CN105307650A - Tablet-formed pharmaceutical composition and preparation method thereof - Google Patents
Tablet-formed pharmaceutical composition and preparation method thereof Download PDFInfo
- Publication number
- CN105307650A CN105307650A CN201480006100.3A CN201480006100A CN105307650A CN 105307650 A CN105307650 A CN 105307650A CN 201480006100 A CN201480006100 A CN 201480006100A CN 105307650 A CN105307650 A CN 105307650A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- tablet
- compositions
- preparation
- lactose monohydrate
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 28
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- 229940114926 stearate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 201000010740 swine influenza Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Abstract
The invention relates to the field of medicine and to the chemical/pharmaceutical industry, and relates to agents exhibiting virus-tropic and immunogenic activity. A tablet-formed pharmaceutical composition exhibiting virus-tropic and immunogenic activity is characterized in including glutaryl histamine as an active principle, and in including, as excipients, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide (aerosil 300) and calcium stearate.
Description
Technical field
The present invention relates to medical science, chemical pharmacy industrial circle, particularly relate to the medicament demonstrating Fructus Alpiniae Oxyphyllae and neuroregulation activity.The present invention relates to compositions and the manufacture method thereof of new GH.Particularly, GH preparation and the various mixed with excipients for the preparation of solid GH preparation.
In some embodiments, solid preparation is tablet form, and in other embodiments, it is capsule.
Another aspect of the present invention comprises a kind of method of the GH for the production of preparation form.Other aspects of the present invention comprise the purposes that these compositionss are used for the treatment of the virus disease in its mammal of needs, and it comprises the compositions according to the present invention for the treatment of effective dose is incorporated into this mammal.
Background technology
Influenza presents the most serious problem in virus disease.
From EPDML viewpoint, influenza is one of the most dangerous infection.Such as, in the population of 14,200 ten thousand, record is had an appointment 7,000,000 routine influenza infections every year, and it accounts for about 20% in the structure of infectious disease and parasitic disease, and this is an important index.One of evolvability of influenza virus is the ability that it makes a variation fast due to antigenic variability.Influenza virus is general in the animal (comprising mammal and birds) of the mankind and several types.Therefore, the influenza virus of some animals (such as birds and pig) is the most pathogenic.
Vaccine prevention is the most general form of infected by influenza effect.Vaccinotherapy gives good result in the reduction of fall ill prevention and/or disease intensity.And even these measures can not stop large-scale illness outbreak, especially at the cold period of a year.
Even if utilize the high technology approach for the treatment of, mortality rate is also greater than 50% in the case of several influenza form.In such case, disease, as other influenza forms of other causes of disease, be characterised in that acute attack and serious clinical course, i.e. the temperature of high (more than 40 DEG C) and the long-term fever with poisoning symptom (pain, the meninges symptom in headache, insomnia, muscle and joint).One of disadvantageous clinical course is instant form, namely fast-developing blood loss toxic pulmonary edema and the fatal consequences [Int.J.Tuberc.LungDis. // 2007-V.11.-N7.-P.710-721] caused by respiratory failure and cardiovascular exhaustion.
During treatment of influenza, amantadine and rimantadine are widely used-demonstrate the preparation [Am.J.Med.-1997.-V.102 (3A)-N17.-P.55-60] of the antiviral activity of infected by influenza strain, [WattsJ. " Asiannationsstepupactiontocurbspreadofavianinfluenza " //Lancet.-2004.-V.363-N9406.-P.373].Anti-virus formulation rimantadine is general in the Russian Federation.It is used for the treatment of and prevents the infection that caused by influenza A.Said preparation has demonstrated significant therapeutic effect about the influenza virus of H3N2 hypotype.Relevant with blocking virus protein function in film to the mechanism of action of virus.The activity of this virus is suppressed [RAMNVestnik (BulletinoftheRussiaAcademyofMedicalSciences//1993.No.3.-p.10-15] in receptor-mediated endocytosis, decrustation in phagolysosome and the assembling of virion and the stage of conversion, but, rimantadine, as the representative of diamantane (obsolete) group, there is certain limitation in use.If dosage is high, then there is side effect at CNS, particularly spastic effect.Also produce disadvantageous effect to liver and kidney, it is unlikely used to the patient with these organ diseases thus simultaneously.
