CN105307650B - The pharmaceutical composition and its manufacture method of tablet form - Google Patents
The pharmaceutical composition and its manufacture method of tablet form Download PDFInfo
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- CN105307650B CN105307650B CN201480006100.3A CN201480006100A CN105307650B CN 105307650 B CN105307650 B CN 105307650B CN 201480006100 A CN201480006100 A CN 201480006100A CN 105307650 B CN105307650 B CN 105307650B
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- CERZMXAJYMMUDR-UHFFFAOYSA-N neuraminic acid Natural products NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO CERZMXAJYMMUDR-UHFFFAOYSA-N 0.000 description 1
- 229960002194 oseltamivir phosphate Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 210000000680 phagosome Anatomy 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229940114930 potassium stearate Drugs 0.000 description 1
- ANBFRLKBEIFNQU-UHFFFAOYSA-M potassium;octadecanoate Chemical compound [K+].CCCCCCCCCCCCCCCCCC([O-])=O ANBFRLKBEIFNQU-UHFFFAOYSA-M 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002940 repellent Effects 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- VILMUCRZVVVJCA-UHFFFAOYSA-M sodium glycolate Chemical group [Na+].OCC([O-])=O VILMUCRZVVVJCA-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 229940114926 stearate Drugs 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
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease 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
- 230000001225 therapeutic effect Effects 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
- 230000035899 viability Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Immunology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to medical science, chemical pharmacy industrial circle, also, more particularly to show virus tropism and immunogenic activity medicament.Show the pharmaceutical composition of virus tropism and immunogenic activity tablet form, it is characterized in that it includes the GH as active material, and it is used as the lactose monohydrate of adjuvant, microcrystalline cellulose, Ac-Di-Sol, colloidal silica (Aerosil 300) and calcium stearate.
Description
Technical field
The present invention relates to medical science, chemical pharmacy industrial circle, more particularly to show that virus tropism and immunogenicity are lived
The medicament of property.The present invention relates to the composition of new GH and its manufacture method.Particularly, GH preparation is with using
Mixed in the various excipient for preparing solid GH preparation.
In some embodiments, solid pharmaceutical preparation is tablet form, in other embodiments, and it is capsule.
Another aspect of the present invention includes a kind of method for being used to produce the GH of preparation form.The present invention's
Other aspects, which include these compositions, to be used to treat the purposes needing the virus disease in its mammal, and it includes controlling
The composition according to the present invention for treating effective dose is incorporated into the mammal.
Background technology
The problem of influenza shows most serious in virus disease.
From the viewpoint of epidemiology, influenza is one of most dangerous infection.For example, the annual population 142,000,000
Middle record has about 7,000,000 influenza infections, and it accounts for about 20% in the structure of infectious disease and parasitic disease, and this is one
Individual important index.One of evolvability of influenza virus is the ability that it is quickly made a variation due to antigenic variability.Influenza disease
Poison is universal in the animal (including mammal and birds) of the mankind and several types.Therefore, some animal (such as birds
And pig) influenza virus be most pathogenic.
Vaccine prevention is the most common form of infected by influenza effect.Vaccinotherapy is in morbidity prevention and/or disease
Good result is given in terms of the reduction of sick intensity.And even these measures can not prevent large-scale illness outbreak, especially
It is the cold period in 1 year.
