invention, described basifier refers to the reagent making water-insoluble and/or spraingly water-soluble acidic drug active component be dissolved completely in the alkaline solution containing basifier。According to this area general knowledge, described basifier should be pharmaceutically acceptable, and the reagent compatible with water-insoluble and/or spraingly water-soluble acidic drug active component。In the present invention, described compatibility refers to and can coexist, and has no adverse effects。Described basifier can be single basifier, it is alternatively the compound basifier that two or more one-tenth is grouped into, it is selected from various alkali, such as inorganic base and/or organic base, highly basic and/or weak base, it is advantageous to one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, Sodium ethylate, meglumine, diethanolamine and triethanolamine。Following basifier specifically preferred according to the invention:
When water-insoluble and/or spraingly water-soluble acidic drug active component are indapamide, described basifier is sodium hydroxide, potassium hydroxide or Sodium ethylate, and best is sodium hydroxide。
When water-insoluble and/or spraingly water-soluble acidic drug active component are glipizide, described basifier is sodium hydroxide or potassium hydroxide, and best is sodium hydroxide。
When water-insoluble and/or spraingly water-soluble acidic drug active component are folic acid, described basifier is 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 are methotrexate, described basifier is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate。
When water-insoluble and/or spraingly water-soluble acidic drug active component are bendroflumethiazide, described basifier is sodium hydroxide or potassium hydroxide。
The consumption of described basifier is at least and can make water-insoluble and/or the consoluet minimum of spraingly water-soluble acidic drug active component, it is advantageous to be 1～1.5 times of this minimum, 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 factors, and 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, basifier and pastille alkalies preparation condition (such as temperature, time, charging sequence, alr mode) etc. are relevant。Wherein, described acid centre refers in water-insoluble and/or spraingly water-soluble acidic drug active component can anion is combined in basifier molecule group or position。Therefore, above-mentioned minimum refers under same solvent and pastille alkalies preparation condition, for certain water-insoluble and/or spraingly water-soluble acidic drug active component, certain basifier can by the minimum of its dissolving, namely this minimum is can determine that: under same solvent and pastille alkalies preparation condition by simple conventional method, adopt the consumption being gradually increased certain basifier to dissolve certain water-insoluble and/or spraingly water-soluble acidic drug active component, when being just completely dissolved, be minimum。The present inventor gropes to draw through great many of experiments, and specifically, the molar ratio of basifier and water-insoluble and/or spraingly water-soluble acidic drug active component is generally 0.1～2.5, is mostly 0.9～1.5, the basifier of following dosage specifically preferred according to the invention:
For indapamide, it is particularly preferred to the sodium hydroxide of its mole 0.7～1.1 times or Sodium ethylate。
For glipizide, it is particularly preferred to the sodium hydroxide of its mole 0.95～1.1 times。
For folic acid, it is particularly preferred to the sodium hydroxide of its mole 1.8～2.1 times or the sodium carbonate of its mole 0.95～1.1 times or potassium carbonate。
For methotrexate, it is particularly preferred to the sodium hydroxide of its mole 1.4～1.6 times or the sodium carbonate of mole 0.85～1.1 times。
For bendroflumethiazide, it is particularly preferred to the sodium hydroxide of its mole 0.9～1.6 times。
In the present invention, the described solvent in the alkaline solution containing 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 solvent that basifier intermediate ion can dissociate。Such as, when basifier is inorganic matter, the mixed liquor of optional water or water and organic solvent；When basifier is Organic substance, can be mixed liquor or the organic solvent of water, water and organic solvent。If active constituents of medicine has the dissolubility being better than in water in some organic solvent, it is advantageous to the mixed liquor selecting water and this organic solvent, be beneficial to the dissolving of active constituents of medicine, reduce the consumption of basifier or solvent, be beneficial to the operation of follow-up granulation step。Described organic solvent selects in the acceptable solvent of pharmaceutical arts according to its principle that dissolubility of water-insoluble and/or spraingly water-soluble acidic drug active component is better than water, it it is preferably water-miscible organic solvent, such as the water-soluble alcohol kind solvent that pharmaceutical arts is conventional, such as ethanol, propylene glycol, glycerol, acetone, isopropanol or the tert-butyl alcohol etc., one or more in preferred alcohol, acetone, propylene glycol and glycerol, it is particularly preferred to ethanol。Water is with the mixed liquor of organic solvent, and the concentration of organic solvent can arbitrarily select。In described alkaline solution, the consumption of solvent is with at least so that medicinal soluble solution, is at least granulation liquid minimum needed for wet granulation, is generally the mass percent 5～100% of wet granulation dry material, it is advantageous to be 10～50%。
