CN104840436B - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
- Publication number
- CN104840436B CN104840436B CN201510320016.5A CN201510320016A CN104840436B CN 104840436 B CN104840436 B CN 104840436B CN 201510320016 A CN201510320016 A CN 201510320016A CN 104840436 B CN104840436 B CN 104840436B
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- China
- Prior art keywords
- terazosin
- injection
- pharmaceutical composition
- freeze
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 76
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 claims abstract description 144
- 229960001693 terazosin Drugs 0.000 claims abstract description 138
- 238000000034 method Methods 0.000 claims abstract description 72
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 46
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 30
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 28
- 229930195725 Mannitol Natural products 0.000 claims abstract description 28
- 239000000594 mannitol Substances 0.000 claims abstract description 28
- 235000010355 mannitol Nutrition 0.000 claims abstract description 28
- 108010010803 Gelatin Proteins 0.000 claims abstract description 23
- 229920000159 gelatin Polymers 0.000 claims abstract description 23
- 239000008273 gelatin Substances 0.000 claims abstract description 23
- 235000019322 gelatine Nutrition 0.000 claims abstract description 23
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 23
- -1 sorbierite Chemical compound 0.000 claims abstract description 19
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 15
- 239000004471 Glycine Substances 0.000 claims abstract description 15
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 15
- 239000008101 lactose Substances 0.000 claims abstract description 15
- 238000002347 injection Methods 0.000 claims description 103
- 239000007924 injection Substances 0.000 claims description 103
- 238000004108 freeze drying Methods 0.000 claims description 83
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 75
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 66
- 238000001914 filtration Methods 0.000 claims description 60
- 239000000243 solution Substances 0.000 claims description 59
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 38
- 239000000843 powder Substances 0.000 claims description 36
- 239000008215 water for injection Substances 0.000 claims description 36
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 33
- 239000003607 modifier Substances 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 29
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 26
- 239000012535 impurity Substances 0.000 claims description 23
- 239000004695 Polyether sulfone Substances 0.000 claims description 19
- 229920006393 polyether sulfone Polymers 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 17
- 230000000694 effects Effects 0.000 claims description 14
- 238000005262 decarbonization Methods 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- 238000005261 decarburization Methods 0.000 claims description 10
- 238000011049 filling Methods 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- 239000003292 glue Substances 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 239000008240 homogeneous mixture Substances 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 abstract description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 8
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 abstract description 8
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 abstract description 8
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 abstract description 8
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 abstract description 8
- 239000008103 glucose Substances 0.000 abstract description 8
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000811 xylitol Substances 0.000 abstract description 8
- 235000010447 xylitol Nutrition 0.000 abstract description 8
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 abstract description 8
- 229960002675 xylitol Drugs 0.000 abstract description 8
- 108010009736 Protein Hydrolysates Proteins 0.000 abstract description 6
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 abstract description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 abstract description 4
- 244000144730 Amygdalus persica Species 0.000 abstract description 4
- 241000416162 Astragalus gummifer Species 0.000 abstract description 4
- 229920001353 Dextrin Polymers 0.000 abstract description 4
- 239000004375 Dextrin Substances 0.000 abstract description 4
- 229920002907 Guar gum Polymers 0.000 abstract description 4
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- 229920002125 Sokalan® Polymers 0.000 abstract description 4
- 229920001615 Tragacanth Polymers 0.000 abstract description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 abstract description 4
- 229940072056 alginate Drugs 0.000 abstract description 4
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- 239000001768 carboxy methyl cellulose Substances 0.000 abstract description 4
- 235000019425 dextrin Nutrition 0.000 abstract description 4
- 235000010417 guar gum Nutrition 0.000 abstract description 4
- 239000000665 guar gum Substances 0.000 abstract description 4
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- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 abstract description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 abstract description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 abstract description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 abstract description 4
- 239000001814 pectin Substances 0.000 abstract description 4
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 14
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- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The present invention relates to a kind of pharmaceutical composition, including：Terazosin, excipient, the excipient are selected from：Mannitol, lactose, sorbierite, xylitol, glucose, maltose, glycine, soluble dextrins, xanthans, gelatin, gelatin hydrolysate, Arabic gum, pectin, guar gum, peach gum, tragacanth, acacin, sodium carboxymethylcellulose, polyvinylpyrrolidone, carbomer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, alginate or its combination；The weight ratio of the Terazosin and excipient is 1：10~1000.The invention further relates to the method for preparing described pharmaceutical composition.Pharmaceutical composition of the present invention has excellent properties as used in the description.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a based composition, more particularly to the combination of a kind of injectable administration
Thing.
Background technology
Terazosin (Terazosin) is generally used for clinic with its hydrochloride, and the specification for having listed tablet or capsule has
1mg, 2mg and 5mg etc..Terazosin Hydrochloride can be used for treating benign prostate hyperplasia, it can also be used to hypertension is treated, can be single
Solely use or shared with other drugs for hypertension such as diuretics or Alpha 1 adrenergic blocking agent.For existing clinical suitable
Disease is answered, the daily dose usual range that Terazosin is used to be grown up is 1~10mg.Terazosin is used to treat benign prostatic hyperplasis
(BPH), benign prostate hyperplasia shape mitigates after medication and uroflow speed improves and the α 1- adrenaline in neck of urinary bladder and prostate
Smooth muscle relaxation caused by energy receptor blocking is relevant.Because there is relatively little of alpha 1 adrenergic receptor in body of urinary bladder, because
This Terazosin can mitigate contraction of the obstruction of bladder outlet without influenceing bladder.In addition, Terazosin is total outer by reducing
All vascular resistences are so that blood pressure reduces.Vasodilation, the blood pressure reduction effect of Terazosin seem mainly by α 1- adrenal gland
Caused by plain energy receptor blocking.
Entitled (4- (4- amino -6,7- dimethoxyquinazoline -2- bases) piperazine -1- bases) (the tetrahydrochysene furan of Terazosin chemistry
Mutter -2- bases) ketone, molecular formula C19H25N5O4, chemical structural formula is with following formula I：
Existing Terazosin or its pharmaceutical salts are clinically mainly presented with oral dosage form, such as tablet, capsule
Agent etc..But when being treated for acute disease, these oral formulations can not meet clinical demand, typically injection system
Agent is beneficial.
Therefore, the medicine for having the Terazosin used available for acute illness treatment and the like is still expected in this area
Composition.
The content of the invention
It is an object of the invention to provide a kind of available for the acute illness Terazosin that uses for the treatment of or its pharmaceutical salts
Pharmaceutical composition, and expect that gratifying pharmaceutical characteristic is presented in this pharmaceutical composition.The present invention is unexpected
It was found that the pharmaceutical composition with feature of present invention uses as pharmaceutical preparation can obtain technology effect as described in the present invention
Fruit.The present invention is accomplished based on this discovery.
Therefore, first aspect present invention provides a kind of pharmaceutical composition, including：Terazosin, excipient.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the Terazosin can also be it
Pharmaceutical salts or its solvate such as hydrate.