Even with the high technology approach for the treatment of, the death rate is in the case of several influenza forms also greater than 50%.At this
In the case of sample, disease, as other influenza forms of other causes of disease, is characterised by acute attack and serious clinical process,
The temperature of i.e. high (more than 40 DEG C) and with poisoning symptom (headache, insomnia, muscle and joint pain, meninx symptom) length
Phase generates heat.One of unfavorable clinical process is instant form, i.e., fast-developing blood loss toxic pulmonary edema and declined by breathing
Exhaust and [the Int.J.Tuberc.Lung Dis. // 2007-V.11.-N7.-P.710- of fatal consequences caused by cardiovascular exhaustion
721]。
During treatment of influenza, amantadine and Rimantadine are widely used-shown the anti-of infected by influenza strain
The preparation [Am.J.Med.-1997.-V.102 (3A)-N17.-P.55-60] of virus activity, [Watts J.《Asian
nations step up action to curb spread of avian influenza》//Lancet.-2004.-
V.363-N9406.-P.373].Anti-virus formulation Rimantadine is universal in the Russian Federation.It is used for treat and prevent by
Infected caused by influenza A.Said preparation has shown that significant therapeutic effect on the influenza virus of H3N2 hypotypes.It is right
Virus the mechanism of action with film blocking virus protein function it is relevant.The virus activity receptor-mediated encytosis,
The stage of assembling and the conversion of decrustation and virion in phagolysosome is suppressed [RAMN Vestnik
(Bulletin of the Russia Academy of Medical Sciences//1993.No.3.-p.10-15], so
And, Rimantadine, as the representative of adamantane group, when in use with certain limitation.If dosage is high, go out in CNS
Existing side effect, particularly spastic effect.Unfavorable effect is also produced to liver and kidney simultaneously, thus its unlikely by with
In the patient with these organ diseases.
At present, the inhibitor of influenza virus A and B neuraminidase is widely used, such as oseltamivir phosphate and bundle
Na meter Wei, the water repellent region of the active region of the neuraminidase by being connected to influenza virus, it has blocked the latter from quilt
The ability of the sialic acid of separating residual on the surface of the cell of infection, so as to inhibit the passage that the virion newly formed comes out.
Olympic Competition rice Wei beTrade name, zanamivir isTrade name；They are considered as
Effective anti-virus formulation [Cheung C.L., Rayner J.M., Smith G.J.et al.Distribution 20of
amantadine-resistant H5N1avian influenza variants in Asia//J.Infect.Dis.-
2006.-Vol.193.-P.1626-1629].At present, it was recently reported that the case [Menno of resistance to Olympic Competition rice Wei and zanamivir occur
D.de Jong,Tran Tan Thanh,Truong Huu Khanh et al.Oseltamivir Resistance during
Treatment of Influenza A(H5N1)Infection//N.Engi.J.Med.-2005.-N353.-P.2667-
2572], [Smee D.F., Wong M.H., Bailey K.W., et al.Activities of oseltamivir and
ribavirin used alone and in combination against infections in mice with
recent isolates of influenza A(H1N1)andВviruses//Antivir Chem Chemother.-
2006.-V.17,N4.-P.185-192].Itself and coding M2Variation in the gene of albumen is related, the variation make virus resistance this
Class compound [Li K.S., Guan Y., Wang J., et al.Genesis of a highly pathogenic and
potentially pandemic H5N1influenza virus in eastern Asia//Nature.-2004.-
V.430, N6996.-P.209-213], [Hui-Ling Y., Ilyshina N.A., Salomon R.et
al.Neuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04(H5N1)
influenza viruses retain their replication efficiency and pathogenicity in
vitro and vivo//J.Virol.-2007.-Vol.81.-P.12418-12426；Le Q.M.,Kiso M.,Someya
K.et al.Avian flu:isolation of drug-resistant H5N1virus//30Nature.-2005.-
Vol.437.-P.1108].According to some data, variation is appeared in about 30% case.In addition, neuraminic acid enzyme level
Agent shows obvious side effect on CNS.Therefore, the brainstrust of Britain's health protection administration provides him to British government
Suggestion, Olympic Competition rice Wei to the effect that, or Tamiflu, because many undesired side effects without that should give children are used for A/
H1N1 influenzas are prevented.