When preparing pastille alkalies, some adjuvants can be added, such as the water-solubility carrier etc. of binding agent, surfactant, solubilizing agent and solid dispersion。Preferably, while water-insoluble and/or spraingly water-soluble acidic drug active component are dissolved in the alkaline solution containing basifier and/or afterwards, be additionally added in the water-solubility carrier of surfactant, solubilizing agent and solid dispersion one or more, then gained pastille alkalies is carried out subsequent step, namely with adjuvant Homogeneous phase mixing, wet granulation is carried out。Wherein, when being simultaneously introduced in the alkaline solution containing basifier by the water-solubility carrier of solid dispersion with water-insoluble and/or spraingly water-soluble acidic drug active component, the amount of the water-solubility carrier of the solid dispersion now added need to control can guarantee that below the amount that water-insoluble and/or spraingly water-soluble acidic drug active component are dissolved completely in the alkaline solution containing basifier；Can also adding the water-solubility carrier of solid dispersion afterwards again in this solution, when addition is bigger, gained pastille Acidic Liquid is likely suspension or viscous solution form。One or more in addition polyvidone specifically preferred according to the invention, Polyethylene Glycol (preferred PEG400-8000), sodium lauryl sulphate, poloxamer, polyoxyethylene castor oil, tween (preferred Tween 80), s6, lactose, mannitol, sucrose, HP-β-CD, beta-schardinger dextrin-and maltose alcohol。Described surfactant and/or the addition of solubilizing agent are preferably 0.05～5 times of water-insoluble and/or spraingly water-soluble acidic drug active component quality, more preferably be 0.05～2 times。The addition of the water-solubility carrier of described solid dispersion is preferably 0.5～20 times of water-insoluble and/or spraingly water-soluble acidic drug active component quality, more preferably be 0.5～2 times。Add surfactant and/or solubilizing agent by aforesaid operations, water-insoluble and/or spraingly water-soluble acidic drug active component dissolubility in alkaline solution can be increased, reduce solvent load, be beneficial to the operation of follow-up granulation step。It will be further appreciated that, add in the water-solubility carrier of surfactant, solubilizing agent and solid dispersion by aforesaid operations one or more, especially the water-solubility carrier of solid dispersion can make the dissolution characteristic of solid preparation more preferably。
It is also preferred that the left when preparing pastille alkalies, it is possible to by conventional heating methods such as hot baths, suitably raise the preparation temperature of pastille alkalies, be beneficial to the dissolving of active constituents of medicine。During with water for solvent, it is advantageous to be increased to 40～80 DEG C。During with the mixed solution of water and organic solvent for solvent, it is advantageous to rising be 40～70 DEG C。During with ethanol for solvent, it is advantageous to rising be 30～50 DEG C。
In the present invention, described adjuvant is selected from any of and widely used adjuvant in this area, such as filler, binding agent, disintegrating agent, adsorbent and lubricant etc.。The content of described adjuvant can according to this area is conventional or existing knowledge selects。Wherein, described filler is preferably one or more in lactose, microcrystalline Cellulose, starch, pregelatinized Starch, mannitol, sucrose and maltose alcohol。Described binding agent is preferably one or more in hypromellose, polyvidone, methylcellulose and hydroxypropylcellulose。Described disintegrating agent is preferably one or more in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone and cross-linking sodium carboxymethyl cellulose。Described lubricant is preferably magnesium stearate, micropowder silica gel (colloidal silica), Pulvis Talci or sodium stearyl fumarate。
By adjuvant and described pastille alkalies Homogeneous phase mixing, when carrying out the step of wet granulation, also can add acidulant, make the alkaline reduction relative to pastille alkalies of acidulant and the alkalescence of the mixed liquor of pastille alkalies。