In the present invention, when referring to Terazosin, it not only includes the compound shown in above structure, in addition to above-mentioned
The pharmaceutically acceptable salt (such as hydrochloride) of structural compounds, and the solvate of said structure compound and its salt is for example
Hydrate.In a preferred embodiment of the invention, the Terazosin refers to Terazosin Hydrochloride dihydrate.This hair
Bright use below has carried out numerous studies to show that the present invention is unexpected as the Terazosin of compound of formula I typical case
Effect；Test in particularly biological test, be such as not indicated otherwise below, reagent Terazosin used refers to that hydrochloric acid is special and drawn
Azoles piperazine dihydrate.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the Terazosin is Terazosin
Hydrochloride.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, drawn wherein the Terazosin is that hydrochloric acid is special
Azoles piperazine dihydrate.In testing below, such as it is not indicated otherwise, reagent Terazosin used refers to the water of Terazosin Hydrochloride two
Compound.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the excipient is selected from：Mannitol,
Lactose, sorbierite, xylitol, glucose, maltose, glycine, soluble dextrins, xanthans, gelatin, gelatin hydrolysate, I
Primary glue, pectin, guar gum, peach gum, tragacanth, acacin, sodium carboxymethylcellulose, polyvinylpyrrolidone, carbomer, hydroxyl
Propyl cellulose, hydroxypropyl methyl cellulose, alginate or its combination.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the Terazosin and excipient
Weight ratio is 1：10~1000.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the Terazosin and excipient
Weight ratio is 1：20~750.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the Terazosin and excipient
Weight ratio is 1：25~500.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the excipient is selected from：Mannitol,
Lactose, sorbierite, xylitol, glucose, maltose, glycine.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the excipient is selected from：Mannitol,
Lactose, glycine.It has been unexpectedly discovered that when Terazosin combines with the particular excipient of specified quantitative, can be effective
The growth rate of the impurity relevant with Terazosin in ground composite inhibiting.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the excipient include gelatin or
Gelatin hydrolysate.It has been unexpectedly discovered that the preparation of addition gelatin or gelatin hydrolysate for composition is unfavorable.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is the composition of freeze-drying.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is freeze-drying available for injection
Powder-injection.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is freeze-drying available for injection
Powder-injection, the powder-injection are seal-packed with vial.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is freeze-drying available for injection
Powder-injection, the powder-injection are seal-packed with vial, and the amount of the Terazosin in every bottle is 0.1mg~5mg, such as every bottle
In the amount of Terazosin be 0.1mg~2.5mg.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the pharmaceutical composition is in air-proof condition
Under, within 40 DEG C of avoid light places time of 6 months, impurity A increment rate be less than 100%, especially less than 75%, it is more particularly small
In 50%.
Term " impurity A " is N- (4-Amino-6,7-dimethoxy-2-quinazolinyl) piperazine or is
6,7-dimethoxy-2- (piperazin-1-yl) quinazolin-4-amine, i.e., with the following formula: compound that R is H：
It is believed that the impurity A is caused by active component hydrolysis.Although pharmaceutical composition of the present invention is a kind of substantially anhydrous (logical
Chang Eryan moistures are less than freeze-dried preparation 5%), it has however been found that even in this substantially anhydrous drying shape
Under state, this impurity is still significantly had as the storage time of composition extends and increases.This is also current edition U.S. medicine
The original strictly monitored is given in allusion quotation (USP35), current edition British Pharmacopoeia (BP2013) and current edition European Pharmacopoeia (EP8.0)
Cause.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is packed by cillin bottle.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is packed by cillin bottle, and
It is in round pie in cillin bottle.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein moisture are less than 10%, preferably
Less than 8%, preferably shorter than 7%, more preferably less than 5%.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein also including acid-base modifier.One
In individual embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid
Potassium dihydrogen, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.In one embodiment, described soda acid is adjusted
Section agent is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
It is well known that freeze-drying powder-injection (the often referred to simply as freeze-dried powder obtained through cryogenic freezing-vacuum drying
Agent or freeze-dried powder), it is that each material is dissolved into (being dissolved with water) with solvent first, is configured to a solution, so
After make the solution carry out cryogenic freezing, then vacuumized, distilled, dry and obtain a kind of substantially anhydrous (typically water
Content is less than 8%, is especially generally lower than 7%, is especially generally lower than powdered thing or block 5%).Therefore, this is solid
The acid-base value of body lyophilized products is generally controlled by the pH value of process for preparation regulation solution；Or can by prescription adjust so that
The solid lyophilized products of acquisition control the pH value of the dissolving/dilution (referred to herein as to be controlled to control under defined dissolving/dilute strength
The acid-base value of solid lyophilized products processed)；Latter means generally more generally use, such as many freeze drying powder injections contained in pharmacopeia
The acid-base value of product is controlled in this way, and this mode controls the acid-base value of product generally can not concrete regulation soda acid tune
The recipe quantity of agent is saved, and only provides the acid-base value of finished product.The present invention is equally applicable to, according to first party of the present invention
Freeze drying powder injection described in any embodiment of face, wherein the amount of the optional acid-base modifier is to make the freeze-dried powder
The pH value of the solution is in the range of 3.0~5.0 when agent is dissolved into the solution of the concentration of 0.5mg/ml containing Terazosin with water for injection
Amount, such as amount of the pH value in the range of 3.5~4.5 of the solution.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein also including citric acid.In a reality
Apply in scheme, the weight ratio of Terazosin and citric acid is 1：1~10.In one embodiment, Terazosin and citric acid
Weight ratio be 1：2~5.It has been unexpectedly discovered that working as appropriate citron is added into freeze-dried manufactured composition
The weight ratio of acid particularly Terazosin and citric acid is 1：Can be valuably made during the citric acid of 2~5 amounts has superiority
The powder-injection of energy.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, it, which is substantially pressed, is included as follows
Prepared by step：
(a) Terazosin and excipient (and optional citric acid) of recipe quantity are weighed, appropriate water for injection is added, stirs
Mixing makes dissolving,
(b) activated carbon is added in rapid gained decoction one step up, stirred, filtering decarbonization；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH3.0~5.0, preferably pH3.5~4.5；
(d) it is filling in cillin bottle by decoction aseptic filtration；
(e) freeze-drying removes moisture, tamponade, produces.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, it is appropriate wherein described in step (a)
Water for injection is the water for injection of 60~70% amounts of prescription full dose.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, it is active wherein described in step (b)
The addition of charcoal is the amount that concentration of activated carbon reaches 0.05~0.15% in decoction.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, is wherein stirred described in step (b)
It is 10~20min of stirring and adsorbing, such as stirring and adsorbing 15min.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, is wherein filtered described in step (b)
Taking off the mode of charcoal is：With aperture be 1um stud decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, is wherein added described in step (c)
Water for injection to prescription full dose refers to add water for injection until activity component concentration is 0.1~5mg/ml (such as 0.2~2mg/
Ml amount).
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, it is degerming wherein described in step (d)
Filtering is to carry out aseptic filtration using 0.22um polyether sulfone filter core.
Further, second aspect of the present invention provides the method for making Terazosin stable, and this method includes making special drawing azoles
The step of pharmaceutical composition is made in piperazine and excipient, Terazosin forms homogeneous mixture with excipient in the pharmaceutical composition.
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition are the groups of freeze-drying
Compound.
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition be freeze-drying can
Powder-injection for injection.
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition be freeze-drying can
For the powder-injection of injection, the powder-injection is seal-packed with vial.
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition be freeze-drying can
For the powder-injection of injection, the powder-injection be it is seal-packed with vial, the amount of the Terazosin in every bottle for 0.1mg~
The amount of Terazosin in 5mg, such as every bottle is 0.1mg~2.5mg.
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition include：Spy draws azoles
Piperazine, excipient.
The method of any embodiment according to a second aspect of the present invention, wherein the Terazosin can also be its pharmaceutical salts
Or its solvate such as hydrate.