One of most common preparation for treating and preventing virus infection (including influenza), be in the Russian FederationBut, if it is caused according to the rule of acute prevention and treatment for the high of internal influenza virus A (H5N1)
Characteristic of disease bacterial strain is administered orally with delayed (135mg/kg of small white mouse body weight), then the efficiency of its protection is only 25% and 10% respectively.This
Level of protection does not meet the existing national requirements (at least 30%) of the efficiency of anti-virus formulation [referring to " Manual for
Experimental(Pre-Clinical)Studies of New Pharmacological Substances".-M.,
2005.-p.541]。
Highly pathogenic virus disease also includes serious acute respiratory syndrome (SARS), and it is caused by the genotype IV factors
New acute coronary virus disease and be characterized in that the death rate up to 10% [Revised U.S.Surveillance
case definition for severe acute respiratory syndrome(SARS)and update on SARS
cases-United States and worldwide,December 2003//MMWR Wkly Rep.-2003.-Vol.52,
N.49.-P.1202-1206]。
The content of the invention
Method for preparing GH composition is proposed according to the present invention, said composition does not include the magnesium salts of silicic acid
And/or talcum.Propose GH composition, said composition include one or more diluents, disintegrant, adhesive and
Lubricant.One embodiment proposes a kind of composition, and it includes GH and one or more diluents, collapsed
Solve agent, adhesive and lubricant.Other are preferred, but are not unique, and embodiment proposes a kind of composition, and it includes penta
Two acyl histamine, one or more diluents, the diluent is selected from starch, lactose monohydrate or microcrystalline cellulose, Yi Zhonghuo
A variety of disintegrants, each of which is independently selected from the starch or Ac-Di-Sol of pregelatinized, adhesive
And lubricant.Also other are preferred, but are not unique, and embodiment includes being used as polyvinylpyrrolidone
(polyvynilpyrrolidone) lubricant of adhesive and the magnesium salts as silicic acid.Also other preferred embodiment party
Formula include as lactose monohydrate diluent, selected from one group and be Ac-Di-Sol disintegrant, Yi Jizuo
For the adhesive of PVP (povidone, povidone).
According to the commercial embodiment of the present invention there is provided a kind of method for manufacturing pharmaceutical composition, its feature exists
In：The sieving powder of microcrystalline cellulose is sufficiently mixed 1-2 minutes；Add the sieving powder of GH and the lactose of sieving
Monohydrate；And be thoroughly mixed obtained mixture 5-7 minutes；Then, the sieving powder of Ac-Di-Sol is added
End, and by obtained mixture mixing 3-5 minutes；The sieving powder of colloidal silica and calcium stearate is added, and will
Obtained mixture is remixed 2-4 minutes；And resulting mixture by direct pressing is pressed into tablet.
According to the commercial embodiment of the present invention, the GH composition is made into capsule.
Adjuvant is selected for the purpose of the GH of delivering respective amount in the preparation that is industrially made.All assistants
Agent is chosen such that so that turning into inert, organ sensation is acceptable and compatible with GH.For oral administration
Generally included with the adjuvant that solid preparation form is used, excipient or diluent, adhesive, disintegrant, lubricant, anti-bonding
Agent, antiseize paste, wetting agent and surfactant, pigment, flavor enhancement, sweetener, adsorbent and improve organ sensory characteristic medicine
Agent.
Excipient or diluent are added in active material to increase the volume of tablet.They include being crystallization
Or amorphous lactose.Various types of lactose include lactose monohydrate, the breast of alpha-lactose monohydrate, such as anhydrous form
Sugar (α-, β -) and the lactose condensed.Other diluents include sugar, such as sugar derivatives.Also, one of most common excipient is breast
Sugared monohydrate.Microcrystalline cellulose and cellulose fine particle can also be used.
Starch and starch derivatives are also referred to as diluent and excipient.
Other starch include pregelatinised starch or the starch being modified with sodium glycollate.Starch and starch derivatives can be with
It is used as disintegrant.Other diluents include inorganic salts, such as calcium monohydrogen phosphate, tricalcium phosphate and calcium sulfate., can be with as diluent
Use polyalcohol, such as mannitol, sorbierite and xylitol.Many diluents also play disintegrant and adhesive；And work as
These additional properties are contemplated that when forming preparation.Disintegrant is included in tablet formulation so that the Viability medicine of tablet disintegratable
The particle of thing composition and adjuvant, this is beneficial to the dissolving of active component and improves its bioavilability.The starch of pregel can
To be disintegrant.Ac-Di-Sol is another disintegrant.Disintegrant also includes PVPP (example
Such as, PVPP) and microcrystalline cellulose.