According to this area general knowledge, described acidulant all should be pharmaceutically acceptable, and the reagent compatible with water-insoluble and/or spraingly water-soluble acidic drug active component。It is also preferred that the left the combination of the basifier of the preferred following type of the present invention and 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 alkaline amount reduced that at least can make acidulant and the alkalescence of the mixed liquor of pastille alkalies relative to pastille alkalies。It is also preferred that the left the consumption of basifier and acidulant meets following relation: formula 1 income value is 0.01～1.5, it is advantageous to be 0.2～1.1, more preferably be 0.9～1.1。
Wherein, A is the hydrion number in acidulant molecule to (acidulant molal quantity × A)/(basifier molal quantity × B) formula 1, and B is the total valence state number of basifier molecular anion。
Formula 1 value specifically preferred according to the invention is following basifier and the combination of acidulant of 0.9～1.1: 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, the stability of solid preparation can be more beneficial for。And for some water-insoluble and/or spraingly water-soluble acidic drug active component, formula is not added with acidulant or acidulant consumption little, solid preparation still can have preferably stability, but under the premise not affecting preparation stability, suitably increase acidulant consumption and reduce alkalescence, can be conducive to relaxing the acid-base value of solid preparation。
In the present invention; described wet granulation can belong to the conventional steps of various method of granulating of wet granulation category by this area and condition carries out, as extruding granulate (as wobbler extrude, screw extrusion or rotary squeezing etc.), stirring granulate, fluidized-bed spray granulation or centrifugal spray granulation etc.。For dosage in solid preparation relatively big (being generally higher than 10%); or dissolubility is less in the alkaline solution containing basifier; need larger amount of alkaline solution just solubilized water-insoluble completely and/or spraingly water-soluble acidic drug active component; the optional wet granulation technology that the restriction of granulation solution amount is little, as fluidized-bed spray granulation or centrifugal spray are granulated。
When using acidulant, it is advantageous in the following manner in any one carry out concrete operations: mode (1) by acidulant or the solution containing acidulant and adjuvant Homogeneous phase mixing, then with pastille alkalies Homogeneous phase mixing, carry out extruding and granulate or stirring is granulated；Mode (2) by pastille alkalies with, acidulant or the solution containing acidulant mix uniformly, obtain granulation liquid, this granulation liquid and adjuvant carry out extruding is granulated, stirring is granulated afterwards again, fluidized-bed spray granulation or centrifugal spray granulation etc.；Pastille alkalies is mixed uniformly by mode (3) with adjuvant, mixes uniformly with the solution containing acidulant more afterwards, carries out extruding and granulates or stirring granulation；Mode (4) by pastille alkalies with; the adjuvant of less than 1/3; and acidulant or the solution containing acidulant mix uniformly, and (concrete operations can be: first by the adjuvant of less than 1/3 and acidulant or the solution Homogeneous phase mixing containing acidulant; again gained mixture is mixed with pastille alkalies; or; first the adjuvant of less than 1/3 and pastille alkalies are mixed; again with acidulant or the solution Homogeneous phase mixing containing acidulant), mix with residue adjuvant more afterwards and carry out extruding granulation or stirring granulation。Adjuvant in the adjuvant of described less than 1/3 is preferably water soluble adjuvant。Described less than 1/3 generally can be less than 1/4～1/10。The described solution containing acidulant refers to, by this area routine operation, with the solution of a small amount of solvent dissolving acid agent gained, carries out mixing step to facilitate；Described solvent can be the mixed liquor of water, organic solvent or water and organic solvent。Described organic solvent is with aforementioned。
After wet granulation completes, solid particle preparation can be directly obtained, it is possible to as preparation intermediate, through further conventional steps, prepare the solid preparation of other forms such as tablet or capsule。
Further, the invention still further relates to the solid preparation prepared by said method。
In the present invention, above-mentioned each optimum condition, combination in any on the basis of this area general knowledge can met, the preferred embodiments of the invention。
In the present invention, agents useful for same and raw material can pass through commercially。
The actively progressive effect of the present invention is in that: the preparation method of the present invention avoids mechanical activation comminution and processes seriously polluted, loss is big and potential safety hazard the is serious defect brought, namely reaches to reduce the effect of water-insoluble and/or spraingly water-soluble acidic drug active component particle diameter in pelletization。The method is easy to operation, and safety coefficient is high, is easily applied to industrialized production。The solid preparation pharmaceutical active grain diameter of components of the present invention is little, has the dissolution characteristic of excellence, and bioavailability is high, and individual variation is little, and also has preferably stability and uniformity of dosage units。
