WO2016197738A1 - 药物组合物 - Google Patents

药物组合物 Download PDF

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Publication number
WO2016197738A1
WO2016197738A1 PCT/CN2016/080459 CN2016080459W WO2016197738A1 WO 2016197738 A1 WO2016197738 A1 WO 2016197738A1 CN 2016080459 W CN2016080459 W CN 2016080459W WO 2016197738 A1 WO2016197738 A1 WO 2016197738A1
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Prior art keywords
terazosin
injection
pharmaceutical composition
amount
acid
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PCT/CN2016/080459
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English (en)
French (fr)
Inventor
刘磊
官清华
Original Assignee
刘磊
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Publication of WO2016197738A1 publication Critical patent/WO2016197738A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—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

Definitions

  • the present invention is in the field of medical technology and relates to a class of compositions, particularly to a class of compositions for injectable administration.
  • Terazosin is usually used in clinical practice with its hydrochloride salt, and the specifications of the marketed tablets or capsules are 1 mg, 2 mg, and 5 mg.
  • Terazosin hydrochloride can be used to treat benign prostatic hyperplasia and can also be used to treat hypertension. It can be used alone or in combination with other antihypertensive drugs such as diuretics or alpha 1-adrenergic blockers.
  • the daily dose of terazosin for adults is usually in the range of 1 to 10 mg.
  • Terazosin is used to treat benign prostatic hyperplasia (BPH), and the reduction in benign prostatic hyperplasia and improvement in urinary flow rate after administration are associated with smooth muscle relaxation caused by alpha1-adrenergic receptor blockade in the bladder neck and prostate. Because there are relatively few alpha 1-adrenergic receptors in the bladder, terazosin can reduce blockage of the bladder outlet without affecting bladder contraction. In addition, terazosin lowers blood pressure by reducing total peripheral vascular resistance. The vasodilation and blood pressure lowering effects of terazosin appear to be mainly caused by blockade of ⁇ 1-adrenergic receptors.
  • terazosin (4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone
  • molecular formula is C 19 H 25 N 5 O 4
  • chemical structural formula is the following formula I:
  • the existing terazosin or a pharmaceutically acceptable salt thereof is mainly clinically presented in the form of an oral preparation such as a tablet, a capsule or the like.
  • an oral preparation such as a tablet, a capsule or the like.
  • these oral preparations do not meet clinical needs, and in general injection preparations are beneficial.
  • the present inventors have surprisingly found that a pharmaceutical composition having the features of the present invention can be used as a pharmaceutical preparation to obtain the technical effects as described in the present invention. The present invention has been completed based on this finding.
  • the first aspect of the present invention provides a pharmaceutical composition comprising: terazosin, an excipient.
  • terazosin when terazosin is mentioned, it includes not only the compound represented by the above structure but also a pharmaceutically acceptable salt (for example, hydrochloride) of the above structural compound, and the above structural compound and a salt thereof. Solvates such as hydrates.
  • the terazosin refers to terazosin hydrochloride dihydrate.
  • the present invention has been extensively studied using terazosin as a typical example of a compound of formula I to demonstrate the surprising effect of the present invention; in the following experiments, particularly biological tests, the test reagents used are not mentioned, unless otherwise indicated. Refers to terazosin hydrochloride dihydrate.
  • terazosin is terazosin hydrochloride dihydrate.
  • a pharmaceutical composition according to any one of the first aspects of the present invention wherein the excipient is selected from the group consisting of: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine, soluble dextrin, xanthan gum, Gelatin, hydrolyzed gelatin, gum arabic, pectin, guar gum, peach gum, tragacanth, acacia gum, sodium carboxymethylcellulose, polyvinylpyrrolidone, carbomer, hydroxypropylcellulose, hydroxypropylmethyl Cellulose, alginate, or a combination thereof.
  • the excipient is selected from the group consisting of: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine, soluble dextrin, xanthan gum, Gelatin, hydrolyzed gelatin, gum arabic, pectin, guar gum,
  • a pharmaceutical composition according to any one of the first aspects of the invention which is a freeze-dried composition.
  • a pharmaceutical composition according to any one of the first aspects of the invention which is a freeze-dried powder injection for injection.
  • a pharmaceutical composition according to any one of the first aspects of the present invention which is a freeze-dried powder injection for injection, which is hermetically sealed with a glass bottle.
  • a pharmaceutical composition according to any one of the first aspects of the present invention which is a freeze-dried powder injection for injection, which is sealed in a glass bottle, the amount of terazosin in each bottle being 0.1 From mg to 5 mg, for example, the amount of terazosin in each bottle is from 0.1 mg to 2.5 mg.
  • a pharmaceutical composition according to any one of the first aspects of the present invention wherein the pharmaceutical composition is sterilized at 40 ° C under sealed conditions During the 6-month period of light placement, the rate of increase of impurity A is less than 100%, especially less than 75%, more particularly less than 50%.
  • impurity A is N-(4-Amino-6,7-dimethoxy-2-quinazolinyl)piperazine or 6,7-dimethoxy-2-(piperazin-1-yl)quinazolin-4-amine, ie A compound of the formula R wherein H is H:
  • the impurity A is produced by hydrolysis of the active ingredient.
  • the pharmaceutical composition of the present invention is a lyophilized preparation which is substantially anhydrous (generally having a moisture content of less than 5%), it has been found that even in such a substantially anhydrous dry state, the impurities are still apparent. It will increase as the storage time of the composition increases. This is why the current USP (USP35), the current British Pharmacopoeia (BP2013) and the current European Pharmacopoeia (EP8.0) are strictly monitored.
  • a pharmaceutical composition according to any one of the first aspects of the invention which is hermetically sealed by a vial.