At present, the inhibitor of the neuraminidase of influenza virus A and B is widely used, such as oseltamivir phosphate and zanamivir, by being connected to the water repellent region of the active region of the neuraminidase of influenza virus, it has blocked the sialic ability of the latter from separating residual the surface of infected cell, thus inhibits the new virion passage out formed.
Oseltamivir is
trade name, zanamivir is
trade name; They are considered to effective anti-virus formulation [CheungC.L., RaynerJ.M., SmithG.J.etal.Distribution20ofamantadine-resistantH5N1av ianinfluenzavariantsinAsia//J.Infect.Dis.-2006.-Vol.193.-P.1626-1629].At present, report the case [MennoD.deJong occurring resistance to oseltamivir and zanamivir, TranTanThanh, TruongHuuKhanhetal.OseltamivirResistanceduringTreatmento fInfluenzaA (H5N1) Infection//N.Engi.J.Med.-2005.-N353.-P.2667-2572], [SmeeD.F., WongM.H., BaileyK.W., etal.Activitiesofoseltamivirandribavirinusedaloneandinco mbinationagainstinfectionsinmicewithrecentisolatesofinfl uenzaA (H1N1) andBviruses//AntivirChemChemother.-2006.-V.17, N4.-P.185-192].Its with coding M
2variation in the gene of albumen is correlated with, this variation makes this compounds of virus resistance [LiK.S., GuanY., WangJ., etal.GenesisofahighlypathogenicandpotentiallypandemicH5N 1influenzavirusineasternAsia//Nature.-2004.-V.430, N6996.-P.209-213], [Hui-LingY., IlyshinaN.A., SalomonR.etal.Neuraminidaseinhibitor-resistantrecombinan tA/Vietnam/1203/04 (H5N1) influenzavirusesretaintheirreplicationefficiencyandpatho genicityinvitroandvivo//J.Virol.-2007.-Vol.81.-P.12418-1 2426, LeQ.M., KisoM., SomeyaK.etal.Avianflu:isolationofdrug-resistantH5N1virus// 30Nature.-2005.-Vol.437.-P.1108].According to some data, variation appears in the case of about 30%.In addition, neuraminidase inhibitor is about CNS showing obvious side effect.Therefore, the brainstrust of healthy protect administration of Britain provides their suggestion to British government, oseltamivir to the effect that, or oseltamivir phosphate capsule, should not give child due to many undesired side effect and prevent for A/H1N1 influenza.
Be used for the treatment of and one of modal preparation of prophylaxis of viral infections (comprising influenza), in the Russian Federation be
but if it is administered orally with delayed (135mg/kg of white mice body weight) according to the highly pathogenic bacterial strain of the rule of acute prevention and therapy for the influenza virus A (H5N1) in body, then the efficiency of its protection is only 25% and 10% respectively.This level of protection do not meet the efficiency of anti-virus formulation existing national requirements (at least 30%) [see; " ManualforExperimental (Pre-Clinical) StudiesofNewPharmacologicalSubstances " .-M., 2005.-p.541].
Highly pathogenic virus disease also comprises severe acute respiratory syndrome (SARS), it is the new acute coronary virus disease that caused by the genotype IV factor and it is characterized in that mortality rate can reach 10% [RevisedU.S.Surveillancecasedefinitionforsevereacuterespi ratorysyndrome (SARS) andupdateonSARScases-UnitedStatesandworldwide, December2003//MMWRWklyRep.-2003.-Vol.52, N.49.-P.1202-1206].
Summary of the invention
The present invention proposes, and for the preparation of the method for GH compositions, said composition does not comprise magnesium salt and/or the Talcum of silicic acid.Other embodiments comprise GH compositions, and said composition includes one or more diluent, disintegrating agent, binding agent and lubricant.A detailed description of the invention proposes a kind of compositions, and it comprises GH and one or more diluent, disintegrating agent, binding agent and lubricant.Other are preferred, but not unique, embodiment proposes a kind of compositions, it comprises GH, one or more diluent, described diluent is selected from starch, lactose monohydrate or microcrystalline Cellulose, one or more disintegrating agents, each starch independently selected from pregelatinized in them or cross-linking sodium carboxymethyl cellulose, binding agent and lubricant.Also have other preferred, but be not unique, embodiment comprises the lubricant as the binding agent of polyvinylpyrrolidone (polyvynilpyrrolidone) and the magnesium salt as silicic acid.Also have other preferred embodiment to comprise diluent as lactose monohydrate, be selected from one group and be the disintegrating agent of cross-linking sodium carboxymethyl cellulose, and as the binding agent of polyvidone (povidone, povidone).