Detailed description of the invention
Further illustrate the present invention by embodiment below, but the present invention is not intended to be limited thereto。
The experimental technique of unreceipted actual conditions in the following example, generally conventionally condition, or according to manufacturer it is proposed that condition。Dosage form specification is with active constituents of medicine content meter, such as 2mg/ sheet, refers to every middle drug containing active component 2mg。
Consumption unit is gram, and percentage ratio is mass percent。
The mass percent of active constituents of medicine and solvent is the mass percent accounting for wet granulation dry material。Wherein, the consumption of solvent includes 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 preparation method (indapamide molecular weight: 365.83)
Embodiment 2～3 indapamide granular recipe and preparation method
Embodiment 4 indapamide granular recipe and preparation method
Embodiment 5 indapamide tablets (2.5mg/ sheet) formula and preparation method
Comparative example 2 and embodiment 6 indapamide tablets (2.5mg/ sheet) formula and preparation method
Embodiment 7 indapamide tablets (2.5mg/ sheet) formula and preparation method
Embodiment 8 indapamide tablets (2.5mg/ sheet) formula and preparation method
Embodiment 9 indapamide capsule (2.5mg/ grain) formula and preparation method
Embodiment 10 indapamide capsule (2.5mg/ grain) formula and preparation method
Granule before Example 6 tabletting crosses 30 mesh sieves, encapsulated after mix homogeneously。
Comparative example 3 glipizide granular recipe and preparation method (glipizide molecular weight 445.54)
Embodiment 11～12 glipizide granular recipe and preparation method
Comparative example 4 and embodiment 13 glipizide tablet (2.5mg/ sheet) formula and preparation method
Embodiment 14 glipizide tablet (2.5mg/ sheet) formula and preparation method
Embodiment 15 glipizide tablet (5mg/ sheet) formula and preparation method
Embodiment 16 glipizide capsule (2.5mg/ grain) formula and preparation method
Granule before Example 14 tabletting crosses 30 mesh sieves, encapsulated after mix homogeneously。
Embodiment 17 folic acid granular recipe and preparation method (folate molecule amount 441.4)
Comparative example 5 and embodiment 18 folic acid granular recipe and preparation method (folate molecule amount 441.4)
Embodiment 19 folic acid granular recipe and preparation method
Comparative example 6 YESUAN PIAN (5mg/ sheet) formula and preparation method
Embodiment 20 YESUAN PIAN (5mg/ sheet) formula and preparation method
Embodiment 21 YESUAN PIAN (5mg/ sheet) formula and preparation method
Embodiment 22 YESUAN PIAN (5mg/ sheet) formula and preparation method
Embodiment 26 methotrexate granular recipe and preparation method
Embodiment 27 methotrexate (2.5mg/ sheet) formula and preparation method
Embodiment 28 methotrexate (2.5mg/ sheet) formula and preparation method
Embodiment 29 bendroflumethiazide sheet (2.5mg/ sheet) formula and preparation method (bendroflumethiazide molecular weight: 421.41)
Embodiment 23 folic acid capsule (5mg/ grain) formula and preparation method
Granule before Example 21 tabletting crosses 30 mesh sieves, encapsulated after mix homogeneously。
Embodiment 24 YESUAN PIAN (5mg/ sheet) formula and preparation method
Embodiment 25 methotrexate granular recipe and preparation method (methotrexate molecule amount 454.45)
Embodiment 30 indapamide tablets (2.5mg/ sheet) formula and preparation method
Embodiment 31 indapamide tablets (2.5mg/ sheet) formula and preparation method
Embodiment 32 glipizide tablet (5mg/ sheet) formula and preparation method
Embodiment 33 glipizide tablet (2.5mg/ sheet) formula and preparation method
Embodiment 34 YESUAN PIAN (5mg/ sheet) formula and preparation method
Embodiment 35 YESUAN PIAN (5mg/ sheet) formula and preparation method
Embodiment 36 methotrexate slice prescription and preparation method
Embodiment 37 bendroflumethiazide sheet (2.5mg/ sheet) formula and preparation method
Embodiment 38 bendroflumethiazide granular recipe and preparation method
Embodiment 39 bendroflumethiazide sheet (5mg/ sheet) formula and preparation method
Embodiment 40 indapamide tablets (2.5mg/ sheet) formula and preparation method
Effect example 1 particle diameter comparative test
Test instrunment: BT-9300S laser fineness gage；BT-800 Automatic Cycle sampling system。
Test condition: the medium in circulation sample injection system is water, volume is about 570ml, and centrifugal pump rotating speed is 1600rpm。
Method of testing: taking granule and be about 2g, add circulation sample injection system, the system absorbance of making reaches about 15%, opens ultrasonic disperse 3 minutes, continuous 6 sampling tests, obtain mean particle size。D10, D50 and D90 are that cumulative particle sizes percentile reaches particle diameter corresponding when 10%, 50% and 90% respectively。