  • a pharmaceutical composition according to any one of the first aspects of the present invention which is hermetically sealed by a vial and is in the shape of a round cake in a vial.
  • a pharmaceutical composition according to any one of the first aspects of the present invention which further comprises an acid-base regulator.
  • the acid-base regulator is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid. Or a combination thereof.
  • the acid-base regulator is a hydrochloric acid solution or a sodium hydroxide solution, such as a 1 M hydrochloric acid solution or a 1 M sodium hydroxide solution.
  • freeze-dried powder injections (commonly referred to as freeze-dried powder injections or freeze-dried powder needles) obtained by low-temperature freeze-vacuum drying are first prepared by dissolving each material in a solvent (usually dissolved in water). a solution, which is then subjected to cryogenic freezing, followed by vacuuming, sublimation, and drying to obtain a substantially anhydrous (generally water content of less than 8%, especially usually less than 7%, especially usually less than 5%) powder or cake.
  • a solvent usually dissolved in water
  • the pH of the solid lyophilizate is typically controlled by adjusting the pH of the solution during the formulation process; or it can be adjusted by formulation to control the pH of the dissolution/diluent at a defined level of dissolution/dilution of the obtained solid lyophilizate.
  • the value is controlled (this is called controlling the pH of the solid lyophilizate); the latter method is usually more commonly used, for example, the lyophilized powder injections contained in the Pharmacopoeia control the pH of the product in this way, and this way controls
  • the pH of the product can usually not specify the amount of the acid-base regulator, but only the pH of the final product.
  • the lyophilized powder injection according to any one of the first aspect of the present invention, wherein the amount of the optional acid-base regulator is such that the lyophilized powder injection is for water for injection
  • the pH of the solution is in the range of 3.0 to 5.0, for example, the pH of the solution is in the range of 3.5 to 4.5.
  • a pharmaceutical composition according to any one of the first aspects of the present invention which further comprises citric acid.
  • the weight ratio of terazosin to citric acid is from 1:1 to 10. In one embodiment, the weight ratio of terazosin to citric acid is from 1:2 to 5. It has been surprisingly found that when a suitable amount of citric acid, in particular terazosin and citric acid, is added to the composition prepared by lyophilization A powder injection having excellent properties can be advantageously obtained in the case of a 1:2 to 5 amount of citric acid.
  • a lyophilized powder injection according to any one of the first aspects of the present invention which is prepared substantially as follows:
  • freeze-dried powder injection according to any one of the first aspect of the present invention, wherein the appropriate amount of water for injection in the step (a) is a prescribed amount of 60 to 70% by volume of water for injection.
  • the sulfone filter will filter the solution.
  • the freeze-dried powder injection according to any one of the first aspect of the present invention, wherein the supplemental water for injection to the total amount of the prescription in the step (c) means adding water for injection until the concentration of the active ingredient is 0.1 to 5 mg/ml (for example, 0.2) The amount of ⁇ 2 mg/ml).
  • a second aspect of the present invention provides a method for stabilizing terazosin, which comprises the step of preparing terazosin and an excipient into a pharmaceutical composition, and the composition of the drug is terazosin and The agent forms a homogeneous mixture.
  • the pharmaceutical composition is a freeze-dried powder injection for injection, the powder injection being sealed in a glass bottle, and the content of terazosin in each bottle
  • the amount is from 0.1 mg to 5 mg, for example, the amount of terazosin in each bottle is from 0.1 mg to 2.5 mg.
  • the pharmaceutical composition comprises: terazosin, an excipient.
  • terazosin is further a pharmaceutically acceptable salt thereof or a solvate thereof such as a hydrate.
  • terazosin when terazosin is mentioned, it includes not only the compound represented by the above structure but also the above structural compound.
  • a pharmaceutically acceptable salt for example, a hydrochloride
  • a solvate such as a hydrate of the above structural compound and a salt thereof.
  • the terazosin refers to terazosin hydrochloride dihydrate.
  • the present invention has been extensively studied using terazosin as a typical example of a compound of formula I to demonstrate the surprising effect of the present invention; in the following experiments, particularly biological tests, the test reagents used are not mentioned, unless otherwise indicated. Refers to terazosin hydrochloride dihydrate.
  • terazosin is terazosin hydrochloride dihydrate.
  • the excipient is selected from the group consisting of: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine, soluble dextrin, xanthan gum, gelatin, Hydrolyzed gelatin, gum arabic, pectin, guar gum, peach gum, tragacanth, acacia gum, sodium carboxymethylcellulose, polyvinylpyrrolidone, carbomer, hydroxypropylcellulose, hydroxypropylmethylcellulose , alginate, or a combination thereof.
  • the excipient is selected from the group consisting of: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine.
  • the excipient is selected from the group consisting of: mannitol, lactose, glycine. It has been surprisingly found that when terazosin is combined with a specific amount of a particular excipient, the rate of growth of terazosin-related impurities in the composition can be effectively inhibited.
  • a method according to any one of the second aspects of the present invention which allows the pharmaceutical composition to have an impurity A increase rate of less than 100%, particularly less than 75%, under sealed conditions at 40 ° C for 6 months in the dark. More specifically less than 50%.
  • the pharmaceutical composition has a moisture content of less than 10%, preferably less than 8%, preferably less than 7%, more preferably less than 5%.
  • the pharmaceutical composition further comprises an acid-base regulator.
  • the acid-base regulator is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid. Or a combination thereof.
  • the acid-base regulator is a hydrochloric acid solution or a sodium hydroxide solution, such as a 1 M hydrochloric acid solution or a 1 M sodium hydroxide solution.