Adhesive is used for wet granulation.The effect of adhesive is to make powder loose and be conducive to suppressing.Adhesive is fiber
Plain derivative, such as microcrystalline cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxy ethyl fiber
Element and hydroxy propyl cellulose.Other adhesives are PVP, polyvinylpyrrolidone, gel, lac, such as Arab
Natural gum, tragacanth, guar gum and pectin natural gum, gelatinized corn starch, pregelatinized starch, sucrose, corn syrup, polyethylene glycol and alginic acid
Sodium, calcium ammonium alginate, aluminium-magnesium silicate, polyethylene glycol.It is preferred that, but be not unique, adhesive is polyvinylpyrrolidone, special
It is not PVP.
Lubricant, which is used in tabletting preparation form, to be used to prevent adhering of tablets to shock surface and reduces in pressing step
In friction.Lubricant generally include vegetable oil (such as corn oil, mineral oil), PEG polyethylene glycol, stearic salt (for example,
Calcium stearate, magnesium stearate and sodium stearyl fumarate), it is mineral salt (for example, talcum), inorganic salts (such as sodium chloride), organic
Salt (such as sodium benzoate, sodium acetate and enuatrol) and polyvinyl alcohol.Preferred lubricant in commercial Application is stearic acid
Magnesium.
Antiseize paste be used to be used to improve the mobility of tablet quality in solid pharmaceutical preparation.Generally, such medicament such as crystallite
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 derivative；Talcum；Cataloid, for example, it is known that
According to some embodiments, the scope of the GH content is from about the 30% of composition weight to about
50%.Said composition includes the diluent as lactose monohydrate, and microcrystalline cellulose is also selected as diluent, in advance
The starch of gelling is selected as disintegrant；Cross-linked carboxymethyl cellulose is selected as the second disintegrant, polyvinylpyrrolidine
Ketone is selected as adhesive, and magnesium stearate is selected as lubricant.
According to another embodiment, the scope of lactose monohydrate content is from about 25% to about 40%, microcrystalline cellulose
The scope of cellulose content is that the scope of pregelatinized starch content is, from about 5% to about 15%, to be crosslinked carboxylic first from about 5% to about 15%
The scope of base sodium cellulosate content is that the scope of polyvinyl pyrrolidone content is from about 1% to about from about 1% to about 10%
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 the 40.0% of composition weight, lactose monohydrate
Content be about 30%, the content of microcrystalline cellulose is about 10.5%, and the content of pregelatinized starch is about 11%, cross-linked carboxymethyl
The content of cellulose is about 4.0%, and the content of PVP is about 5.5%, and the content of magnesium stearate is about 0.5%.According to
Other embodiment, 80% (70-80%) of the GH content up to composition weight.Said composition can further comprise
Account for the lactose of the 2.5-20% of composition weight amount；Disintegrant, i.e. cross-linked carboxymethyl cellulose, accounts for said composition weight
1-10% amount；The adhesive of selection, for example, as polyvinylpyrrolidone, accounting for the 2-10% of said composition weight amount；With
And the lubricant selected from stearic acid group, for example, magnesium stearate (potassium), accounts for the 0.2%-2.0% of said composition weight amount.
Always according to the other embodiment of the present invention, lactose monohydrate is selected as diluent, and cross-linked carboxymethyl is fine
The plain sodium of dimension is selected as disintegrant, and PVP is selected as adhesive, and magnesium stearate is selected as lubricant.
Always according to other embodiment, the content of GH is up to the 80% of composition weight, lactose monohydrate
Diluent is selected as, the scope of its content is 8% to 15% from composition weight；Account for the 1-10% of said composition weight
The Ac-Di-Sol of amount be selected as disintegrant；With the poly- second of the 1-10% of composition weight content
Alkene pyrrolidone is adhesive；Magnesium stearate is another adhesive with the 0.2-2.0% of composition weight content.
According to a preferred embodiment, it is chosen to make with the lactose monohydrate of 9.5% content of the composition weight
For diluent, Ac-Di-Sol is selected as disintegrant and content is the 5% of said composition weight, and adhesive is
With the PVP of 5% content of composition weight, the magnesium stearate for accounting for 0.5% amount of said composition weight is lubricant.