In order to send the object of the GH of respective amount in the preparation industrially made and select adjuvant.All adjuvants are chosen such that and make to become inertia, and organ sensation is acceptable and compatible with GH.Preparing with solid the adjuvant that form uses and generally include for oral administration, excipient or diluent, binding agent, disintegrating agent, lubricant, anti-adhesive, antiseize paste, wetting agent and surfactant, pigment, flavoring agent, sweeting agent, adsorbent and improve the medicament of organ sensory characteristic.
Excipient or diluent are joined in active substance to increase the volume of tablet.They comprise can be crystallization or amorphous lactose.Various types of lactose comprises lactose monohydrate, alpha-lactose monohydrate, as the lactose (α-, β-) of anhydrous form and the lactose of cohesion.Other diluent comprise sugar, as sugar derivatives.Further, one of modal excipient is lactose monohydrate.Also microcrystalline Cellulose and cellulose fine particle can be used.
Starch and starch derivatives are also referred to as diluent and excipient.
Other starch comprise pregelatinised starch or the starch with sodium glycollate modification.Starch and starch derivatives can also be used as disintegrating agent.Other diluent comprise inorganic salt, as calcium hydrogen phosphate, tricalcium phosphate and calcium sulfate.As diluent, polyhydric alcohol can be used, as mannitol, sorbitol and xylitol.Many diluent also play disintegrating agent and binding agent; And these additional properties should be considered when forming preparation.Disintegrating agent is included in make the granule of tablet disintegratable active drugs composition and adjuvant in tablet formulation, and this will be conducive to the dissolving of active component and improve its bioavailability.The starch of pregel can be disintegrating agent.Cross-linking sodium carboxymethyl cellulose is another kind of disintegrating agent.Disintegrating agent also comprises crospolyvinylpyrrolidone (such as, polyvinylpolypyrrolidone) and microcrystalline Cellulose.
Binding agent is used for wet granulation.The effect of binding agent makes pulverulent bulk and is conducive to compacting.Binding agent is cellulose derivative, such as microcrystalline Cellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose and hydroxy propyl cellulose.Other binding agents are polyvidone, polyvinylpyrrolidone, gel, lac, such as Radix Acaciae senegalis, tragacanth, guar gum and pectin natural gum, gelatinized corn starch, pregelatinized starch, sucrose, corn syrup, Polyethylene Glycol and sodium alginate, calcium ammonium alginate, aluminium-magnesium silicate, Polyethylene Glycol.Preferably, but be not unique, binding agent is polyvinylpyrrolidone, particularly polyvidone.
Lubricant is used in tabletting to be prepared in form for preventing adhering of tablets to shock surface and reducing the friction in pressing step.Lubricant generally includes vegetable oil (such as Semen Maydis oil, mineral oil), PEG Polyethylene Glycol, stearic salt (such as, calcium stearate, magnesium stearate and sodium stearyl fumarate), mineral salt (such as, Talcum), inorganic salt (such as sodium chloride), organic salt (such as sodium benzoate, sodium acetate and enuatrol) and polyvinyl alcohol.Preferred lubricant in commercial Application is magnesium stearate.
Antiseize paste is used in solid preparation for improving the mobility of tablet quality.Usually, such medicament is as microcrystalline Cellulose; Alkali metal stearic acid salt, such as magnesium stearate or calcium stearate; Silicate, such as magnesium silicate, calcium silicates; Starch and its variant and/or its derivant; Talcum; Silica sol, such as, known
According to some embodiments, the scope of described GH content is from composition weight about 30% to about 50%.Said composition comprises the diluent as lactose monohydrate, and microcrystalline Cellulose is also selected as diluent, and pregelatinised starch is selected as disintegrating agent; Cross-linked carboxymethyl cellulose is selected as the second disintegrating agent, and polyvinylpyrrolidone is selected as binding agent, and magnesium stearate is selected as lubricant.