In the present invention, when referring to Terazosin, it not only includes the compound shown in above structure, in addition to above-mentioned
The pharmaceutically acceptable salt (such as hydrochloride) of structural compounds, and the solvate of said structure compound and its salt is for example
Hydrate.In a preferred embodiment of the invention, the Terazosin refers to Terazosin Hydrochloride dihydrate.This hair
Bright use below has carried out numerous studies to show that the present invention is unexpected as the Terazosin of compound of formula I typical case
Effect；Test in particularly biological test, be such as not indicated otherwise below, reagent Terazosin used refers to that hydrochloric acid is special and drawn
Azoles piperazine dihydrate.
The method of any embodiment according to a second aspect of the present invention, wherein the Terazosin is Terazosin hydrochloric acid
Salt.
The method of any embodiment according to a second aspect of the present invention, wherein the Terazosin is Terazosin Hydrochloride two
Hydrate.In testing below, such as it is not indicated otherwise, reagent Terazosin used refers to Terazosin Hydrochloride dihydrate.
The method of any embodiment according to a second aspect of the present invention, wherein the excipient is selected from：Mannitol, lactose,
Sorbierite, xylitol, glucose, maltose, glycine, soluble dextrins, xanthans, gelatin, gelatin hydrolysate, Arabic gum,
Pectin, guar gum, peach gum, tragacanth, acacin, sodium carboxymethylcellulose, polyvinylpyrrolidone, carbomer, hydroxypropyl
Cellulose, hydroxypropyl methyl cellulose, alginate or its combination.
The method of any embodiment according to a second aspect of the present invention, wherein the weight of the Terazosin and excipient ratio
For 1：10~1000.
The method of any embodiment according to a second aspect of the present invention, wherein the weight of the Terazosin and excipient ratio
For 1：20~750.
The method of any embodiment according to a second aspect of the present invention, wherein the weight of the Terazosin and excipient ratio
For 1：25~500.
The method of any embodiment according to a second aspect of the present invention, wherein the excipient is selected from：Mannitol, lactose,
Sorbierite, xylitol, glucose, maltose, glycine.
The method of any embodiment according to a second aspect of the present invention, wherein the excipient is selected from：Mannitol, lactose,
Glycine.It has been unexpectedly discovered that when Terazosin combines with the particular excipient of specified quantitative, can effectively suppress
The growth rate of the impurity relevant with Terazosin in composition.
The method of any embodiment according to a second aspect of the present invention, wherein the excipient does not include gelatin or hydrolysis is bright
Glue.It has been unexpectedly discovered that the preparation of addition gelatin or gelatin hydrolysate for composition is unfavorable.
The method of any embodiment according to a second aspect of the present invention, it causes the pharmaceutical composition under air-proof condition,
Within 40 DEG C of avoid light places time of 6 months, impurity A increment rate is less than 100%, especially less than 75%, more specifically less than
50%.
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition are sealed by cillin bottle
Packaging.
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition are sealed by cillin bottle
Packaging, and be in round pie in cillin bottle.
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition moisture are less than
10%, preferably shorter than 8%, preferably shorter than 7%, more preferably less than 5%.
Also include soda acid in the method for any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition to adjust
Save agent.In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, phosphoric acid hydrogen
Disodium, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.In one embodiment, it is described
Acid-base modifier be hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
It is well known that freeze-drying powder-injection (the often referred to simply as freeze-dried powder obtained through cryogenic freezing-vacuum drying
Agent or freeze-dried powder), it is that each material is dissolved into (being dissolved with water) with solvent first, is configured to a solution, so
After make the solution carry out cryogenic freezing, then vacuumized, distilled, dry and obtain a kind of substantially anhydrous (typically water
Content is less than 8%, is especially generally lower than 7%, is especially generally lower than powdered thing or block 5%).Therefore, this is solid
The acid-base value of body lyophilized products is generally controlled by the pH value of process for preparation regulation solution；Or can by prescription adjust so that
The solid lyophilized products of acquisition control the pH value of the dissolving/dilution (referred to herein as to be controlled to control under defined dissolving/dilute strength
The acid-base value of solid lyophilized products processed)；Latter means generally more generally use, such as many freeze drying powder injections contained in pharmacopeia
The acid-base value of product is controlled in this way, and this mode controls the acid-base value of product generally can not concrete regulation soda acid tune
The recipe quantity of agent is saved, and only provides the acid-base value of finished product.The present invention is equally applicable to, according to first party of the present invention
Freeze drying powder injection described in any embodiment of face, wherein the amount of the optional acid-base modifier is to make the freeze-dried powder
The pH value of the solution is in the range of 3.0~5.0 when agent is dissolved into the solution of the concentration of 0.5mg/ml containing Terazosin with water for injection
Amount, such as amount of the pH value in the range of 3.5~4.5 of the solution.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein also including citric acid.In a reality
Apply in scheme, the weight ratio of Terazosin and citric acid is 1：1~10.In one embodiment, Terazosin and citric acid
Weight ratio be 1：2~5.
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition are substantially by including
Prepared by the steps：
(a) Terazosin and excipient (and optional citric acid) of recipe quantity are weighed, appropriate water for injection is added, stirs
Mixing makes dissolving,
(b) activated carbon is added in rapid gained decoction one step up, stirred, filtering decarbonization；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH3.0~5.0, preferably pH3.5~4.5；
(d) it is filling in cillin bottle by decoction aseptic filtration；
(e) freeze-drying removes moisture, tamponade, produces.
The method of any embodiment according to a second aspect of the present invention, appropriate water for injection is wherein described in step (a)
The water for injection of 60~70% amounts of prescription full dose.
The method of any embodiment according to a second aspect of the present invention, the addition of activated carbon wherein described in step (b)
It is the amount that concentration of activated carbon reaches 0.05~0.15% in decoction.
The method of any embodiment according to a second aspect of the present invention, stirring is stirring and adsorbing wherein described in step (b)
10~20min, such as stirring and adsorbing 15min.
The method of any embodiment according to a second aspect of the present invention, the mode of filtering decarbonization wherein described in step (b)
It is：With aperture be 1um stud decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration.
The method of any embodiment according to a second aspect of the present invention, mend and inject water to wherein described in step (c)
Prescription full dose refers to add water for injection the amount until activity component concentration is 0.1~5mg/ml (such as 0.2~2mg/ml).
The method of any embodiment according to a second aspect of the present invention, aseptic filtration is to use wherein described in step (d)
0.22um polyether sulfone filter core carries out aseptic filtration.
The method of any embodiment according to a second aspect of the present invention, it also includes reduction described pharmaceutical composition and freezed
The processing step of spray bottle incidence in drying process.In one embodiment, the step is to composition together with excipients
Middle addition citric acid.In one embodiment, the weight of Terazosin and citric acid ratio is 1：1~10.In an embodiment party
In case, the weight ratio of Terazosin and citric acid is 1：2~5.
Further, third aspect present invention provides the method for preparing pharmaceutical composition, and the pharmaceutical composition includes：
Terazosin, excipient, the pharmaceutical composition are by made of freeze drying process.
The method of any embodiment according to a third aspect of the present invention, wherein the Terazosin can also be its pharmaceutical salts
Or its solvate such as hydrate.
In the present invention, when referring to Terazosin, it not only includes the compound shown in above structure, in addition to above-mentioned
The pharmaceutically acceptable salt (such as hydrochloride) of structural compounds, and the solvate of said structure compound and its salt is for example
Hydrate.In a preferred embodiment of the invention, the Terazosin refers to Terazosin Hydrochloride dihydrate.This hair
Bright use below has carried out numerous studies to show that the present invention is unexpected as the Terazosin of compound of formula I typical case
Effect；Test in particularly biological test, be such as not indicated otherwise below, reagent Terazosin used refers to that hydrochloric acid is special and drawn
Azoles piperazine dihydrate.