  • freeze-dried powder injections (commonly referred to as freeze-dried powder injections or freeze-dried powder needles) obtained by low-temperature freeze-vacuum drying are first prepared by dissolving each material in a solvent (usually dissolved in water). Solution, then the solution is cryopreserved, a powder or lumps which are substantially anhydrous (generally having a water content of less than 8%, especially usually less than 7%, especially usually less than 5%), which is obtained by vacuuming, sublimation and drying. Things.
  • the pH of the solid lyophilizate is typically controlled by adjusting the pH of the solution during the formulation process; or it can be adjusted by formulation to control the pH of the dissolution/diluent at a defined level of dissolution/dilution of the obtained solid lyophilizate.
  • the value is controlled (this is called controlling the pH of the solid lyophilizate); the latter method is usually more commonly used, for example, the lyophilized powder injections contained in the Pharmacopoeia control the pH of the product in this way, and this way controls
  • the pH of the product can usually not specify the amount of the acid-base regulator, but only the pH of the final product.
  • the lyophilized powder injection according to any one of the first aspect of the present invention, wherein the amount of the optional acid-base regulator is such that the lyophilized powder injection is for water for injection
  • the pH of the solution is in the range of 3.0 to 5.0, for example, the pH of the solution is in the range of 3.5 to 4.5.
  • a pharmaceutical composition according to any one of the first aspects of the present invention which further comprises citric acid.
  • the weight ratio of terazosin to citric acid is from 1:1 to 10. In one embodiment, the weight ratio of terazosin to citric acid is from 1:2 to 5.
  • the appropriate amount of water for injection in the step (a) is a prescribed amount of 60 to 70% by volume of water for injection.
  • agitation in the step (b) is agitation adsorption for 10 to 20 minutes, for example, agitation adsorption for 15 minutes.
  • step of decarburizing in the step (b) is: decarburization filtration with a titanium rod having a pore size of 1 ⁇ m, and then using a 0.45 ⁇ m polyethersulfone filter element The crude liquid is filtered.
  • supplemental water for injection to the total amount of the prescription in the step (c) means adding water for injection until the concentration of the active ingredient is 0.1 to 5 mg/ml (for example, 0.2 to 2 mg/ The amount of ml).
  • the sterilizing filtration in the step (d) is sterilizing filtration using a 0.22 um polyethersulfone filter.
  • the method according to any of the embodiments of the second aspect of the invention further comprising the step of reducing the incidence of shot blasting of the pharmaceutical composition during the freeze drying process.
  • this step is the addition of citric acid to the composition with the excipient.
  • the weight ratio of terazosin to citric acid is from 1:1 to 10. In one embodiment, the weight ratio of terazosin to citric acid is 1:2 ⁇ 5.
  • a third aspect of the present invention provides a method of preparing a pharmaceutical composition comprising: terazosin, an excipient, which is produced by a freeze-drying process.
  • terazosin is further a pharmaceutically acceptable salt thereof or a solvate thereof such as a hydrate.
  • terazosin when terazosin is mentioned, it includes not only the compound represented by the above structure but also a pharmaceutically acceptable salt (for example, hydrochloride) of the above structural compound, and the above structural compound and a salt thereof. Solvates such as hydrates.
  • the terazosin refers to terazosin hydrochloride dihydrate.
  • the present invention has been extensively studied using terazosin as a typical example of a compound of formula I to demonstrate the surprising effect of the present invention; in the following experiments, particularly biological tests, the test reagents used are not mentioned, unless otherwise indicated. Refers to terazosin hydrochloride dihydrate.
  • terazosin is terazosin hydrochloride dihydrate.
  • the excipient is selected from the group consisting of: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine, soluble dextrin, xanthan gum, gelatin, Hydrolyzed gelatin, gum arabic, pectin, guar gum, peach gum, tragacanth, acacia gum, sodium carboxymethylcellulose, polyvinylpyrrolidone, carbomer, hydroxypropylcellulose, hydroxypropylmethylcellulose , alginate, or a combination thereof.
  • the excipient is selected from the group consisting of: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine.
  • the excipient is selected from the group consisting of: mannitol, lactose, glycine. It has been surprisingly found that when terazosin is combined with a specific amount of a particular excipient, the rate of growth of terazosin-related impurities in the composition can be effectively inhibited.
  • the pharmaceutical composition is a freeze-dried powder injection for injection, the powder injection being sealed in a glass bottle, and the content of terazosin in each bottle
  • the amount is from 0.1 mg to 5 mg, for example, the amount of terazosin in each bottle is from 0.1 mg to 2.5 mg.
  • the pharmaceutical composition has an increase rate of impurity A of less than 100%, particularly less than 75%, under a sealed condition at a temperature of 40 ° C for 6 months. More specifically less than 50%.
  • the pharmaceutical composition has a moisture content of less than 10%, preferably less than 8%, preferably less than 7%, more preferably less than 5%.
  • the pharmaceutical composition further comprises an acid-base regulator.
  • the acid-base regulator is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid. Or a combination thereof.
  • the acid-base regulator is a hydrochloric acid solution or a sodium hydroxide solution, such as a 1 M hydrochloric acid solution or a 1 M sodium hydroxide solution.
  • freeze-dried powder injections (commonly referred to as freeze-dried powder injections or freeze-dried powder needles) obtained by low-temperature freeze-vacuum drying are first prepared by dissolving each material in a solvent (usually dissolved in water). a solution, which is then subjected to cryogenic freezing, followed by vacuuming, sublimation, and drying to obtain a substantially anhydrous (generally water content of less than 8%, especially usually less than 7%, especially usually less than 5%) powder or cake.
  • a solvent usually dissolved in water
  • the pH of the solid lyophilizate is typically controlled by adjusting the pH of the solution during the formulation process; or it can be adjusted by formulation to control the pH of the dissolution/diluent at a defined level of dissolution/dilution of the obtained solid lyophilizate.