According to another embodiment, the scope of lactose monohydrate content is from about 25% to about 40%, the scope of microcrystalline cellulose cellulose content is from about 5% to about 15%, the scope of pregelatinized starch content is from about 5% to about 15%, the scope of cross-linking sodium carboxymethyl cellulose content is from about 1% to about 10%, the scope of polyvinyl pyrrolidone content is from about 1% to about 10%, and the scope of magnesium stearate content is from about 0.2% to about 2.0%.
According to another embodiment, the content of GH is about 40.0% of composition weight, the content of lactose monohydrate is about 30%, the content of microcrystalline Cellulose is about 10.5%, the content of pregelatinized starch is about 11%, the content of cross-linked carboxymethyl cellulose is about 4.0%, and the content of polyvidone is about 5.5%, and the content of magnesium stearate is about 0.5%.According to other embodiments, GH content can reach 80% (70-80%) of composition weight.Said composition can comprise the lactose of the amount of the 2.5-20% accounting for composition weight further; Disintegrating agent, that is, cross-linked carboxymethyl cellulose, account for the amount of the 1-10% of said composition weight; The binding agent selected, such as, as polyvinylpyrrolidone, accounts for the amount of the 2-10% of said composition weight; And be selected from the lubricant of stearic acid group, such as, magnesium stearate (potassium), accounts for the amount of the 0.2%-2.0% of said composition weight.
Also according to other embodiments of the present invention, lactose monohydrate is selected as diluent, and cross-linking sodium carboxymethyl cellulose is selected as disintegrating agent, and polyvidone is selected as binding agent, and magnesium stearate is selected as lubricant.
Also according to other embodiments, the content of GH can reach 80% of composition weight, and lactose monohydrate is selected as diluent, and the scope of its content is from composition weight 8% to 15%; The cross-linking sodium carboxymethyl cellulose accounting for the amount of the 1-10% of said composition weight is selected as disintegrating agent; Binding agent with the polyvinylpyrrolidone of the content of the 1-10% of described composition weight; Magnesium stearate is the another kind of binding agent with the content of the 0.2-2.0% of described composition weight.According to a preferred embodiment, diluent is selected as with the lactose monohydrate of the content of 9.5% of described composition weight, cross-linking sodium carboxymethyl cellulose is selected as disintegrating agent and content is 5% of said composition weight, binding agent is with the polyvidone of the content of 5% of composition weight, and the magnesium stearate accounting for the amount of 0.5% of said composition weight is lubricant.According to further embodiment, GH is about 90% of composition weight.Preferably, but be not unique, said composition also comprises diluent, such as lactose monohydrate, is preferably the amount of the 3-10% of composition weight; Disintegrating agent, as cross-linked carboxymethyl cellulose, accounts for the amount of the 2-5% of said composition weight; Binding agent, as polyvinylpyrrolidone, accounts for the amount of the 2-5% of said composition weight; Lubricant, as magnesium stearate, accounts for the amount of the 0.2%-2.0% of said composition weight.According to other preferred embodiment, the lactose monohydrate accounting for the amount of 3.5% of said composition weight is selected as diluent, the cross-linking sodium carboxymethyl cellulose accounting for the amount of about 3% of said composition weight is selected as disintegrating agent, the polyvidone accounting for the amount of about 3% of said composition weight is selected as binding agent, and the magnesium stearate accounting for the amount of about 1% of said composition weight is selected as lubricant.
According to another embodiment of the present invention, the amount of suggestion GH compositions is 90mg, and wherein the content of GH is the 40-90% of composition weight.According to another embodiment, compositions comprises the GH of the amount of 60-90% or 70-80%.According to another embodiment, these compositionss can comprise starch, as the cross-linked sodium salt of corn starch, pregelatinized starch, carboxymethyl ester starch, and lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose; Hydroxypropyl emthylcellulose; Polyvinylpyrrolidone, silicate, such as magnesium silicate; Stearate, such as potassium stearate, and mineral compound, as Talcum, in one and/or multiple.
According to embodiment, these compositionss comprise, and preferably, but are not unique, the GH of a standard dose.Preferably, standard dose is the form with solid preparation, as tablet or capsule, and, more preferably, be tablet.Particularly, in the solid preparation of 250mg, this tablet can comprise 30,60,100 and, preferably, the GH of 90mg.