The method of any embodiment according to a third aspect of the present invention, wherein the Terazosin is Terazosin hydrochloric acid
Salt.
The method of any embodiment according to a third aspect of the present invention, wherein the Terazosin is Terazosin Hydrochloride two
Hydrate.In testing below, such as it is not indicated otherwise, reagent Terazosin used refers to Terazosin Hydrochloride dihydrate.
The method of any embodiment according to a third aspect of the present invention, wherein the excipient is selected from：Mannitol, lactose,
Sorbierite, xylitol, glucose, maltose, glycine, soluble dextrins, xanthans, gelatin, gelatin hydrolysate, Arabic gum,
Pectin, guar gum, peach gum, tragacanth, acacin, sodium carboxymethylcellulose, polyvinylpyrrolidone, carbomer, hydroxypropyl
Cellulose, hydroxypropyl methyl cellulose, alginate or its combination.
The method of any embodiment according to a third aspect of the present invention, wherein the weight of the Terazosin and excipient ratio
For 1：10~1000.
The method of any embodiment according to a third aspect of the present invention, wherein the weight of the Terazosin and excipient ratio
For 1：20~750.
The method of any embodiment according to a third aspect of the present invention, wherein the weight of the Terazosin and excipient ratio
For 1：25~500.
The method of any embodiment according to a third aspect of the present invention, wherein the excipient is selected from：Mannitol, lactose,
Sorbierite, xylitol, glucose, maltose, glycine.
The method of any embodiment according to a third aspect of the present invention, wherein the excipient is selected from：Mannitol, lactose,
Glycine.It has been unexpectedly discovered that when Terazosin combines with the particular excipient of specified quantitative, can effectively suppress
The growth rate of the impurity relevant with Terazosin in composition.
The method of any embodiment according to a third aspect of the present invention, wherein the excipient does not include gelatin or hydrolysis is bright
Glue.It has been unexpectedly discovered that the preparation of addition gelatin or gelatin hydrolysate for composition is unfavorable.
The method of any embodiment according to a third aspect of the present invention, wherein described pharmaceutical composition be freeze-drying can
Powder-injection for injection.
The method of any embodiment according to a third aspect of the present invention, wherein described pharmaceutical composition be freeze-drying can
For the powder-injection of injection, the powder-injection is seal-packed with vial.
The method of any embodiment according to a third aspect of the present invention, wherein described pharmaceutical composition be freeze-drying can
For the powder-injection of injection, the powder-injection be it is seal-packed with vial, the amount of the Terazosin in every bottle for 0.1mg~
The amount of Terazosin in 5mg, such as every bottle is 0.1mg~2.5mg.
The method of any embodiment according to a third aspect of the present invention, wherein described pharmaceutical composition under air-proof condition,
Within 40 DEG C of avoid light places time of 6 months, impurity A increment rate is less than 100%, especially less than 75%, more specifically less than
50%.
The method of any embodiment according to a third aspect of the present invention, wherein described pharmaceutical composition are by cillin bottle sealed bundle
Dress.
The method of any embodiment according to a third aspect of the present invention, wherein described pharmaceutical composition are by cillin bottle sealed bundle
Dress, and be in round pie in cillin bottle.
Moisture is less than in the method for any embodiment according to a third aspect of the present invention, wherein described pharmaceutical composition
10%, preferably shorter than 8%, preferably shorter than 7%, more preferably less than 5%.
Also include soda acid in the method for any embodiment according to a third aspect of the present invention, wherein described pharmaceutical composition to adjust
Save agent.In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, phosphoric acid hydrogen
Disodium, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.In one embodiment, it is described
Acid-base modifier be hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
It is well known that freeze-drying powder-injection (the often referred to simply as freeze-dried powder obtained through cryogenic freezing-vacuum drying
Agent or freeze-dried powder), it is that each material is dissolved into (being dissolved with water) with solvent first, is configured to a solution, so
After make the solution carry out cryogenic freezing, then vacuumized, distilled, dry and obtain a kind of substantially anhydrous (typically water
Content is less than 8%, is especially generally lower than 7%, is especially generally lower than powdered thing or block 5%).Therefore, this is solid
The acid-base value of body lyophilized products is generally controlled by the pH value of process for preparation regulation solution；Or can by prescription adjust so that
The solid lyophilized products of acquisition control the pH value of the dissolving/dilution (referred to herein as to be controlled to control under defined dissolving/dilute strength
The acid-base value of solid lyophilized products processed)；Latter means generally more generally use, such as many freeze drying powder injections contained in pharmacopeia
The acid-base value of product is controlled in this way, and this mode controls the acid-base value of product generally can not concrete regulation soda acid tune
The recipe quantity of agent is saved, and only provides the acid-base value of finished product.The present invention is equally applicable to, according to first party of the present invention
Freeze drying powder injection described in any embodiment of face, wherein the amount of the optional acid-base modifier is to make the freeze-dried powder
The pH value of the solution is in the range of 3.0~5.0 when agent is dissolved into the solution of the concentration of 0.5mg/ml containing Terazosin with water for injection
Amount, such as amount of the pH value in the range of 3.5~4.5 of the solution.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein also including citric acid.In a reality
Apply in scheme, the weight ratio of Terazosin and citric acid is 1：1~10.In one embodiment, Terazosin and citric acid
Weight ratio be 1：2~5.
The method of any embodiment according to a third aspect of the present invention, it consists essentially of following steps：
(a) Terazosin and excipient (and optional citric acid) of recipe quantity are weighed, appropriate water for injection is added, stirs
Mixing makes dissolving,
(b) activated carbon is added in rapid gained decoction one step up, stirred, filtering decarbonization；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH3.0~5.0, preferably pH3.5~4.5；
(d) it is filling in cillin bottle by decoction aseptic filtration；
(e) freeze-drying removes moisture, tamponade, produces.
The method of any embodiment according to a third aspect of the present invention, appropriate water for injection is wherein described in step (a)
The water for injection of 60~70% amounts of prescription full dose.
The method of any embodiment according to a third aspect of the present invention, the addition of activated carbon wherein described in step (b)
It is the amount that concentration of activated carbon reaches 0.05~0.15% in decoction.
The method of any embodiment according to a third aspect of the present invention, stirring is stirring and adsorbing wherein described in step (b)
10~20min, such as stirring and adsorbing 15min.
The method of any embodiment according to a third aspect of the present invention, the mode of filtering decarbonization wherein described in step (b)
It is：With aperture be 1um stud decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration.
The method of any embodiment according to a third aspect of the present invention, mend and inject water to wherein described in step (c)
Prescription full dose refers to add water for injection the amount until activity component concentration is 0.1~5mg/ml (such as 0.2~2mg/ml).
The method of any embodiment according to a third aspect of the present invention, aseptic filtration is to use wherein described in step (d)
0.22um polyether sulfone filter core carries out aseptic filtration.
In the step of above-mentioned preparation method of the invention, although the specific steps of its description are in some details or language
The step of described in preparation example in description with following detailed description part, is otherwise varied, however, people in the art
Member can summarize approach described above step completely according to the detailed disclosure of full text of the present invention.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not
Contradiction occurs.In addition, in any embodiment of either side of the present invention, any technical characteristic goes for other realities
The technical characteristic in scheme is applied, as long as they are not in contradiction.
The invention will be further described below.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary
When offering expressed implication and the inconsistent present invention, it is defined by the statement of the present invention.In addition, the various terms that use of the present invention and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention
The implication stated is defined.