According to further embodiment, GH is about the 90% of composition weight.Preferably, but be not it is unique, should
Composition also includes diluent, the 3-10% of such as lactose monohydrate, preferably composition weight amount；Disintegrant, is such as handed over
Join carboxymethyl cellulose, account for the 2-5% of said composition weight amount；Adhesive, such as polyvinylpyrrolidone, account for said composition weight
The 2-5% of amount amount；Lubricant, such as magnesium stearate, account for the 0.2%-2.0% of said composition weight amount.It is preferred according to other
Embodiment, the lactose monohydrate for accounting for 3.5% amount of said composition weight is selected as diluent, accounts for said composition
The Ac-Di-Sol of about 3% amount of weight is selected as disintegrant, accounts for about 3% amount of said composition weight
PVP be selected as adhesive, and account for the magnesium stearate of about 1% amount of said composition weight and be selected as profit
Lubrication prescription.
According to another embodiment of the present invention, it is proposed that the amount of GH composition is 90mg, wherein glutaryl group
The content of amine is the 40-90% of composition weight.According to another embodiment, composition includes 60-90% or 70-80% amount
GH.According to further embodiment, these compositions can include starch, such as cornstarch, pregelatinized starch,
The cross-linked sodium salt of carboxymethyl ester starch, lactose monohydrate, microcrystalline cellulose, Ac-Di-Sol；Hydroxypropyl methyl
Cellulose；Polyvinylpyrrolidone, such as silicate, magnesium silicate；Stearate, such as potassium stearate, and mineral compound,
Such as talcum, in one kind and/or a variety of.
According to embodiment, these compositions are included, it is preferable that but be not unique, the glutaryl of a standard dose
Histamine.Preferably, standard dose is such as tablet or capsule in the form of solid pharmaceutical preparation, also, it is highly preferred that is tablet.Especially
Be, in 250mg solid pharmaceutical preparation, this tablet can comprising 30,60,100 and, it is preferable that 90mg GH.
It is mixed there is provided a kind of wet type by GH and adjuvant and water according to the commercial embodiment of the present invention
Close, granulation, the method for the solid pharmaceutical preparation for crushing to prepare GH of dry and granular mixture.According to embodiment party
One of formula, final mixture is pressed for manufacturing tablet.According to other embodiment, final mixture is encapsulated.The party
Method comprises the following steps：GH and one or more adjuvants are carried out into dry type mixing is used to produce drying composite；With
The water of preparation is used to produce wet granulated mixture to soak drying composite；Dry to produce dry granulation mixture；Crush
Granulation mixture is crushed to produce；Granulation mixture will be crushed with mix lubricant to produce final mixture；From final mixing
The solid pharmaceutical preparation that thing production is administered orally.According to some preferred embodiment, final mixture is pressed for producing tablet.
According to other preferred embodiment, final mixture is encapsulated.
Embodiment
For preferred embodiment of the present invention
Embodiment 1
The preparation of GH 100mg tablets
The production of dry granulation material
Consumption (total) in the step of table 1.
(total) produced in step
Table 2.
The production of wet granulation material
The GH of sieving, 100%-3.000 (7.751) kg, the dried potato amylo-1:4,1:6-transglucosidase .414 of drying and screening
(3.652) kg, lactose (milk sugar) -4.193 (10.832) kg, 5% gelatinized corn starch -2.028 (5.240) kg of sieving is equal
It is weighed with production containers.
The GH of sieving, the farina of drying and screening, the lactose (milk sugar) of sieving are admitted to height
(the minimum operation of fast mixer-granulator, such as GHL-250GF-335：To production containers GF-201), and mix 3-5 minutes.Then, plus
Enter 5% gelatinized corn starch and mix 20-30 seconds (for minimum operation：2-3 minutes), until producing uniform moist mass.The agglomerate,
When being pressed in hand, it should be easy to aggregation, and should be disintegrated in touch.
Wet agglomerate is sent to drying steps.