According to commercial embodiment of the present invention, provide a kind of wet mixed by GH and adjuvant and water, pelletize, the method for the solid preparation of GH is prepared in pulverizing that is dry and granular mixture.According to one of embodiment, final mixture is pressed for the manufacture of tablet.According to other embodiments, final mixture is encapsulated.The method comprises the following steps: GH and one or more adjuvants are carried out dry type and be mixed for producing drying composite; Moistening drying composite is carried out for the production of wet granulated mixture with the water of preparation; Dry to produce dry granulation mixture; Pulverize and pulverize granulation mixture to produce; Granulation mixture and mix lubricant will be pulverized to produce final mixture; The solid preparation orally used is produced from final mixture.According to some preferred embodiment, final mixture is pressed for the production of tablet.According to other preferred embodiment, final mixture is encapsulated.
Detailed description of the invention
For implementing best mode of the present invention
Embodiment 1
The preparation of GH 100mg tablet
The production of dry granulation material
Consumption (total) in table 1. step
(total) of producing in step
Table 2.
The production of wet granulation material
The GH sieved, 100%-3.000 (7.751) kg, dried potato amylo-1:4,1:6-transglucosidase .414 (3.652) kg of drying and screening, lactose (milksugar)-4.193 (10.832) kg sieved, gelatinized corn starch-2.028 (5.240) kg of 5% is all weighed to produce container.
The GH sieved, the potato starch of drying and screening, the lactose (milksugar) sieved are admitted to high-speed mixing granulating machine, as GHL-250GF-335 (minimum operation: to producing container GF-201), and mix 3-5 minute.Then, add the gelatinized corn starch of 5% and mix 20-30 second (for minimum operation: 2-3 minute), until produce uniform wet agglomerate.This agglomerate, when pressing in hands, should be easy to assemble, and answering disintegrate when touching.
Wet agglomerate is sent to drying steps.
Drying and dry granulation
In granulator in FL-60 fluosolids SSH-337 at the temperature of 45 ± 5 DEG C the mixture 20-45 minute of dry wet; until residual moisture content be 2.0-3.0% (Sai Duolisi moisture analyser is at 100 DEG C) or, for minimum operation: the mixture 10-12 hour of dry wet on pallet in atmosphere).Before utilizing Sai Duolisi moisture analyser to measure moisture, in order to obtain the object measured more accurately, the sample of dry agglomerate will be granulated.
The mixture of drying is entered and produces in container, and by the general granulator GR-1GF-332 of the bulging bore dia with 1.0-1.5 millimeter (for minimum operation: the hands sieve GF-210 of bore dia by having 1000 microns in VSH-208 (1) in drying baker), and be collected in and produce container (KT-3; TP-3.2) in.
GH output is 90.00 (98.00) % in this step.
Allow with deviation (98.00 ± 0.50) % of regulation output: (65.808-66.470) kg or (90.00 ± 0.50) %:(8.491-8.577) the dry granulation material of kg.
The production of GH 100mg tablet
The preparation of tablet agglomerate
By dry granulation material-8.534 (22.046) kg, grinding and stearic acid-0.081 (0.228) kg sieved, magnesium stearate-0.081 (0.228) kg sieved, calcining and Talcum-0.081 (0.228) kg sieved, silica sol (Aerosil)-0.020 (0.057) kg sieved, grind underproof tablet and screening-0.025 (0.107) kg to carry out weighing and send into and produce container GF-201, in GF-302 (KT-1, TP-4.1).
By dry granulation material, the silica sol (Aerosil) sieved, grinds underproof tablet and screening is sent to dragee pot DR-5GF-340 (for minimum operation: send into and produce container GF-201), and mixes 1-2 minute.Then, add the magnesium stearate of sieving, the Talcum calcined and sieve, grind and the stearic acid that sieves mix 2-3 minute (KT-2; TP-4.1).
This tablet agglomerate is divided equally 3-5 minute in dragee pot DR-5GF-340, analyze the GH content of tablet lump sample, and if obtain gratifying result, then tablet agglomerate is fed to tableting step (KT-3, TP-4.1).
Tabletting is with discarded
Tabletting is performed in the rotary compresion machine MRC-30NGF-230 with 9mm punch diameter.Tablet should have white or have creamy white, the shape of the flat cylinder of band inclined-plane and recess, continual edge, smooth and uniform outer surface, and should not have crackle or slight crack.