It has been found that the pharmaceutical composition in freeze-drying powder-injection form that the inventive method is prepared has people
The advantages of expectation.Such as embody stability test in the following areas, redissolve time, spray bottle rate etc.：
Stability test：The all compositions that Examples below 1 is prepared to embodiment 12, it is placed at 40 DEG C and places 6
Month to carry out high-temperature treatment experiment；For each composition, American Pharmacopeia USP35 versions Terazosin piece of page 4787 is used
(http://www.drugfuture.com/Pharmacopoeia/usp35/data/v35300/
Usp35nf30s0m80842.html) it【Impurity】Method in detection, measure said composition is at 0 month and during in June
Relevant material be impurity A (relative to principal component) content, be calculated as follows impurity A content increase percentage (%, can letter
Referred to as " impurity A increment ")：
Above-mentioned to be all prepared in the composition use of powder form with a collection of bulk drug, whole powder-injection were at 0 month
When Impurity A content it is substantially suitable, in the range of 0.08~0.11%, but after above-mentioned high-temperature treatment, different samples
Visibly different impurity A situation of change is presented.Specifically：Embodiment 10 and the gained all compositions of embodiment 12 and implementation
The gained #111 to #114 of example 11 impurity A increment (%) is in the range of 114~235%, such as #121 and #122
Impurity A increment (%) is respectively 207% and 234%；All compositions and the gained #115 of embodiment 11 obtained by embodiment 1-9
To #119 impurity A increment (%) in the range of 17~32%, such as the impurity A increment (%) of the composition of embodiment 1
For 22%.It can be seen that compared with using insufficient amount of mannitol, or compared with the conventional freeze-dried excipient using other species,
Can assign composition excellent stability using present invention amount mannitol, lactose, glycine, particularly impurity A it is this it is believed that
For hydrolysis impurity, growth rate is inhibited during composition long-term storage.Even and insufficient amount of mannitol or same
The conventional freeze-dried excipient of class, but have unexpectedly shown that they can not assign this effect of composition.
Redissolve timing：The composition powder injection that each embodiment of text is prepared is removed, appropriate note is added in every bottle
The degree for making solid concentration reach 5% with water is penetrated, is stood, is calculated from the time added water to required for being completely dissolved.As a result：
The redissolution time of whole powder-injection and the gained #111 to #117 of embodiment 11 obtained by embodiment 1-9 is respectively less than 20 seconds,
In the range of 9~18 seconds；But the gained #118 to both #119 of the embodiment 11 redissolution time is respectively up to 132 seconds and 184 seconds, mistake
Substantial amounts of mannitol causes the powder-injection redissolution time significantly to extend, therefore for the dosage of mannitol, less than equal to 500 parts
It is beneficial (relative to 1 part of Terazosin).It is different with reference to formula/preparation method of embodiment 11 in other supplementary test
It is to use lactose or glycine instead, as a result similarly shows, lactose or glycine dosage is more than or equal to 1000 parts (relative to 1 part of spy
Draw azoles piperazine) powder-injection redissolve the time and be all higher than 110 seconds, the powder-injection less than or equal to 500 parts (relative to 1 part of Terazosin) is answered
The molten time is respectively less than 30 seconds；In addition, using the powder pin of lactose or glycine instead with reference to embodiment 11, carrying out placing June at 40 DEG C
When, similar to the acquired results of embodiment 11, amount of excipient is more than or equal to miscellaneous in the powder pin of 25 parts (relative to 1 part of Terazosin)
Matter A increments (%) increment is respectively less than 40%, and amount of excipient is less than or equal in the powder pin of 15 parts (relative to 1 part of Terazosin)
Impurity A increment (%) increment is all higher than 95%.
Hereafter in the whole embodiments of powder-injection are prepared, at least 500 bottles are freeze-dried when lyophilized per batch, and half
After the decoction freeze-drying jumped a queue, whether the powder pin of at least 250 bottles of observation has the problem of spray bottle, and counts spray bottle hair
Raw rate.It has been found that in the powder-injection of embodiment 1-8 whole batches, there is the spray bottle incidence that 2-5% is not waited, although middle kind
Incidence is not high and is only to influence powder pin outward appearance, but generally this phenomenon is that those skilled in the art expect to overcome
's；But the spray bottle composition incidence of the 9 batches of powder-injection of gained of embodiment 9 is but 0, in view of the freeze drying process and reality of embodiment 9
It is identical to apply a 1-3, therefore embodiment 1-8 spray bottle phenomenon is relevant with prescription, and the addition of micro citric acid can overcome
This phenomenon.
In the present invention, it is preferred to freeze drying powder injection composition of the present invention contain active component being made of water in every 1ml
It is that pH value determination method measure should further according to the method under Chinese Pharmacopoeia two annex VI H items of version in 2010 after 0.5mg solution
The acid-base value of freeze-dried powder.
The preparation process of freeze-drying powder-injection is lyophilized bent well known to a person skilled in the art pharmaceutical technology, such as follows
Two kinds of schematical freeze-drying curves shown in line A and freeze-drying curve B：
Prepare below in the instantiation in freeze-drying powder-injection, if not otherwise specified, lyophilized song used
Line is freeze-drying curve A.
Water content in freeze-drying powder-injection is preferably shorter than 7%, more preferably less than 5% typically below 8%.Water
Sub-control system can be controlled by suitably adjusting freeze-drying program.Moisture in the freeze-drying powder-injection can be according to many
Known method determines, such as dry weight-loss method.
In the present invention, for the pH value of regulating liquid medicine when necessary, appropriate pH regulations can be added into composition
Agent.Although the present inventor is only with the strong acid or strong base solution such as sodium hydrate aqueous solution and aqueous hydrochloric acid solution for not having buffer capacity
It is adjusted, if however, it will be appreciated by those skilled in the art that body can be met with this pH adjusting agent processing for not having buffer capacity
The pH requirements of system, then the pH adjusting agent with buffer capacity will be better able to realize the object of the invention, therefore these buffers are not
But pH value can be adjusted, and can stable pH value.Therefore any pH adjusting agent or its combination are included in this hair listed by the present invention
In bright spirit and scope.
When preparing freeze drying powder injection of the present invention, in the decoction prepared, solid content be for 1~20% (w/v), it is excellent
1~15% (w/v) is selected, even more preferably 1~10%.Because freeze drying powder injection is typically to be freeze-dried in tubulose cillin bottle
Obtain, skilled artisan understands that this product is obtaining finished product even before for doctor's use, be typically each presented one
Round pie, although lecture is fewer than the volume of original aqueous solution in the volume theory of the cake (slightly reducing), however it is generally this
Diminution will not generally narrow down to raw water liquor capacity 50%, it will usually between the 80-120% of raw water liquor capacity, more generally
Between the 90-100% of raw water liquor capacity, and raw water liquid level of solution vestige (main body can be observed out of finished product cillin bottle
Pie after lyophilized reduce because remaining in the liquid level vestige in bottle wall, even if the dried frozen aquatic products in cillin bottle for example touches because of a variety of causes
The reason such as hit in powdered, still can generally retain original liquid level vestige), vestige can also estimate the freezing and do accordingly
Aqueous solution volume of the dry composition before freeze-drying.Therefore, although the present invention is to provide a kind of substantially anhydrous freezing
Powder-injection is dried, but it still can be substantially estimated according to the powder-injection when preparing, at least in freeze-drying beginning
Preceding medicine liquid volume, the weight of the drying end-product in the volume estimated according to this and cillin bottle, can also calculate and make
During standby freeze drying powder injection of the present invention, the content of the solid content in the decoction prepared.Therefore, jelly according to a first aspect of the present invention
Dry powder injection, the solid content of its decoction when preparing be for 1~20% (w/v), preferably 1~15% (w/v), it is then more excellent
Select 1~10%.