  • the value is controlled (this is called controlling the pH of the solid lyophilizate); the latter method is usually more commonly used, for example, the lyophilized powder injections contained in the Pharmacopoeia control the pH of the product in this way, and this way controls
  • the pH of the product can usually not specify the amount of the acid-base regulator, but only the pH of the final product.
  • the lyophilized powder injection according to any one of the first aspect of the present invention, wherein the amount of the optional acid-base regulator is such that the lyophilized powder injection is for water for injection
  • the pH of the solution is in the range of 3.0 to 5.0, for example, the pH of the solution is in the range of 3.5 to 4.5.
  • a pharmaceutical composition according to any one of the first aspects of the present invention which further comprises citric acid.
  • the weight ratio of terazosin to citric acid is from 1:1 to 10. In one embodiment, the weight ratio of terazosin to citric acid is from 1:2 to 5.
  • a method according to any of the embodiments of the third aspect of the invention which basically comprises the steps of:
  • the appropriate amount of water for injection in the step (a) is a prescribed amount of 60 to 70% by volume of water for injection.
  • the activated carbon in the step (b) is added in an amount of activated carbon in the liquid
  • the concentration is in an amount of 0.05 to 0.15%.
  • agitation in the step (b) is agitation adsorption for 10 to 20 minutes, for example, agitation adsorption for 15 minutes.
  • step of decarburizing in the step (b) is: decarburization filtration with a titanium rod having a pore diameter of 1 ⁇ m, and then using a 0.45 ⁇ m polyethersulfone filter element The crude liquid is filtered.
  • supplemental water for injection to the total amount of the prescription in the step (c) means supplemental water for injection until the concentration of the active ingredient is 0.1 to 5 mg/ml (for example, 0.2 to 2 mg/ The amount of ml).
  • the sterilizing filtration in the step (d) is sterilizing filtration using a 0.22 um polyethersulfone filter.
  • any of the embodiments of any of the aspects of the invention may be combined with other embodiments as long as they do not contradict each other.
  • any of the technical features may be applied to the technical features in other embodiments as long as they do not contradict each other.
  • compositions in the form of lyophilized powder injections prepared by the process of the invention have surprising advantages.
  • stability test, reconstitution time, spray rate, etc. are reflected in the following aspects:
  • compositions in the form of powder injections are prepared by using the same batch of raw materials.
  • the content of impurity A in all powder injections is basically equivalent in the range of 0.08 to 0.11% at 0 months, but after the above high temperature treatment, different samples are presented. Significantly different changes in impurity A.
  • Example 10 and Example 12 and the amounts of impurity A (%) of #111 to #114 obtained in Example 11 were in the range of 114 to 235%, for example, #121 and #
  • the impurity A increments (%) of 122 were 207% and 234%, respectively;
  • the total composition obtained in Examples 1-9 and the impurity A increments (%) of the #115 to #119 obtained in Example 11 were both 17 to 17 Within 32%, examples
  • the impurity A increment (%) as in the composition of Example 1 was 22%.
  • the use of the amount of the present invention, mannitol, lactose, glycine can impart excellent stability to the composition, particularly impurity A, as compared to the use of insufficient amounts of mannitol, or as compared to the use of other types of conventional lyophilized excipients. This is believed to be the inhibition of the growth rate of the hydrolyzed impurities during long-term storage of the composition. Insufficient amounts of mannitol or even conventional freeze-dried excipients of the same type unexpectedly show that they do not impart this effect to the composition.
  • Reconstitution time determination Take the powder injection of the composition prepared in each of the following examples, add appropriate amount of water for injection to each bottle to achieve a solid concentration of 5%, and let stand, calculate the time from water addition to complete dissolution. .
  • RESULTS All the powder injections obtained in Examples 1-9 and the reconstitution time of #111 to #117 obtained in Example 11 were all less than 20 seconds, both in the range of 9 to 18 seconds; however, #118## obtained in Example 11
  • the reconstitution time of 119 is 132 seconds and 184 seconds respectively.
  • the excessive amount of mannitol makes the re-dissolving time of the powder injection significantly prolonged. Therefore, the amount of mannitol is less than or equal to 500 parts (relative to 1 part of the total).
  • Laazosin is beneficial.
  • the re-dissolving time of the powder injection is more than 110 seconds, and the re-dissolving time of the powder injection of 500 parts or less (relative to 1 part of terazosin) is less than 30 seconds; in addition, the powder needle of lactose or glycine is changed to refer to Example 11, When placed at 40 ° C for 6 months, similar to the results obtained in Example 11, the amount of excipients was 25 or more (relative to 1 part of terazosin). Less than 40%, and the amount of excipients is less than or equal to 15 parts (relative to 1 part of terazosin).
  • At least 500 bottles are freeze-dried in each batch after lyophilization, and after the semi-plugged liquid is freeze-dried, it is observed whether at least 250 bottles of the powder needle have a problem of spray bottle. And statistics on the incidence of spray bottle.
  • the preferred freeze-dried powder composition of the present invention is prepared by using a solution containing 0.5 mg of the active ingredient per 1 ml of water, and then determining the pH according to the method of the Chinese Pharmacopoeia 2010 edition two appendix VI H. The pH of the lyophilized powder needle was determined by the method.
  • lyophilization curve A The preparation of the lyophilized powder injection is a pharmaceutical process well known to those skilled in the art, such as the two exemplary freeze-drying curves shown in lyophilization curve A and lyophilization curve B as follows:
  • the lyophilization curve used is the lyophilization curve A, unless otherwise specified.
  • the water content in the freeze-dried powder injection is generally below 8%, preferably below 7%, more preferably below 5%.
  • Moisture control can be controlled by appropriate adjustment of the freeze-drying procedure.