Dry and dry granulation
Dry wet mixture 20-45 at a temperature of 45 ± 5 DEG C in FL-60 fluosolids SSH-337 in granulator
Minute, until residual moisture content be 2.0-3.0% (Sai Duolisi moisture analysers are at 100 DEG C) or, for minimum fortune
OK：Wet mixture is dried on pallet in atmosphere 10-12 hours).Moisture is being determined using Sai Duolisi moisture analysers
Before content, in order to obtain the purpose more accurately measured, the sample of dry agglomerate will be granulated.
Dry mixture is discharged into production containers, and passes through the general system with 1.0-1.5 millimeters of drum bore dia
Grain machine GR-1GF-332 is (for minimum operation：Pass through the bore dia with 1000 microns in VSH-208 (1) in drying box
Hand sieves GF-210), and collect in production containers (KT-3；TP-3.2 in).
GH yield is 90.00 (98.00) % in this step.
And deviation (98.00 ± 0.50) % of regulation output is allowed：(65.808-66.470) kg or (90.00 ±
0.50) %：(8.491-8.577) kg dry granulation material.
The production of GH 100mg tablets
The preparation of tablet agglomerate
By dry granulation material -8.534 (22.046) kg, stearic acid -0.081 (0.228) kg of grinding and sieving, sieving
Magnesium stearate -0.081 (0.228) kg, calcining and sieving talcum -0.081 (0.228) kg, the cataloid of sieving
(Aerosil) -0.020 (0.057) kg, grinds underproof tablet and screening -0.025 (0.107) kg is weighed and sent into
In production containers GF-201, GF-302 (KT-1, TP-4.1).
By dry granulation material, the cataloid (Aerosil) of sieving grinds underproof tablet and screening feeding
To dragee pot DR-5GF-340 (for minimum operation：Send into production containers GF-201), and mix 1-2 minutes.Then, add
The stearic acid of the talcum of the magnesium stearate of sieving, calcining and sieving, grinding and sieving simultaneously mixes 2-3 minutes (KT-2；TP-4.1).
The tablet agglomerate is divided equally 3-5 minutes in dragee pot DR-5GF-340, and the penta 2 of analytic plate agent lump sample
Acyl histamine content, also, if obtaining gratifying result, then tablet agglomerate is fed to tableting step (KT-3, TP-
4.1)。
Tabletting and discarded
Tabletting is performed in the rotary compresion machine MRC-30N GF-230 with 9mm punch diameters.Tablet should have white
Color or with creamy white, with inclined-plane and recess, continual edge, smooth and uniform outer surface flat cylinder shape,
And should not have crackle or slight crack.
Before tabletting is started, rotary compresion machine MRC-30N GF-230 are provided with label, label instruction preparation title,
Run number, tablet weight.Tablet agglomerate is admitted in the hopper of press, and starts tabletting.Automatic performing chip bolus block plus
Enter and dedusting.During tabletting, any deviation, description, the hardness of tablet average weight and tablet average weight are examined.
Underproof tablet is returned, and general granulator GR-1GF-332 is collected and fed into GF-201 container and is entered
Row grinding.Due to high pressure, the tablet of standard conditions keeps the stress produced for relaxation inside tablet, and the high pressure is by press
Formed through 6-8 hours.
Embodiment 2
The production of dry granulation material
Table 3.
Consumption (total) in step
Table 4.
Result from step (total)
The production of wet granulation material
The GH of sieving, 100%-4.066 (9.785) kg, the farina -5.970 of drying and screening
(3.561) kg, lactose -13.594 (9.839) kg of sieving, 5% gelatinized corn starch -4.480 (5.100) kg is weighed to production
Container GF-201,302.(KT1, TP-3.1)
The lactose of sieving, the farina of drying and screening, the GH of sieving are admitted to high-speed mixing granulating machine
In GHL-250GF-222 and mix 3-5 minutes.Then, add 5% gelatinized corn starch and mix 20-30 second, until production uniformly
Moist mass.Agglomerate, when being pressed in hand, it should be easy to aggregation, and should be disintegrated (KT-2, TP-3.1) in touch
Wet agglomerate is collected in production containers GF-201,302 and is sent to drying steps TP-3.2.