Before beginning tabletting, rotary compresion machine MRC-30NGF-230 is provided with label, this label instruction preparation title, operation number, tablet weight.Tablet agglomerate is admitted in the hopper of press, and starts tabletting.Automatically perform adding and dedusting of tablet agglomerate.During tabletting, tablet average weight, all examined with any deviation of tablet average weight, description, hardness.
Underproof tablet is returned, and collects and is sent to general granulator GR-1GF-332 and grind in the container of GF-201.Due to high pressure, the tablet of standard conditions is kept for the stress produced in tablet inside that relaxes, and this high pressure is formed through 6-8 hour by press.
Embodiment 2
The production of dry granulation material
Table 3.
Consumption (total) in step
Table 4.
Result from (total) in step
The production of wet granulation material
The GH sieved, 100%-4.066 (9.785) kg, potato starch-5.970 (3.561) kg of drying and screening, lactose-13.594 (9.839) kg sieved, gelatinized corn starch-4.480 (5.100) kg of 5% is all weighed to production container GF-201, and 302.(KT1，TP-3.1)
The lactose sieved, the potato starch of drying and screening, the GH sieved to be admitted in high-speed mixing granulating machine GHL-250GF-222 and to mix 3-5 minute.Then, add the gelatinized corn starch of 5% and mix 20-30 second, until produce uniform wet agglomerate.This agglomerate, when pressing in hands, should be easy to assemble, and answering disintegrate (KT-2, TP-3.1) when touching
Wet agglomerate is collected in produces container GF-201, is sent to drying steps TP-3.2 in 302.
Drying and non-slurry pelletizing
In drying and granulating machine SG-30MSSH-219 in FL-60 fluosolids GF-337 at the temperature of 55 ± 5 DEG C the mixture 40-60 minute of dry wet, until residual moisture content is 2.0-3.0%.Before utilizing Sai Duolisi moisture analyser to measure moisture, in order to the sample of the agglomerate obtaining the object drying of measuring more accurately will be granulated.
The mixture of drying is entered and produces container GF-201, in GF-302 and by the general granulator GR-1GF-218 (2) of the bulging bore dia with 1.0-1.5 millimeter, GF-332 (2), and be collected in production container (KT-3; TP-3.2) in.
Dry granulation material is sent to the step of the mixture produced for encapsulating TP-4.1.
Encapsulating
Encapsulating is compressed in capsule fillers device GF-237, capsule fillers device NJP-800CGF-338 and capsule fillers device SF-100NGF-at MG and is carried out.
Mixture for encapsulating is admitted in the hopper 1 of capsule fillers device, and solid gelatinous capsule is admitted in hopper 2, then starts encapsulating.When these two hoppers are empty, be automatically added for the mixture encapsulated.
The object of the invention is to expand the scope of the medicament demonstrating virus tropism and immunogenic activity.
This object is realized by the new pharmaceutical composition in solid pharmaceutical preparation, that it shows virus tropism and immunogenic activity, it is characterized in that it comprise as active substance up to 94 % by weight amount GH and form the adjuvant of remainder.According to most preferred embodiment, the scope of GH content can be from 80 to 94 % by weight.This preparation can comprise lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose as adjuvant, colloidal silica (Aerosil300) and calcium stearate.This high-load of active substance is not disclosed in prior art level.
What demonstrate virus tropism is it with the particular example of the new pharmaceutical composition of the tablet form of immunogenic activity formulation characteristics is, it comprises the GH as active substance and the lactose monohydrate as adjuvant, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, colloidal silica (Aerosil300) and calcium stearate, described composition has following content, by weight percentage:
In order to improve the stability of said composition further, first active substance is dried to the moisture being no more than 1.5%.
Embodiments of the present invention
Embodiment A. compositions
Active substance:
GH 30.00mg
Adjuvant:
Embodiment B. compositions
Active substance:
GH 100.00mg
Adjuvant:
The value of pharmacokinetic parameter does not show the deviation of any essence during studying.
Elimination rate constant is 0.22 ± 0.004.
Absorption rate constant is 1.695 ± 0.028.
The time (Tmax, hour) reaching Cmax is 1.3 ± 0.1.
Cmax (Cmax, μ g/mL) is 70.3 ± 2.0
The research of embodiment 3. preparation
3.1. toxicologic study (table 5,6).
toxicologic study result
According to acute and chronic toxicity data, GH compositions can be called as the preparation of relative harmless.