  • the moisture content of the freeze-dried powder injection can be determined according to a number of known methods, such as the dry weight loss method.
  • a suitable pH adjusting agent may be added to the composition.
  • a strong acid or strong alkali solution having no buffering ability such as aqueous sodium hydroxide solution and aqueous hydrochloric acid
  • pH-adjusting pH adjusters will be more capable of achieving the object of the present invention, so that these buffers can not only adjust the pH but also stabilize the pH.
  • any pH adjusting agent or combination thereof listed herein is included within the spirit and scope of the present invention.
  • the solid content of the prepared drug solution is 1 to 20% (w/v), preferably 1 to 15% (w/v), and still more preferably 1 to 10%.
  • lyophilized powder injections are usually obtained by lyophilization in tubular vials, those skilled in the art understand that such products generally exhibit a round cake shape even after obtaining the finished product, even before being used by a doctor, despite the volume theory of the wafer.
  • the above will be less than the original aqueous solution (slightly reduced), but usually this reduction will usually not shrink to 50% of the original aqueous solution volume, usually between 80-120% of the original aqueous solution volume, more usually in the original aqueous solution volume.
  • the freeze-dried product can also be estimated.
  • the volume of the aqueous solution of the dried composition prior to lyophilization it is still possible to estimate, based on the powder injection, the volume of the liquid at least prior to the start of freeze-drying, based on the estimate.
  • the volume and the weight of the dried end product in the vial can also be calculated as the solid content of the prepared liquid in the preparation of the lyophilized powder of the present invention. Therefore, the lyophilized powder injection according to the first aspect of the present invention has a solid content of the chemical solution at the time of preparation of 1 to 20% (w/v), preferably 1 to 15% (w/v), and more It is preferably 1 to 10%.
  • the symbol % may have a meaning that is easily understood by those skilled in the art.
  • the symbol indicates the weight/volume percentage (w/v, eg g/100 ml); and for example when referring to the "water content" in the freeze-dried powder injection, for example, the water content is 8 Below %, the symbol % indicates the weight/weight percentage (w/w, g/100g).
  • % means weight/volume percent; when the solid is dispersed in the solid or the liquid is dispersed in the solid (for example, the water content of the powder needle), % means weight/weight percentage.
  • the symbol % indicates weight/weight percentage unless otherwise stated.
  • a microporous membrane of about 0.45 um, for example, about 0.22 um can be used before filling the drug solution into a vial.
  • the microporous membrane is subjected to fine filtration to remove bacteria, and may be filtered as many times as necessary.
  • the lyophilized powder injection according to the present invention is reconstituted with water for injection, and usually the reconstitution time is within 30 seconds, preferably within 20 seconds, more preferably within 15 seconds.
  • a composition in the form of a lyophilized powder injection according to the present invention which is made into a solution containing 0.5 mg of the active compound per 1 ml of water and is determined according to the method of the Chinese Pharmacopoeia 2010 Edition, Part II, Appendix VI, the pH of the solution. It is 3.0 to 5.0. In one embodiment, the pH is between 3.5 and 4.5.
  • the lyophilized powder injection provided by the invention can be stored in a dry place below 25 ° C for at least 24 months, which can meet the storage requirements of the general freeze-dried powder injection.
  • terazosin hydrochloride can be used to treat benign prostatic hyperplasia. Terazosin hydrochloride is also indicated for the treatment of hypertension and can be used alone or in combination with other antihypertensive drugs such as diuretics or beta-adrenergic blockers.
  • BPH benign prostatic hyperplasia
  • the symptoms associated with BPH involve bladder outlet obstruction, which consists of two basic components: the static part and the dynamic part.
  • the static part is the result of an enlarged prostate.
  • the prostate will continue to expand over time.
  • the dynamic part is a function of increased tension in the smooth muscle of the prostate and bladder neck, leading to a narrowing of the bladder outlet. Smooth muscle tone is mediated by sympathetic stimulation of the alpha 1-adrenergic receptor, which is abundant in the prostate, prostatic sac and bladder neck.
  • terazosin Symptom relief and improvement in urinary flow rate after administration of terazosin are associated with smooth muscle relaxation caused by alpha1-adrenergic receptor blockade in the bladder neck and prostate. Because there are relatively few alpha 1-adrenergic receptors in the bladder, terazosin can reduce blockage of the bladder outlet without affecting bladder contraction. A comprehensive evaluation of the overall function and symptoms of urination was performed, and patients treated with terazosin had a significant (p ⁇ 0.001) overall improvement compared with patients treated with blank. In the long-term trial, terazosin significantly improved the maximum scores of symptoms and urine flow, suggesting that terazosin relaxes smooth muscle cells. Although blocking ⁇ 1-adrenergic receptors also reduced blood pressure in hypertensive patients due to increased peripheral vascular resistance, normal blood pressure in BPH male patients did not cause clinically significant blood pressure lowering effects when treated with terazosin.
  • terazosin lowers blood pressure by reducing total peripheral vascular resistance.
  • the vasodilation and blood pressure lowering effects of terazosin appear to be mainly caused by blockade of ⁇ 1-adrenergic receptors.
  • terazosin gradually lowered blood pressure.
  • the initial dose is 1 mg, then adjusted to a fixed dose or adjusted to a specific blood pressure endpoint (usually The diastolic pressure in the supine position is 90 mmHg). Blood pressure was measured at the end of the dosing period (usually 24 hours), and the results showed that the antihypertensive effect continued throughout the interval. Usually, the systolic blood pressure in the supine position was reduced by 5-10 mmHg larger than the blank, and the decrease in diastolic blood pressure was 3.5-8 mmHg. The heart rate was not measured 24 hours after administration.
  • the amount that causes a blood pressure response is similar to prazosin but lower than hydrochlorothiazide.