1) indapamide particle diameter contrast:
From above-mentioned data, in the indapamide granule that the method for the employing present invention prepares, indapamide volume average particle size is decreased to the 8.5～21.8% of crude drug particle diameter, reaches 4.78～12.25 microns。
2) glipizide particle diameter contrast:
From above-mentioned data, the glipizide volume average particle size in the glipizide granule that the method for the employing present invention prepares is decreased to the 8.8～8.5% of the crude drug particle diameter processed through micropowder, reaches 0.62～0.60 micron。
3) folic acid particle diameter contrast:
From above-mentioned data, the folic acid volume average particle size in the folic acid granule that the method for the employing present invention prepares is decreased to the 15.9～34.6% of the crude drug particle diameter processed through micropowder, reaches 0.89～1.94 micron。
4) methotrexate particle diameter:
From above-mentioned data, the methotrexate volume average particle size in the methotrexate granule that the method for the employing present invention prepares is decreased to the 5.2～10.9% of crude drug particle diameter, reaches 4.43～9.37 microns。
4) bendroflumethiazide particle diameter:
From above-mentioned data, the bendroflumethiazide volume average particle size in the bendroflumethiazide granule that the method for the employing present invention prepares is decreased to the 8.9% of crude drug particle diameter, reaches 6.43 microns。
Effect example 2 Comparative Study on Dissolution
1) indapamide tablets Dissolution Rate Testing
Dissolution determination method: take sample, according to dissolution method (Chinese Pharmacopoeia two annex XC the second methods of version in 2010), dissolution fluid 900ml, take 0.2mol/l potassium dihydrogen phosphate 250ml, adding 0.2mol/ sodium hydroxide solution 118m and be diluted with water to 1000ml, regulate pH to 6.8, rotating speed is 100 turns per minute, operate in accordance with the law, and prepare contrast solution。According to spectrophotography (Chinese Pharmacopoeia two annex IVA of version in 2010), measure trap at the wavelength place of 240nm, calculate the stripping quantity of every。
2) glipizide tablet Dissolution Rate Testing
Dissolution determination method (1): take sample, according to dissolution method (Chinese Pharmacopoeia two annex XC the second methods of version in 2010), dissolution fluid is phosphate buffer (pH7.4) 500ml, and rotating speed is 100 turns per minute, operate in accordance with the law, and prepare contrast solution。According to spectrophotography (Chinese Pharmacopoeia two annex IVA of version in 2010), measure trap at the wavelength place of 222nm, calculate the stripping quantity of every。
Dissolution determination method (2): take sample, according to dissolution method (Chinese Pharmacopoeia two annex XC the second methods of version in 2010), dissolution fluid is water 500ml, and rotating speed is 100 turns per minute, operates in accordance with the law, and prepares contrast solution。According to spectrophotography (Chinese Pharmacopoeia two annex IVA of version in 2010), measure trap at the wavelength place of 222nm, calculate the stripping quantity of every。
3) YESUAN PIAN Dissolution Rate Testing
Dissolution determination method (1): take sample, according to dissolution method (Chinese Pharmacopoeia two annex XC the second methods of version in 2010), dissolution fluid is phosphate buffer (pH6.8) buffer 900ml, rotating speed is 100 turns per minute, operate in accordance with the law, and prepare contrast solution。According to spectrophotography (Chinese Pharmacopoeia two annex IVA of version in 2010), measure trap at the wavelength place of 281nm, calculate the stripping quantity of every。
Dissolution determination method (2): take sample, according to dissolution method (Chinese Pharmacopoeia two annex XC the second methods of version in 2010), dissolution fluid is water 900ml, and rotating speed is 100 turns per minute, operates in accordance with the law, and prepares contrast solution。According to spectrophotography (Chinese Pharmacopoeia two annex IVA of version in 2010), measure trap at the wavelength place of 281nm, calculate the stripping quantity of every。
Effect example 3 stability comparative test
1) indapamide
Being set high respectively by test specimen in density polyethylene plastic bottle, seal, put into acceleration and investigate in case, in temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5% condition carries out the Stability Determination of relevant item after carrying out the accelerated test of 3 months。
There is the assay method of related substance: lucifuge operates。Take this product fine powder appropriate, add mobile phase appropriate, put jolting 5 minutes in hot bath, make indapamide dissolve, make in every 1ml the solution containing about indapamide 0.5mg, filtration with mobile phase dilution, take subsequent filtrate as test sample。According to high performance liquid chromatography (Chinese Pharmacopoeia two annex VD of version in 2010), it is filler with octadecylsilane chemically bonded silica, measures respectively。It is calculated according to area normalization method。