Dry and non-slurry pelletizing
Done in drying and granulating machine SG-30M SSH-219 in FL-60 fluosolids GF-337 at a temperature of 55 ± 5 DEG C
The mixture of eliminating dampness 40-60 minutes, until residual moisture content is 2.0-3.0%.Surveyed using Sai Duolisi moisture analysers
Determine before moisture, in order to which the sample for obtaining the agglomerate that the purpose more accurately measured is dried will be granulated.
Dry mixture is discharged into production containers GF-201, GF-302 and by the drum with 1.0-1.5 millimeters
The general granulator GR-1GF-218 (2) of bore dia, GF-332 (2), and collect in production containers (KT-3；TP-3.2 in).
Dry granulation material is sent to the step of production is used to encapsulate TP-4.1 mixture.
Encapsulating
Encapsulating is in MG compression capsule fillers devices GF-237, capsule fillers device NJP-800C GF-338 and capsule fillers device
Carried out in SF-100N GF-.
Mixture for encapsulating is admitted in the hopper 1 of capsule fillers device, and solid gelatinous capsule is admitted in hopper 2,
Then encapsulating is started.When the two hoppers are empty, the mixture for encapsulating is automatically added.
The purpose of the present invention is the scope for expanding the medicament for showing virus tropism and immunogenic activity.
This purpose is to realize that it shows virus tropism by the new pharmaceutical composition in solid pharmaceutical preparation
And immunogenic activity, it is characterised in that it include as active material up to 94 weight % amount GH and
Constitute the adjuvant of remainder.According to most preferred embodiment, GH content may range from from 80 to 94 weights
Measure %.This preparation may include the lactose monohydrate, microcrystalline cellulose, Ac-Di-Sol as adjuvant, colloidal state two
Silica (Aerosil 300) and calcium stearate.There is no this high content of open active material in state of the art.
Show that the new pharmaceutical composition of virus tropism and immunogenic activity tablet form is characterised by, it
It is fine including the GH as active material and the lactose monohydrate as adjuvant, microcrystalline cellulose, cross-linked carboxymethyl
The plain sodium of dimension, colloidal silica (Aerosil 300) and calcium stearate, the composition has following contents, with weight percent
Number meter：
In order to further improve the stability of said composition, active material is dried to the moisture no more than 1.5% first
Content.
Preferred embodiment of the present invention
Embodiment A. compositions
Active material：
GH 30.00mg
Adjuvant：
Embodiment B. compositions
Active material：
GH 100.00mg
Adjuvant：
The value of pharmacokinetic parameter does not show any substantive deviation during studying.
Elimination rate constant is 0.22 ± 0.004.
Absorption rate constant is 1.695 ± 0.028.
The time (Tmax, hour) for reaching Cmax is 1.3 ± 0.1.
Cmax (Cmax, μ g/mL) is 70.3 ± 2.0
The research of the preparation of embodiment 3.
3.1. toxicologic study (table 5,6)
Toxicologic study result
According to acute and chronic toxicity data, GH composition is referred to alternatively as the preparation of relative harmless.
1. composition does not show cause allergy and mutagenesis property.
2. GH composition does not show genotoxicity.
3. the composition in the dosage (0.05,0.5,5.0mg/kg GH) of all researchs does not show cause
Cancer activity, it is shown under the experiment condition of 24 months.
Table 5.
Table 6.
3.2. the efficiency for the GH composition tested in vitro and in vivo on the agent of A- influenzas and adenovirus is studied.
Material and method：
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 cultures of GMK-AH-1 of-green monkey kidney cell, MDCK dog kidneys；
- PS-4 grows semisynthetic medium.
Llowing group of materials is used for In vivo study：
- the outbred mice with 15g weight, is obtained by the VTs NIIM in Moscow, Russia area vivarium.
Intranasal infection is carried out to laboratory animal.
During studying, in vitro in 0.1 infective dose of the cell of cytopathic doses 50/, passed after individual layer is being infected
When passing 2 hours, concentration effectively suppresses the breeding (strain of influenza virus A for 100-200 μ g/mL GH composition
A/Aichi/2/68(H3N2)иА/hen/Kurgan/Russia/2/05(H5N1))。
During studying, in vivo using the GH composition of 5mg/kg dosage as with A types influenza (H3N2 and
H5N1) relevant preventive medicine is effective.