1. compositions does not demonstrate and causes irritated and mutagenesis character.
2. GH compositions does not demonstrate genotoxicity.
3. the compositions in the dosage (0.05,0.5, the GH of 5.0mg/kg) of all research does not demonstrate carcinogenic activity, and it is shown under the experiment condition of 24 months.
Table 5.
Table 6.
2. study the efficiency of the GH compositions of testing in vitro and in vivo about the agent of A-influenza and adenovirus.
Materials and methods:
Llowing group of materials is used in vitro study:
-A/Aichi/2/68 (H3N2) and A/hen/Kurgan/Russia/2/05 (H5N1) strain;
The constant cultivation of GMK-AH-1 of-green monkey kidney cell, MDCK Testis et Pentis Canis;
-PS-4 grows semisynthetic medium.
Llowing group of materials is used to In vivo study:
-there is the outbred mice of 15g weight, obtained by the vivarium of the VTsNIIM in Moscow, Russia area.
Intranasal infection is carried out to laboratory animal.
During studying, external 0.1 infective dose at cytopathic doses 50/ cell, constantly little when transmitting 2 after infection monolayer, concentration is the breeding (strain A/Aichi/2/68 (H3N2) и А/hen/Kurgan/Russia/2/05 (H5N1)) that the GH compositions of 100-200 μ g/mL suppresses influenza virus A effectively.
During studying, body is interior is effective using the GH compositions of 5mg/kg dosage as the preventive medicine relevant with A type influenza (H3N2 and H5N1).
The prophylactic efficiency of GH compositions is slightly poor compared with oseltamivir phosphate capsule (Tamiflu).
When using according to urgent prevention system and be used for the treatment of, GH compositions is poor compared with Tamiflu.Be 15mg/kg according to the optimal dose of the GH compositions of described system.
3.3. the research of the interferon-induced and immunoregulatory activity of GH compositions:
-preparation and dosage: GH compositions, oral administration;
-material for studying: 15 healthy rats take the blood sample before and after said preparation;
Materials and methods:
In 2,4,6,8,12,24,48 hours monitoring IFN-state indices after taking preparation.
3.3.1. the result of study of the interferon-induced and immunoregulatory activity of GH compositions:
In 24-48 hour, single oral administration adds interferon content by 73.3% of the donor within the upper limit of physiology normality;
In 24 hours, said composition stimulates and leukocytic lower α-IFN production capacity in being standardized in fact healthy animal;
The production of GH compositions individually dosed stimulation γ-IFN.
Therefore, new compositions has demonstrated the high effect of pharmacologically active, and can in recommended introducing clinical practice.
Industrial applicibility
The present invention can be applicable to medical science, chemical pharmacy industrial circle, namely for the production of the medicament of activity demonstrating Fructus Alpiniae Oxyphyllae and neuroregulation, and relates to new GH compositions and manufacture method thereof.
Claims (6)
1. a pharmaceutical composition that is that demonstrate virus tropism and the solid preparation of immunogenic activity, it is characterized in that, it comprises: as the GH of active substance, as the lactose monohydrate of adjuvant, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, colloidal silica (Aerosil300) and calcium stearate, these compositions have following content by weight percentage:
GH 18.0-94
Adjuvant all the other.
2. pharmaceutical composition according to claim 1, is characterized in that, it comprises the GH of the amount of 92-94% percetage by weight.
3. pharmaceutical composition according to claim 1, it is characterized in that, it comprises: as the GH of active substance, with as the lactose monohydrate of adjuvant, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, colloidal silica (Aerosil300) and calcium stearate, these compositions have following content by weight percentage:
4. pharmaceutical composition according to claim 1, is characterized in that, first described active substance is dried to moisture and is not more than 1.5%.
5. for the manufacture of a method for the pharmaceutical composition according to any one of claim 1-2, it is characterized in that, the powder that sieves of microcrystalline Cellulose is thoroughly mixed 1 ÷ 2 minutes; Add sieve powder and the lactose monohydrate sieved of GH, and the mixture obtained thoroughly is mixed 5 ÷ 7 minutes; Then add the powder that sieves of cross-linking sodium carboxymethyl cellulose, and the mixture obtained is mixed 3 ÷ 5 minutes; Add the powder that sieves of colloidal silica and calcium stearate, and the mixture obtained is remixed 2 ÷ 4 minutes; And consequent mixture is pressed into tablet by direct pressing.