Dissolution Rate Testing method is with effect example 2。
Effect example 4 uniformity of dosage units comparative experiments
1) indapamide tablets
The assay method of uniformity of dosage units: take this product 1, put in mortar, add appropriate amount of ethanol, grind, and be transferred in 100ml measuring bottle with ethanol gradation, jolting, indapamide is made to dissolve, add ethanol dilution to scale, shake up, filter, precision measures subsequent filtrate 10ml, put in 50ml measuring bottle, add ethanol dilution to scale, shake up, take this solution and the reference substance solution under assay item, according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia two annex IVA of version in 2010), measure trap at the wavelength place of 242nm, calculate。
2) glipizide tablet
The assay method of uniformity of dosage units: take this product 1, finely ground, add phosphate buffer (pH7.4) and grind in right amount, and it is transferred in 200ml measuring bottle with phosphate buffer (pH7.4) gradation, shake up, filter, take subsequent filtrate as need testing solution；Separately taking glipizide reference substance appropriate, the solution being made in the same way of in every 1ml containing about 25 μ g, as reference substance solution。Take above two solution, measure absorbance respectively at the wavelength place of 275nm, calculate。
3) YESUAN PIAN
The assay method of uniformity of dosage units: take this product 1, put in 25ml measuring bottle, adds 0.5% ammonia solution and is about 15ml, put in hot bath and heat 20 minutes, jolting constantly makes folic acid dissolve, and lets cool, and is diluted with water to scale, shake up, filter, take subsequent filtrate as need testing solution, according to high performance liquid chromatography (Chinese Pharmacopoeia two annex VD of version in 2010), it is filler with octadecylsilane chemically bonded silica, records chromatogram；Separately take folic acid reference substance, be measured in the same method, (Chinese Pharmacopoeia two annex XE of version in 2010) by external standard method with calculated by peak area content, should be met。
4) bendroflumethiazide sheet
Determination of Content Uniformity method: take this product 1, put in mortar, finely ground, add 0.4% sodium hydroxide solution appropriate, grind, and it being transferred in 25ml measuring bottle with 0.4% sodium hydroxide solution gradation, shake well makes bendroflumethiazide dissolve, and adds 0.4% sodium hydroxide solution and is diluted to scale, shake up, filtering, precision measures subsequent filtrate 2ml, puts in 25ml measuring bottle, it is diluted with water to scale, shake up, according to spectrophotography (Chinese Pharmacopoeia two annex IVA of version in 2010), measure absorbance at the wavelength place of 274nm；Another precision weighs bendroflumethiazide reference substance, adds 0.01mol/L caustic lye of soda and dissolves and quantitatively the solution containing about 15 μ g is made in every 1ml in dilution, is measured in the same method absorbance, calculates。
Claims (28)
1. the preparation method of a pharmaceutical solid preparation, it is characterised in that it comprises the steps: to be dissolved in the alkaline solution containing basifier by water-insoluble and/or spraingly water-soluble acidic drug active component, prepares pastille alkalies；Afterwards, by adjuvant and described pastille alkalies Homogeneous phase mixing, wet granulation is carried out；Carrying out described by adjuvant and described pastille alkalies Homogeneous phase mixing, when carrying out the step of wet granulation, be additionally added acidulant, making the alkalescence alkalescence reduction relative to pastille alkalies of acidulant and the mixed liquor of pastille alkalies；
Described water-insoluble and/or spraingly water-soluble acidic drug 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；
The consumption of described basifier and acidulant meets following relation: formula 1 income value is 0.9～1.1；
(acidulant molal quantity × A)/(basifier molal quantity × B) formula 1
Wherein, A is the hydrion number in acidulant molecule, and B is the total valence state number of basifier molecular anion。
2. preparation method as claimed in claim 1, it is characterised in that: described water-insoluble and/or water-insoluble that spraingly water-soluble acidic drug active component is content less than 20% in solid preparation or spraingly water-soluble acidic drug active component；Percentage ratio is mass percent。
3. preparation method as claimed in claim 2, it is characterised in that: described water-insoluble and/or water-insoluble that spraingly water-soluble acidic drug active component is content less than 10% in solid preparation or spraingly water-soluble acidic drug active component；Percentage ratio is mass percent。