The prophylactic efficiency of GH composition is slightly worse compared with Tamiflu (Tamiflu).
When being used according to urgent prevention system and being used to treat, GH composition is poor compared with Tamiflu
's.It is 15mg/kg according to the optimal dose of the GH composition of the system.
3.3. the research of the interferon-induced and immunoregulatory activity of GH composition：
- preparation and dosage：GH composition, is administered orally；
- it is used for the material of research：15 healthy rats take the blood sample before and after said preparation；
Material and method：
Take preparation after 2,4,6,8,12,24,48 hours monitoring IFN- state indices.
3.3.1. the result of study of the interferon-induced and immunoregulatory activity of GH composition：
Single 73.3% increase being administered orally by the contributor within the upper limit of physiology normality in 24-48 hours
Interference cellulose content；
Relatively low α-IFN the lifes for the leucocyte that said composition is stimulated and is standardized in actually healthy animal in 24 hours
Production capacity power；
GH composition, which is administered alone, stimulates γ-IFN production.
Therefore, new composition has shown that the high effect of pharmacological activity, and can be recommended introducing clinical practice
In.
Industrial applicibility
Present invention can apply to medical science, chemical pharmacy industrial circle, i.e., show virus tropism and immunogene for producing
Property activity medicament, and be related to new GH composition and its manufacture method.
Claims (4)
1. a kind of pharmaceutical composition for showing virus tropism and immunogenic activity solid pharmaceutical preparation, it is characterised in that its
Including：It is fine as the lactose monohydrate, microcrystalline cellulose, cross-linked carboxymethyl of adjuvant as the GH of active material
The plain sodium of dimension, colloidal silica and calcium stearate, these compositions have following content by weight percentage：
2. pharmaceutical composition according to claim 1, it is characterised in that the active material is dried to moisture and contained first
Amount is not more than 1.5%.
3. pharmaceutical composition according to claim 1, it is characterised in that the pharmaceutical composition of the GH is with glue
The form of capsule is used.
4. a kind of method for being used to manufacture the pharmaceutical composition according to any one of claim 1-2, it is characterised in that will
The sieving powder of microcrystalline cellulose is thoroughly mixed 1-2 minutes；Add the sieving powder of GH and the water of lactose one of sieving
Compound, and obtained mixture is thoroughly mixed 5-7 minutes；Then the sieving powder of Ac-Di-Sol is added, and
And by obtained mixture mixing 3-5 minutes；Add the sieving powder of colloidal silica and calcium stearate, and will obtain
Mixture is remixed 2-4 minutes；And resulting mixture by direct pressing is pressed into tablet.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2014101563/15A RU2546002C1 (en) | 2014-01-20 | 2014-01-20 | Pharmaceutical composition in form of tablet and method of obtaining thereof |
| RU2014101563 | 2014-01-20 | ||
| PCT/RU2014/000164 WO2015108440A1 (en) | 2014-01-20 | 2014-03-14 | Tablet-formed pharmaceutical composition and preparation method thereof |
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| CN105307650B true CN105307650B (en) | 2017-10-20 |
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| CN (1) | CN105307650B (en) |
| HK (1) | HK1214767A1 (en) |
| RU (1) | RU2546002C1 (en) |
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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 |
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| RU2141483C1 (en) * | 1997-07-04 | 1999-11-20 | Небольсин Владимир Евгеньевич | Peptide derivatives or their pharmaceutically acceptable salts, method of their synthesis, use and pharmaceutical composition |
| CA2662956A1 (en) * | 2006-09-16 | 2008-03-20 | Bayer Schering Pharma Aktiengesellschaft | Oral modified release formulations |
| RU2373934C1 (en) * | 2008-03-19 | 2009-11-27 | Общество С Ограниченной Ответственностью "Фарминтерпрайсез" | Application of glutaric acid derivatives or their pharmaceutically acceptable salts as antiarrhythmic drug |
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| SG11201505385VA (en) | 2015-08-28 |
| WO2015108440A1 (en) | 2015-07-23 |
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