In the present invention, symbol %, according to its used linguistic context, can have skilled addressee readily understands that
Implication.Such as when referring to solid content, the symbol represents the percentage (w/v, such as g/100ml) of weight/volume；Example again
Such as in " water content " in referring to freeze-drying powder-injection, such as water content, below 8%, now symbol % represents weight
The percentage (w/w, g/100g) of amount/weight.In general, when solid disperses in a liquid, % represents weight/volume percentage
Number；Scattered in solids or during liquid dispersion (such as water content of powder pin) in solids in solid, % represents w/w
Percentage.In other cases, unless otherwise noted, symbol % represents w/w percentage.
It is as well known to those skilled in the art when preparing the decoction of the present invention, e.g., from about 0.45um miillpore filter can be used
Coarse filtration filtering is carried out, before decoction is filled in cillin bottle, e.g., from about 0.22um miillpore filter can be used to carry out essence
Filtration filter is with degerming, it may be necessary to which filtering is multiple.
According to the freeze drying powder injection of the present invention, it is redissolved with water for injection, typically redissolves the time in 30 seconds, preferably
In 20 seconds, more preferably in 15 seconds.
According to the composition in freeze drying powder injection form of the present invention, it is made in every 1ml with water contains reactive compound
0.5mg solution simultaneously determines according to the method under Chinese Pharmacopoeia two annex VI H items of version in 2010, and the pH value of the solution is 3.0
~5.0.In one embodiment, pH value is 3.5~4.5.
Freeze drying powder injection provided by the invention can preserve at least 24 months below 25 DEG C at drying, can meet general
Freeze-drying powder-injection Storage Requirement.
Clinically, Terazosin Hydrochloride can be used for treating benign prostate hyperplasia.Terazosin Hydrochloride can also be used for controlling
Hypertension is treated, can be used alone or shared with other drugs for hypertension such as diuretics or beta-adrenergic blocking agent.
In terms of pharmacodynamics, benign prostatic hyperplasis (BPH)：The symptom relevant with BPH is related to Bladder outlet obstruction, and it includes
Two elements：Static part and dynamic part.Static part is the result of forefront hylperadenosis.It is preceding in a period of time
Row gland can constantly expand.However, clinical research shows, size and the seriousness of BPH symptoms or the journey of urethral obstruction of prostate
Spend unrelated.Dynamic part is prostate and the nervous increased function of bladder neck smooth muscle, causes the narrow of bladder outlet.Smooth muscle
Anxiety is the sympathetic stimulation effect mediation by alpha 1 adrenergic receptor, and this receptor is in prostate, prostatic utriculus and wing
It is abundant in Guang neck.Give symptom mitigation and uroflow speed after Terazosin improve with the α 1- kidneys in neck of urinary bladder and prostate
Smooth muscle relaxation caused by noradrenergic receptor blockade is relevant.Because have in body of urinary bladder relatively little of alpha 1 adrenergic by
Body, therefore Terazosin can mitigate contraction of the obstruction of bladder outlet without influenceing bladder.General function and disease to urination
Shape has carried out overall merit, and compared with the patient of blank treatment, the patient treated with Terazosin has obvious (p≤0.001) big
Overall improvement.In long term test, Terazosin makes symptom and uroflow speed maximum fraction all have clear improvement, and prompts special drawing azoles
Piperazine makes smooth muscle cell relaxation.Although alpha 1 adrenergic receptor is blocked also to reduce because of caused by peripheral vascular resistance increase
The blood pressure of hypertensive patient, but do not cause clinically significant blood when normotensive BPH male patients are treated with Terazosin
The low effect of pressure drop.
Hypertension：In animal, Terazosin is by reducing Total peripheral vascular resistance so that blood pressure reduces.Terazosin
Vasodilation, blood pressure reduction effect seem mainly to be blocked by alpha 1 adrenergic receptor it is caused.15 points upon administration
In clock, Terazosin makes blood pressure gradually reduce.With slight (about 77%, diastolic pressure 95-105mmHg) or moderate is (about
23%, diastolic pressure 105-115mmHg) hypertension patient, according to the accumulated dose of 5-20mg/ days, give once-or twice-a-day
Terazosin carries out clinical test.It is the same with all antagonists, because Terazosin can make blood first or after preceding administration several times
Dramatic decrease is pressed, therefore initial dose is 1mg, is then adjusted to a certain fixed dosage or is adjusted to a certain specific blood pressure terminal
(diastolic pressure of usual dorsal position is 90mmHg).(the usual 24 hours) end of term measured blood pressure between administration, as a result showed, decompression is made
With continue it is whole between the phase, generally, the systolic pressure of dorsal position reduces, the reduction big 3.5- of diastolic pressure bigger 5-10mmHg than blank
8mmHg.Measure within 24 hours after administration, heart rate does not change.Cause the amount of blood pressure response similar with prazosin, but be less than esodrix
Piperazine.Terazosin small dose group statistically significantly reduces T-CHOL, low-density and the VLDL of patient,
But HDL and triglycerides are not substantially changed.
Toxicity is carcinogenic, mutagenesis and genotoxicity aspect, Terazosin do not have mutagenesis.Also no evidence supports special draw
Azoles piperazine has carcinogenesis.Treat and the weight and form of testis are not had an impact.With 30 and dosage administration in 120mg/kg/ days, son
Smear sperm content compared with compareing smear in palace is reduced and the quantity of sperm has relatively good correlation with subsequent becoming pregnant.When
Rat is orally given with the dosage of 40 and 250mg/kg/ days (29 and 175 times people recommend maximum dose) 1 year or at 2 years, testis
The incidence of ball atrophy substantially increases, but 8mg/kg/ days (>People recommends 6 times of maximum dose) dosage when do not increase.In dog
Experiment in, 300mg/kg/ days (>People recommends 500 times of maximum dose) administration 3 months when also observed orchiatrophy, but
Dosage be 20mg/kg/ days (>People recommends 38 times of maximum dose) when orchiatrophy has been not observed.Period of pregnancy teratogenesis
Enough and good Comparative study is carried out not yet in pregnant woman and Terazosin period of pregnancy security not yet
It is determined that.Do not recommend to use Terazosin in period of pregnancy, unless proving that helpfulness is higher than the danger to puerpera and fetus.
In terms of pharmacokinetics, substantially completely absorbed after male patient's medication.Immediately after meals are taken medicine to degree of absorption
Influence it is minimum, but make plasma concentration peak time postpone about 40 minutes.The liver first-pass metabolism very little of Terazosin.After medication about
Reach within 1 hour peak value, half-life period is about 12 hours.Found in the age is to the research of Terazosin Pharmacokinetic effect, 70
Year and the patient at 20-39 year age, its plasma half-life is respectively 14.0 and 11.4 hours.Plasma protein binding rate is 90-
94%.About 40% discharges through homaluria, about 60% with excrement.
Embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited
In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention carries out general to the material and test method that are arrived used in experiment
And/or specific description.Although for realize many materials used in the object of the invention and operating method be it is known in the art that
But the present invention is still described in detail as far as possible herein.Following examples further illustrate the present invention, rather than limit this hair
It is bright.Any only formal rather than substantial equivalent transformation according to made by present inventive concept is regarded as the present invention
Technical scheme category.
It is use if not otherwise indicated, when preparing powder-injection with a batch of Terazosin raw material in following example
(for Terazosin Hydrochloride dihydrate, the present invention is each meant with free base medicine when being measured to it；After testing, it meets the U.S.