  • the small dose of terazosin statistically significantly reduced the patient's total cholesterol, low density, and very low density lipoprotein, but did not significantly change high density lipoproteins and triglycerides.
  • Terazosin has no mutagenic effects in terms of toxicology, carcinogenesis, mutagenicity and reproductive toxicity. There is also no evidence to support the carcinogenic effects of terazosin. Treatment has no effect on the weight and morphology of the testes. At doses of 30 and 120 mg/kg/day, the uterine smear had a reduced sperm content compared to the control smear and the number of sperm had a better correlation with subsequent conception.
  • testicular atrophy When administered orally to rats for one or two years at doses of 40 and 250 mg/kg/day (29 and 175 times the recommended maximum dose), the incidence of testicular atrophy increased significantly, but at 8 mg/kg/day (> The person recommended a maximum of 6 times the dose did not increase the dose. In the dog's experiment, testicular atrophy was also observed at 300 mg/kg/day (>500 times recommended for the maximum dose), but the dose was 20 mg/kg/day (> 38 times the recommended maximum dose) There was no observed testicular atrophy. Teratogenic effects during pregnancy have not been adequately and well-controlled in pregnant women and the safety of terazosin during pregnancy has not been established. The use of terazosin during pregnancy is not recommended unless it proves to be more beneficial than the risk to the mother and the fetus.
  • terazosin bulk drug which is terazosin hydrochloride dihydrate
  • the present invention refers to the free base in the measurement thereof. It has been tested to meet the quality standards for terazosin hydrochloride (dihydrate) contained in USP 35 USP 3575.
  • the pH adjusting agent used in the present invention, that is, the acid-base adjusting agent
  • the pH adjusting agent used is 1 M hydrogen hydroxide.
  • the sodium solution or the 1M hydrochloric acid solution is used in such a manner that when preparing the powder injection, the pH of the solution prepared before lyophilization is adjusted to a predetermined value or range, and the specified value or range is that the dry powder obtained by freeze-drying is diluted with water for injection.
  • a value or range of pH measured by a solution containing 0.5 mg/ml of the active ingredient if the formulation is below this concentration, the adjustment is not carried out, and the context of the invention is similarly treated).
  • Example 1 Preparation of terazosin freeze-dried powder injection
  • Acid-base regulator If necessary, use an appropriate amount to adjust the pH to the specified value in the following method.
  • step (c) supplement the water for injection to the full amount of the formulation, stir evenly, determine the pH of the solution and optionally determine the active ingredient content, if necessary (or optionally) with an acid-base conditioner to adjust to pH 4.0 (this example and In the whole embodiment of the present invention, step (c) directly adjusts the pH value to the specified value, and the pH value of the solution is obtained by dissolving the powder injection obtained by lyophilization into a solution containing terazosin 0.5 mg/ml in water for injection. , the value is the same as the step (c) directly adjusts the pH value);
  • Acid-base regulator If necessary, use an appropriate amount to adjust the pH to the specified value in the following method.
  • Acid-base regulator If necessary, use an appropriate amount to adjust the pH to the specified value in the following method.
  • Acid-base regulator If necessary, use an appropriate amount to adjust the pH to the specified value in the following method.
  • Acid-base regulator If necessary, use an appropriate amount to adjust the pH to the specified value in the following method.
  • Acid-base regulator If necessary, use an appropriate amount to adjust the pH to the specified value in the following method.
  • cinnamate is added together with mannitol (the amount is 3.5 times that of terazosin), and three batches of powder injections are respectively recorded as # 91, #92, #93; refer to the formulation and preparation method of the examples 1-3, respectively, different only To this is added citric acid (the amount is twice that of terazosin), and three batches of powder injections are respectively recorded as #94, #95, #96; respectively, the formulation and preparation method of Examples 1-3 are respectively referred to.
  • citric acid is added to it (the amount is 5 times that of terazosin), and three batches of powder injections are recorded as #97, #98, and #99, respectively.
  • Example 1 Refer to the formulation and preparation method of Example 1, respectively, except that the mannitol is replaced with an equivalent amount of sorbitol, xylitol, glucose, or maltose, and four batches of powder injections are respectively recorded as #101, #102. , #103, #104.
  • Example 1 Refer to the formulation and preparation method of Example 1, respectively, except that the amount of mannitol is changed to: 0 mg, 5 mg, 10 mg, 15 mg, 25 mg, 100 mg, 500 mg, 1000 mg, or 2000 mg (the amount of water added in the last four)
  • the concentration of the solid matter in the chemical solution was appropriately adjusted to 10%, and four batches of powder injections were designated as #111, #112, #113, #114, #115, #116, #117, #118, #119, respectively.
  • composition #121 2 g of terazosin hydrochloride, 7.5 g of gelatin, 0.5 g of hydrolyzed gelatin, 14 g of mannitol were dissolved in 350 ml of water, and the obtained drug solution was dispensed into a vial, 2 ml per bottle, and then placed in a freeze dryer according to the present invention. Lyophilization curve A was lyophilized to give composition #121.
  • solution A 2 g of terazosin hydrochloride plus 200 ml of water were dissolved to form solution A; 7.5 g of gelatin, 0.5 g of hydrolyzed gelatin, 14 g of mannitol, 1.5 g of aspartame, 1.4 g of menthol, 0.1 g of neohesperidin dihydrogen Chalcone is dissolved in 100 ml of water to form solution B; solution A and solution B are mixed, and diluted with an appropriate amount of water to 350 ml, and stirred well.
  • the obtained drug solution was dispensed into a vial, 2 ml per bottle, and then placed in a freeze dryer to freeze-dry according to the freeze-drying curve A of the present invention to obtain a composition #122.
  • the invention provides an injectable terazosin freeze-dried powder injection having excellent properties, and a preparation method of the terazosin freeze-dried powder injection.