6. for the manufacture of a method for the pharmaceutical composition according to any one of claim 1-4, it is characterized in that, described GH compositions is made into capsule.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2014101563 | 2014-01-20 | ||
| RU2014101563/15A RU2546002C1 (en) | 2014-01-20 | 2014-01-20 | Pharmaceutical composition in form of tablet and method of obtaining thereof |
| PCT/RU2014/000164 WO2015108440A1 (en) | 2014-01-20 | 2014-03-14 | Tablet-formed pharmaceutical composition and preparation method thereof |
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| Publication Number | Publication Date |
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| CN105307650A true CN105307650A (en) | 2016-02-03 |
| CN105307650B CN105307650B (en) | 2017-10-20 |
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| CN201480006100.3A Expired - Fee Related CN105307650B (en) | 2014-01-20 | 2014-03-14 | The pharmaceutical composition and its manufacture method of tablet form |
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| Country | Link |
|---|---|
| CN (1) | CN105307650B (en) |
| HK (1) | HK1214767A1 (en) |
| RU (1) | RU2546002C1 (en) |
| SG (1) | SG11201505385VA (en) |
| WO (1) | WO2015108440A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2737086C2 (en) * | 2018-10-23 | 2020-11-24 | Общество С Ограниченной Ответственностью "Валента-Интеллект" | Liquid dosage form for treating and preventing influenza and arvi |
| RU2770518C2 (en) * | 2020-02-11 | 2022-04-18 | Общество С Ограниченной Ответственностью "Валента-Интеллект" | Liquid dosage form for treatment and prevention of flu and arvi |
| RU2770521C2 (en) * | 2020-02-11 | 2022-04-18 | Общество С Ограниченной Ответственностью "Валента-Интеллект" | Liquid dosage form for treatment and prevention of flu and arvi |
| WO2023204729A1 (en) * | 2022-04-19 | 2023-10-26 | Общество с ограниченной ответственностью "Гелеспон" | Pharmaceutical compositions based on a novel substance of 4-[2-(1н-imidazol-4-yl)-ethylcarbamoyl]-butanoic acid and method for producing said substance |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1020179A2 (en) * | 1997-07-04 | 2000-07-19 | Vladimir Evgenievich Nebolsin | Peptide derivatives or pharmaceutically acceptable salts thereof, method for producing the same, use of said derivatives and pharmaceutical composition |
| WO2008031631A2 (en) * | 2006-09-16 | 2008-03-20 | Bayer Schering Pharma Aktiengesellschaft | Oral modified release formulations |
| US20110224213A1 (en) * | 2008-03-19 | 2011-09-15 | Vladimir Evgenievich Nebolsin | Use of Glutaric Acid Derivatives or the Pharmaceutically Acceptable Salts Thereof as Anti-Arrhythmic Agents |
-
2014
- 2014-01-20 RU RU2014101563/15A patent/RU2546002C1/en active
- 2014-03-14 SG SG11201505385VA patent/SG11201505385VA/en unknown
- 2014-03-14 WO PCT/RU2014/000164 patent/WO2015108440A1/en active Application Filing
- 2014-03-14 CN CN201480006100.3A patent/CN105307650B/en not_active Expired - Fee Related
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2016
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1020179A2 (en) * | 1997-07-04 | 2000-07-19 | Vladimir Evgenievich Nebolsin | Peptide derivatives or pharmaceutically acceptable salts thereof, method for producing the same, use of said derivatives and pharmaceutical composition |
| WO2008031631A2 (en) * | 2006-09-16 | 2008-03-20 | Bayer Schering Pharma Aktiengesellschaft | Oral modified release formulations |
| US20110224213A1 (en) * | 2008-03-19 | 2011-09-15 | Vladimir Evgenievich Nebolsin | Use of Glutaric Acid Derivatives or the Pharmaceutically Acceptable Salts Thereof as Anti-Arrhythmic Agents |
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| Publication number | Publication date |
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| CN105307650B (en) | 2017-10-20 |
| HK1214767A1 (en) | 2016-08-05 |
| RU2546002C1 (en) | 2015-04-10 |
| SG11201505385VA (en) | 2015-08-28 |
| WO2015108440A1 (en) | 2015-07-23 |
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