The quality standard of the pharmacopeia USP35 versions Terazosin Hydrochloride recorded (dihydrate) of page 4785).
In following example, the pH adjusting agent (in the present invention that is, acid-base modifier) that uses, unless otherwise noted,
1M sodium hydroxide solutions or 1M hydrochloric acid solutions, its dosage be when making to prepare powder-injection make to be prepared before freeze-drying it is molten
The pH value of liquid is adjusted to a certain setting or scope, and the setting or scope are that freeze-drying gained dry powder is diluted with water for injection
(it is less than this concentration as matched somebody with somebody in liquid, then without regulation, the context of the invention is similar to be located in into 0.5mg/ml containing active component
Reason) the solution value or scope of the pH value that are determined.Hereafter preparation process is for the purpose of citing, and based on the comparable of each citing
Made some specific description compared with property, those skilled in the art can therefrom summarize to obtain system of the present invention completely according to existing knowledge
The method of standby freeze drying powder injection.Below prepared with liquid in various compositions, if not otherwise indicated, every batch is always with liquid measure
1000 bottles of amount, but when listing formula, illustrated by every bottle of amount containing 1mg in terms of Terazosin.
Embodiment 1：Prepare Terazosin freeze-drying powder-injection
Formula：
Terazosin：1mg,
Mannitol：50mg,
Acid-base modifier：If necessary using in right amount, the setting in pH to following preparation method is adjusted,
Water for injection：To 1ml.
Preparation method：
(a) active component and solid adjuvant material of recipe quantity are weighed, appropriate (the 65% of prescription full dose) water for injection is added, stirs
Mixing makes dissolving,
(b) activated carbon (0.1%) is added in rapid gained decoction one step up, stirred (making absorption 15min), filtering decarbonization
(with aperture be 1um stud decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) with acid-base modifier adjust to pH4.0 (the present embodiment and whole embodiments of the present invention, this
Locating step (c), directly so far setting, freeze-dried obtained powder-injection are dissolved into containing Terazosin regulation pH value with water for injection
The pH value of the solution during solution of 0.5mg/ml concentration, it is identical that the value directly adjusts pH value with step (c))；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 3%), tamponade, produces.
In addition, by the regulation of every bottle of packing amount of liquid medicine, can be made the amount of the Terazosin in every bottle for 0.1mg~
The powder-injection of 2.5mg amounts.
Embodiment 2：Prepare Terazosin freeze-drying powder-injection
Formula：
Terazosin：1mg,
Mannitol：25mg,
Acid-base modifier：If necessary using in right amount, the setting in pH to following preparation method is adjusted,
Water for injection：To 2.5ml.
Preparation method：
(a) active component and solid adjuvant material of recipe quantity are weighed, appropriate (the 70% of prescription full dose) water for injection is added, stirs
Mixing makes dissolving,
(b) activated carbon (0.15%) is added in rapid gained decoction one step up, stirred (making absorption 10min), filtering decarbonization
(with aperture be 1um stud decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH4.5；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 4%), tamponade, produces.
Embodiment 3：Prepare Terazosin freeze-drying powder-injection
Formula：
Terazosin：1mg,
Mannitol：500mg,
Acid-base modifier：If necessary using in right amount, the setting in pH to following preparation method is adjusted,
Water for injection：To 5ml.
Preparation method：
(a) active component and solid adjuvant material of recipe quantity are weighed, appropriate (the 60% of prescription full dose) water for injection is added, stirs
Mixing makes dissolving,
(b) activated carbon (0.05%) is added in rapid gained decoction one step up, stirred (making absorption 20min), filtering decarbonization
(with aperture be 1um stud decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH3.5；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 5%), tamponade, produces.
Embodiment 4：Prepare Terazosin freeze-drying powder-injection
Formula：
Terazosin：1mg,
Mannitol：100mg,
Acid-base modifier：If necessary using in right amount, the setting in pH to following preparation method is adjusted,
Water for injection：To 2ml.
Preparation method：
(a) active component and solid adjuvant material of recipe quantity are weighed, appropriate (the 65% of prescription full dose) water for injection is added, stirs
Mixing makes dissolving,
(b) activated carbon (0.1%) is added in rapid gained decoction one step up, stirred (making absorption 15min), filtering decarbonization
(with aperture be 1um stud decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH3.0；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 3%), tamponade, produces.The present embodiment is bent using freeze-drying
Line B is freezed.
Embodiment 5：Prepare Terazosin freeze-drying powder-injection
Formula：
Terazosin：1mg,
Mannitol：250mg,
Acid-base modifier：If necessary using in right amount, the setting in pH to following preparation method is adjusted,
Water for injection：To 5ml.
Preparation method：
(a) active component and solid adjuvant material of recipe quantity are weighed, appropriate (the 65% of prescription full dose) water for injection is added, stirs
Mixing makes dissolving,
(b) activated carbon (0.1%) is added in rapid gained decoction one step up, stirred (making absorption 15min), filtering decarbonization
(with aperture be 1um stud decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.0；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 3%), tamponade, produces.
Embodiment 6：Prepare Terazosin freeze-drying powder-injection
Formula：
Terazosin：1mg,
Mannitol：25mg,
Acid-base modifier：If necessary using in right amount, the setting in pH to following preparation method is adjusted,
Water for injection：To 0.5ml.
Preparation method：
(a) active component and solid adjuvant material of recipe quantity are weighed, appropriate (the 65% of prescription full dose) water for injection is added, stirs
Mixing makes dissolving,
(b) activated carbon (0.1%) is added in rapid gained decoction one step up, stirred (making absorption 15min), filtering decarbonization
(with aperture be 1um stud decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH4.0；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 3%), tamponade, produces.
Embodiment 7：Prepare Terazosin freeze-drying powder-injection
Embodiment 1-3 formula and preparation method is respectively referred to, different is only the breast that mannitol therein is replaced with to equivalent
Sugar, obtain three batches of powder-injection and be designated as #71, #72, #73 respectively.
Embodiment 8：Prepare Terazosin freeze-drying powder-injection
Embodiment 1-3 formula and preparation method is respectively referred to, different is only that mannitol therein is replaced with into the sweet of equivalent
Propylhomoserin, obtain three batches of powder-injection and be designated as #81, #82, #83 respectively.
Embodiment 9：Prepare Terazosin freeze-drying powder-injection
Embodiment 1-3 formula and preparation method is respectively referred to, different is only to add citron again together with mannitol thereto
Sour (its amount is 3.5 times of Terazosin), obtains three batches of powder-injection and is designated as #91, #92, #93 respectively；Respectively refer to embodiment 1-3
Formula and preparation method, different is only to add citric acid (its amount is 2 times of Terazosin) again thereto, obtains three batches of powder-injection
#94, #95, #96 are designated as respectively；Embodiment 1-3 formula and preparation method is respectively referred to, different is only to add citron again thereto
Sour (its amount is 5 times of Terazosin), obtains three batches of powder-injection and is designated as #97, #98, #99 respectively.
Embodiment 10：Prepare Terazosin freeze-drying powder-injection
The formula and preparation method of embodiment 1 are respectively referred to, different is only the sorb that mannitol therein is replaced with to equivalent
Alcohol, xylitol, glucose or maltose, obtain four batches of powder-injection and be designated as #101, #102, #103, #104 respectively.