  • the injectable terazosin freeze-dried powder injection prepared by the invention has excellent physical and chemical properties.

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Abstract

一种药物组合物以及制备方法。该药物组合物包括：特拉唑嗪、赋形剂，赋形剂选自：甘露醇、乳糖、山梨醇、木糖醇、葡萄糖、麦芽糖、甘氨酸、可溶性糊精、黄原胶、明胶、水解明胶、阿拉伯胶、果胶、瓜尔胶、桃胶、黄芪胶、金合欢胶、羧甲基纤维素钠、聚乙烯吡咯烷酮、卡波姆、羟丙基纤维素、羟丙基甲基纤维素、海藻酸盐或其组合；特拉唑嗪与赋形剂的重量比为1：10～1000。

Description

药物组合物 技术领域
本发明属于医药技术领域，涉及一类组合物，特别是涉及一类可注射给药的组合物。
背景技术
特拉唑嗪(Terazosin)通常以其盐酸盐用于临床，已上市片剂或胶囊剂的规格有1mg、2mg和5mg等。盐酸特拉唑嗪可用于治疗良性前列腺增生症，也可用于治疗高血压，可单独使用或与其它抗高血压药物如利尿剂或α1-肾上腺素能阻滞剂合用。针对现有的临床适应症，特拉唑嗪用于成人的日剂量常用范围为1～10mg。特拉唑嗪用于治疗良性前列腺增生(BPH)，用药后良性前列腺增生症状减轻和尿流速改善与膀胱颈和前列腺中的α1-肾上腺素能受体阻断所引起的平滑肌松弛有关。因为在膀胱体中有相对少的α1-肾上腺素能受体，因此特拉唑嗪能够减轻膀胱出口的阻塞而不影响膀胱的收缩。此外，特拉唑嗪通过减少总外周血管阻力从而使血压降低。特拉唑嗪的血管舒张、血压降低作用似乎主要是由α1-肾上腺素能受体阻断所引起的。
特拉唑嗪化学名为(4-(4-氨基-6,7-二甲氧基喹唑啉-2-基)哌嗪-1-基)(四氢呋喃-2-基)甲酮，分子式为C19H25N5O4，化学结构式为以下式I：
Figure PCTCN2016080459-appb-000001
现有的特拉唑嗪或其药用盐在临床上主要以口服制剂形式呈现，例如片剂、胶囊剂等。然而在用于急性病症治疗时，这些口服制剂是不能满足临床需求的，通常而言注射制剂是有益的。
因此，本领域仍然期待有可用于急性疾病治疗使用的特拉唑嗪及其类似物的药物组合物。
发明内容
本发明的目的在于提供一种可用于急性疾病治疗使用的特拉唑嗪或其药用盐的药物组合物，并且期待这种药物组合物呈现令人满意的药学特征。本发明已经出人意料的发现，具有本发明特征的药物组合物作为药物制剂使用可以获得如本发明所述的技术效果。本发明基于此发现而得以完成。
为此，本发明第一方面提供了一种药物组合物，其中包括：特拉唑嗪、赋形剂。
根据本发明第一方面任一实施方案的药物组合物，其中所述特拉唑嗪还可以是其药用盐或其溶剂 合物例如水合物。
在本发明中，当提及特拉唑嗪时，其不但包括以上结构所示的化合物，还包括上述结构化合物的药学可接受的盐(例如盐酸盐)，以及上述结构化合物及其盐的溶剂合物例如水合物。在本发明的一个优选实施方案中，所述特拉唑嗪是指盐酸特拉唑嗪二水合物。本发明下文使用作为式I化合物典型示例的特拉唑嗪进行了大量研究以表明本发明出人意料的效果；在下文试验特别是生物学试验中，如未另外指明，所用的试药特拉唑嗪是指盐酸特拉唑嗪二水合物。
根据本发明第一方面任一实施方案的药物组合物，其中所述特拉唑嗪是特拉唑嗪盐酸盐。
根据本发明第一方面任一实施方案的药物组合物，其中所述特拉唑嗪是盐酸特拉唑嗪二水合物。在下文试验中，如未另外指明，所用的试药特拉唑嗪是指盐酸特拉唑嗪二水合物。
根据本发明第一方面任一实施方案的药物组合物，其中所述赋形剂选自：甘露醇、乳糖、山梨醇、木糖醇、葡萄糖、麦芽糖、甘氨酸、可溶性糊精、黄原胶、明胶、水解明胶、阿拉伯胶、果胶、瓜尔胶、桃胶、黄芪胶、金合欢胶、羧甲基纤维素钠、聚乙烯吡咯烷酮、卡波姆、羟丙基纤维素、羟丙基甲基纤维素、海藻酸盐、或其组合。
根据本发明第一方面任一实施方案的药物组合物，其中所述特拉唑嗪与赋形剂的重量比为1：10～1000。
根据本发明第一方面任一实施方案的药物组合物，其中所述特拉唑嗪与赋形剂的重量比为1：20～750。
根据本发明第一方面任一实施方案的药物组合物，其中所述特拉唑嗪与赋形剂的重量比为1：25～500。
根据本发明第一方面任一实施方案的药物组合物，其中所述赋形剂选自：甘露醇、乳糖、山梨醇、木糖醇、葡萄糖、麦芽糖、甘氨酸。
根据本发明第一方面任一实施方案的药物组合物，其中所述赋形剂选自：甘露醇、乳糖、甘氨酸。已经出人意料地发现，在特拉唑嗪与特定量的特定赋形剂组合时，可以有效地抑制组合物中与特拉唑嗪有关的杂质的增长速度。
根据本发明第一方面任一实施方案的药物组合物，其中所述赋形剂不包括明胶或水解明胶。已经出人意料地发现，添加明胶或者水解明胶对于组合物的制备是不利的。
根据本发明第一方面任一实施方案的药物组合物，其是冷冻干燥的组合物。