4. preparation method as claimed in claim 3, it is characterised in that: described water-insoluble and/or water-insoluble that spraingly water-soluble acidic drug active component is content less than 5% in solid preparation or spraingly water-soluble acidic drug active component；Percentage ratio is mass percent。
5. preparation method as claimed in claim 1, it is characterised in that: described basifier is inorganic base and/or organic base, or one or more in highly basic and/or weak base。
6. preparation method as claimed in claim 5, it is characterised in that: described basifier is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, Sodium ethylate, meglumine, diethanolamine and triethanolamine。
7. preparation method as claimed in claim 1, it is characterised in that: when described water-insoluble and/or spraingly water-soluble acidic drug active component are indapamide, described basifier is sodium hydroxide, potassium hydroxide or Sodium ethylate；
When described water-insoluble and/or spraingly water-soluble acidic drug active component are glipizide, described basifier is sodium hydroxide or potassium hydroxide；
When described water-insoluble and/or spraingly water-soluble acidic drug active component are folic acid, described basifier is sodium hydroxide, potassium hydroxide, Sodium ethylate, sodium carbonate or potassium carbonate；
When described water-insoluble and/or spraingly water-soluble acidic drug active component are methotrexate, described basifier is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate；
When described water-insoluble and/or spraingly water-soluble acidic drug active component are bendroflumethiazide, described basifier is sodium hydroxide or potassium hydroxide。
8. the preparation method as described in claim 1,5,6 or 7, it is characterised in that: the consumption of described basifier is 1～1.5 times that can make water-insoluble and/or the consoluet minimum of spraingly water-soluble acidic drug active component。
9. preparation method as claimed in claim 8, it is characterised in that: the consumption of described basifier is 1～1.05 times that can make water-insoluble and/or the consoluet minimum of spraingly water-soluble acidic drug active component。
10. the preparation method as described in claim 1,5,6 or 7, it is characterised 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。
11. preparation method as claimed in claim 10, it is characterised in that: the molar ratio of described basifier and water-insoluble and/or spraingly water-soluble acidic drug active component is 0.9～1.5。
12. preparation method as claimed in claim 1, it is characterised in that: when described water-insoluble and/or spraingly water-soluble acidic drug active component are indapamide, described basifier is sodium hydroxide or the Sodium ethylate of indapamide mole 0.7～1.1 times；
When described water-insoluble and/or spraingly water-soluble acidic drug active component are glipizide, described basifier is the sodium hydroxide of glipizide mole 0.95～1.1 times；
Described water-insoluble and/or spraingly water-soluble acidic drug active component are folic acid, and described basifier is the sodium hydroxide of folic acid mole 1.8～2.1 times or the sodium carbonate of its mole 0.95～1.1 times or potassium carbonate；
Described water-insoluble and/or spraingly water-soluble acidic drug active component are methotrexate, and described basifier is the sodium carbonate of the sodium hydroxide of methotrexate mole 1.4～1.6 times or mole 0.85～1.1 times；
Described water-insoluble and/or spraingly water-soluble acidic drug active component are bendroflumethiazide, and described basifier is the sodium hydroxide of bendroflumethiazide mole 0.9～1.6 times。
13. preparation method as claimed in claim 1, it is characterised in that: the described mixed liquor that the solvent in the alkaline solution containing basifier is water, organic solvent or water and organic solvent, and basifier intermediate ion can dissociate in this solvent；
Described organic solvent is the acceptable solvent of pharmaceutical arts that the dissolubility to water-insoluble and/or spraingly water-soluble acidic drug active component is better than water。
14. preparation method as claimed in claim 13, it is characterised in that: described organic solvent is one or more in water soluble alcohols or ketones solvent。
15. preparation method as claimed in claim 14, it is characterised in that: described organic solvent is one or more in ethanol, acetone, propylene glycol and glycerol。
16. preparation method as described in any one claim in claim 1,13～15, it is characterised in that: in described alkaline solution, the consumption of solvent is the mass percent 5～100% of wet granulation dry material。
17. preparation method as claimed in claim 16, it is characterised in that: in described alkaline solution, the consumption of solvent is the mass percent 10～50% of wet granulation dry material。
18. preparation method as claimed in claim 1, it is characterized in that: described water-insoluble and/or spraingly water-soluble acidic drug active component are dissolved in the alkaline solution containing basifier while and/or afterwards, be additionally added in the water-solubility carrier of surfactant, solubilizing agent and solid dispersion one or more, then gained pastille alkalies is carried out subsequent step, namely with adjuvant Homogeneous phase mixing, wet granulation is carried out；