Embodiment 11：Prepare Terazosin freeze-drying powder-injection
The formula and preparation method of embodiment 1 are respectively referred to, different is only to be changed to the amount of mannitol therein：0mg、5mg、
(the suitably adjustment of rear four amount of water makes solid in decoction by 10mg, 15mg, 25mg, 100mg, 500mg, 1000mg or 2000mg
Thing concentration is 10%), to obtain four batches of powder-injection and be designated as #111, #112, #113, #114, #115, #116, #117, #118, # respectively
119。
Embodiment 12：Prepare Terazosin freeze-dried composition
2g Terazosin Hydrochlorides, 7.5g gelatin, 0.5g gelatin hydrolysates, 14g mannitol 350ml water are dissolved, by gained
Decoction is sub-packed in cillin bottle, every bottle of 2ml, is then placed in freeze drier and is freeze-dried by freeze-drying curve A of the present invention,
Obtain composition #121.
Add 200ml water to dissolve 2g Terazosin Hydrochlorides, form solution A；7.5g gelatin, 0.5g gelatin hydrolysates, 14g is sweet
Dew alcohol, 1.5g aspartames, 1.4g menthols, 0.1g NHDCs are dissolved in 100ml water, form solution B；Will
Solution A and solution B mixing, and add suitable quantity of water to be diluted to 350ml, it is sufficiently stirred.Gained decoction is sub-packed in cillin bottle, every bottle
2ml, it is then placed in freeze drier and is freeze-dried by freeze-drying curve A of the present invention, obtain composition #122.
Industrial applicability
The invention provides a kind of Terazosin freeze-drying powder-injection of the injectable with excellent properties, and should
The preparation method of Terazosin freeze-drying powder-injection.The Terazosin freeze dried powder for the injectable that the present invention is prepared
Injection has excellent physicochemical property.
Claims (13)
1. a kind of pharmaceutical composition, it is the composition of freeze-drying, including：Terazosin or its pharmaceutical salts or secondly water
Compound, excipient, citric acid；The excipient is selected from：The weight ratio of mannitol, lactose, glycine, Terazosin and excipient
For 1：25~500；The weight of Terazosin and citric acid ratio is 1：2~5；Do not include gelatin in the pharmaceutical composition or hydrolysis is bright
Glue.
2. pharmaceutical composition according to claim 1, it is the powder-injection that can be used for injection of freeze-drying.
3. pharmaceutical composition according to claim 1, it is the powder-injection that can be used for injection of freeze-drying, and the powder-injection is to use
Vial is seal-packed.
4. pharmaceutical composition according to claim 1, it is the powder-injection that can be used for injection of freeze-drying, and the powder-injection is to use
Vial is seal-packed, and the amount of the Terazosin in every bottle is 0.1mg ~ 5mg.
5. pharmaceutical composition according to claim 1, the amount of the Terazosin in every bottle is 0.1mg ~ 2.5mg.
6. pharmaceutical composition according to claim 1, the pharmaceutical composition under air-proof condition, in 40 °C of avoid light places 6 months
Time in, impurity A increment rate be less than 50%.
7. pharmaceutical composition according to claim 1, wherein moisture are less than 5%.
8. pharmaceutical composition according to claim 1, wherein also including acid-base modifier.
9. pharmaceutical composition according to claim 8, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, di(2-ethylhexyl)phosphate
Hydrogen sodium, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.
10. pharmaceutical composition according to claim 8, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution.
11. pharmaceutical composition according to claim 8, the amount of the optional acid-base modifier is to make the freeze drying powder injection
The pH value of the solution is in the range of 3.0 ~ 5.0 when being dissolved into the solution of the concentration of 0.5mg/ml containing Terazosin with water for injection
Amount.
12. pharmaceutical composition according to claim 1, it is prepared by including the steps：
(a) Terazosin and excipient and citric acid of recipe quantity are weighed, appropriate water for injection is added, is stirred to dissolve,
(b) activated carbon is added in rapid gained decoction one step up, stirred, filtering decarbonization；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component content,
Adjusted if necessary with acid-base modifier to pH3.5 ~ 4.5；
(d) it is filling in cillin bottle by decoction aseptic filtration；
(e) freeze-drying removes moisture, tamponade, produces；
Wherein：
Appropriate water for injection described in step (a) is the water for injection of 60 ~ 70% amounts of prescription full dose；
The addition of activated carbon described in step (b) is the amount that concentration of activated carbon reaches 0.05 ~ 0.15% in decoction；
Stirring is 10 ~ 20min of stirring and adsorbing described in step (b)；
The mode of filtering decarbonization described in step (b) is：After the stud decarburization for being 1um with aperture is filtered, then gathering with 0.45um
Ether sulfone filter core is by decoction coarse filtration；
Mended described in step (c) inject water to prescription full dose refer to add water for injection until activity component concentration be 0.1 ~
5mg/ml amount；
Aseptic filtration described in step (d) is to carry out aseptic filtration using 0.22um polyether sulfone filter core.
13. making the method that Terazosin is stable, the step of this method includes making Terazosin that pharmaceutical composition be made with excipient,
Terazosin forms homogeneous mixture with excipient in the pharmaceutical composition；Described pharmaceutical composition such as claim 1-12 is any
Described in.
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| CN201510320016.5A CN104840436B (en) | 2015-06-11 | 2015-06-11 | Pharmaceutical composition |
| PCT/CN2016/080459 WO2016197738A1 (en) | 2015-06-11 | 2016-04-28 | Pharmaceutical composition |
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| CN201510320016.5A CN104840436B (en) | 2015-06-11 | 2015-06-11 | Pharmaceutical composition |
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| CN104840436B true CN104840436B (en) | 2017-12-05 |
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| US11224572B1 (en) | 2020-08-17 | 2022-01-18 | Novitium Pharma LLC | Stable oral liquid composition of terazosin |
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|---|---|---|---|---|
| CN1148810A (en) * | 1994-05-18 | 1997-04-30 | 千寿制药株式会社 | Medicinal composition for treating glaucoma |
| CN1616091A (en) * | 2004-09-17 | 2005-05-18 | 武汉大学 | Compound protease medicine for treating prostate proliferation and its preparing method |
| CN101134023A (en) * | 2006-08-31 | 2008-03-05 | 海南海灵制药厂有限公司 | Hydrochloric acid terazosin oral cavity disintegrating lyophilized tablets and method for preparing the same |
| CN101780054A (en) * | 2009-01-16 | 2010-07-21 | 江苏联环药业股份有限公司 | Compound sustained-release preparation and preparation method thereof |
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| US20050058696A1 (en) * | 2003-09-12 | 2005-03-17 | Allergan, Inc. | Methods and compositions for the treatment of pain and other alpha 2 adrenergic-mediated conditions |
| CN1732959A (en) * | 2005-08-17 | 2006-02-15 | 王兰周 | Guamecycline hydrochoride injection and preparation process thereof |
| CN103976959B (en) * | 2013-02-07 | 2016-05-25 | 瑞阳制药有限公司 | Rifampin freeze-dried powder and preparation technology thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1148810A (en) * | 1994-05-18 | 1997-04-30 | 千寿制药株式会社 | Medicinal composition for treating glaucoma |
| CN1616091A (en) * | 2004-09-17 | 2005-05-18 | 武汉大学 | Compound protease medicine for treating prostate proliferation and its preparing method |
| CN101134023A (en) * | 2006-08-31 | 2008-03-05 | 海南海灵制药厂有限公司 | Hydrochloric acid terazosin oral cavity disintegrating lyophilized tablets and method for preparing the same |
| CN101780054A (en) * | 2009-01-16 | 2010-07-21 | 江苏联环药业股份有限公司 | Compound sustained-release preparation and preparation method thereof |
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