While water-insoluble and/or spraingly water-soluble acidic drug active component are dissolved in the alkaline solution containing basifier, when being additionally added the water-solubility carrier of solid dispersion, the amount of the water-solubility carrier of described solid dispersion controls can guarantee that below the amount that water-insoluble and/or spraingly water-soluble acidic drug active component are dissolved completely in the alkaline solution containing basifier。
19. preparation method as claimed in claim 18, it is characterised in that: one or more in the water-solubility carrier of described surfactant, solubilizing agent and solid dispersion are one or more in polyvidone, PEG400-8000, sodium lauryl sulphate, poloxamer, polyoxyethylene castor oil, Tween 80, s6, lactose, mannitol, sucrose, HP-β-CD, beta-schardinger dextrin-and maltose alcohol。
20. preparation method as claimed in claim 18, it is characterised in that: described surfactant and/or the addition of solubilizing agent are 0.05～5 times of water-insoluble and/or spraingly water-soluble acidic drug active component quality；
The addition of the water-solubility carrier of described solid dispersion is 0.5～20 times of water-insoluble and/or spraingly water-soluble acidic drug active component quality。
21. preparation method as claimed in claim 20, it is characterised in that: described surfactant and/or the addition of solubilizing agent are 0.05～2 times of water-insoluble and/or spraingly water-soluble acidic drug active component quality；
The addition of the water-solubility carrier of described solid dispersion is 0.5～2 times of water-insoluble and/or spraingly water-soluble acidic drug active component quality。
22. preparation method as claimed in claim 1, it is characterised in that: when the pastille alkalies that preparation is described, carry out solution preparation according to operations described below: when with water for solvent, be warming up to 40～80 DEG C；When with the mixed solution of water and organic solvent for solvent, it is warming up to 40～70 DEG C；When with ethanol for solvent, it is warming up to 30～50 DEG C。
23. preparation method as claimed in claim 1, it is characterised in that: described basifier is inorganic strong alkali, organic alkali or inorganic middle highly basic, and described acidulant is inorganic acid。
24. preparation method as claimed in claim 23, it is characterised in that: described basifier and acidulant are following combination: 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。
25. preparation method as claimed in claim 1, it is characterised in that: any one in the following manner carries out concrete operations:
Mode (1) by acidulant or the solution containing acidulant and adjuvant Homogeneous phase mixing, then with pastille alkalies Homogeneous phase mixing, carry out extruding and granulate or stirring is granulated；
Mode (2) by pastille alkalies with, acidulant or the solution containing acidulant mix uniformly, obtain granulation liquid, this granulation liquid and adjuvant carry out extruding is granulated, stirring is granulated afterwards again, fluidized-bed spray granulation or centrifugal spray granulation etc.；
Pastille alkalies is mixed uniformly by mode (3) with adjuvant, mixes uniformly with the solution containing acidulant more afterwards, carries out extruding and granulates or stirring granulation；
Mode (4) is by pastille alkalies and, the adjuvant of less than 1/3, and acidulant or the solution containing acidulant mix uniformly, mix with residue adjuvant more afterwards and carries out extruding and granulate or stirring granulation。
26. preparation method as claimed in claim 25, it is characterised in that: the adjuvant of less than 1/3 described in mode (4) is water soluble adjuvant。
27. preparation method as claimed in claim 1, it is characterised in that: the solid particle that preparation method as claimed in claim 1 is prepared, through further conventional steps, prepare tablet or capsule。
28. the pharmaceutical solid preparation that the preparation method as described in any one of claim 1～27 prepares。
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| 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 |
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| CN103520122B (en) * | 2013-10-25 | 2015-06-17 | 海南通用康力制药有限公司 | Preparation method for Bumetanide freeze-dried powder preparation for injection |
| CN107714653B (en) * | 2017-11-27 | 2022-01-28 | 济南新科医药科技有限公司 | Stable soluble methotrexate granules |
| 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 |
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| 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 |
| CA2623018A1 (en) * | 2005-11-22 | 2007-05-31 | Teva Pharmaceutical Industries Ltd. | Pharmaceutical compositions of telmisartan |
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