根据本发明第一方面任一实施方案的药物组合物，其是冷冻干燥的可用于注射的粉针剂。
根据本发明第一方面任一实施方案的药物组合物，其是冷冻干燥的可用于注射的粉针剂，该粉针剂是用玻璃瓶密封包装的。
根据本发明第一方面任一实施方案的药物组合物，其是冷冻干燥的可用于注射的粉针剂，该粉针剂是用玻璃瓶密封包装的，每瓶中的特拉唑嗪的量为0.1mg～5mg，例如每瓶中的特拉唑嗪的量为0.1mg～2.5mg。
根据本发明第一方面任一实施方案的药物组合物，其中该药物组合物在密封条件下、在40℃避 光放置6个月的时间内，杂质A增加率小于100％，特别是小于75％，更特别是小于50％。
术语“杂质A”是N-(4-Amino-6,7-dimethoxy-2-quinazolinyl)piperazine或称为6,7-dimethoxy-2-(piperazin-1-yl)quinazolin-4-amine，即具有R为H的下式化合物：
Figure PCTCN2016080459-appb-000002
据信该杂质A是活性成分水解产生的。尽管本发明药物组合物是一种基本无水(通常而言水分含量低于5％)的冷冻干燥制剂，但是已经发现，即使在这种基本无水的干燥状态下，这种杂质仍然明显地会有随着组合物的贮藏时间延长而增加。这也是现行版美国药典(USP35)、现行版英国药典(BP2013)和现行版欧洲药典(EP8.0)中均给予严格监控的原因。
根据本发明第一方面任一实施方案的药物组合物，其由西林瓶密封包装。
根据本发明第一方面任一实施方案的药物组合物，其由西林瓶密封包装，并且在西林瓶中呈圆饼状。
根据本发明第一方面任一实施方案的药物组合物，其中水分含量低于10％，优选低于8％，优选低于7％，更优选低于5％。
根据本发明第一方面任一实施方案的药物组合物，其中还包括酸碱调节剂。在一个实施方案中，所述的酸碱调节剂选自氢氧化钠、氢氧化钾、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、盐酸、磷酸、硝酸、硫酸、或其组合。在一个实施方案中，所述的酸碱调节剂是盐酸溶液或者氢氧化钠溶液，例如1M盐酸溶液或者1M氢氧化钠溶液。
众所周知，经低温冷冻-真空干燥而获得的冷冻干燥粉针剂(通常简称为冻干粉针剂或冻干粉针)，其是首先将各物料用溶剂溶解(通常而言是用水溶解)，配制成一溶液，然后使该溶液进行低温冷冻，再进行抽真空、升华、干燥而获得的一种基本无水(通常而言水含量低于8％，特别是通常低于7％，特别是通常低于5％)的粉末状物或块状物。因此，该固体冻干物的酸碱度通常通过配制过程调节溶液的pH值来控制；或者可以通过处方调整以使获得的固体冻干物在规定的溶解/稀释程度下控制该溶解/稀释液的pH值来控制(此称为控制固体冻干物的酸碱度)；后一方式通常更为普遍使用，例如药典中所载的诸多冻干粉针剂均以此方式控制制品的酸碱度，而这种方式控制产品的酸碱度通常可以不具体规定酸碱调节剂的处方量，而仅规定终产品的酸碱度即可。同样适用于本发明的是，根据本发明第一方面任一实施方案所述的冻干粉针剂，其中所述任选的酸碱调节剂的量是，使所述冻干粉针剂用注射用水溶解成含特拉唑嗪0.5mg/ml浓度的溶液时该溶液的pH值在3.0～5.0范围内的量，例如该溶液的pH值在3.5～4.5范围内的量。
根据本发明第一方面任一实施方案的药物组合物，其中还包括枸橼酸。在一个实施方案中，特拉唑嗪和枸橼酸的重量比为1：1～10。在一个实施方案中，特拉唑嗪和枸橼酸的重量比为1：2～5。已经出人意料地发现，当向经冷冻干燥制成的组合物中添加适量枸橼酸特别是特拉唑嗪和枸橼酸的重量比 为1：2～5量的枸橼酸时可以有益地制得具有优异性能的粉针剂。
根据本发明第一方面任一实施方案的冷冻干燥粉针剂，其基本上是按包括如下的步骤制备的：
(a)称取处方量的特拉唑嗪和赋形剂(以及任选的枸橼酸)，加入适量注射用水，搅拌使溶解，
(b)向上一步骤所得药液中加入活性炭，搅拌，过滤脱炭；
(c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或者任选地)用酸碱调节剂调节至pH3.0～5.0，优选pH3.5～4.5；
(d)将药液除菌过滤，灌装于西林瓶中；
(e)冷冻干燥除去水分，压塞，即得。
根据本发明第一方面任一实施方案的冷冻干燥粉针剂，其中步骤(a)中所述适量注射用水是处方全量的60～70％量的注射用水。
根据本发明第一方面任一实施方案的冷冻干燥粉针剂，其中步骤(b)中所述活性炭的添加量是在药液中活性炭浓度达到0.05～0.15％的量。
根据本发明第一方面任一实施方案的冷冻干燥粉针剂，其中步骤(b)中所述搅拌是搅拌吸附10～20min，例如搅拌吸附15min。
根据本发明第一方面任一实施方案的冷冻干燥粉针剂，其中步骤(b)中所述过滤脱炭的方式是：用孔径为1um的钛棒脱碳过滤后，再用0.45um的聚醚砜滤芯将药液粗滤。
根据本发明第一方面任一实施方案的冷冻干燥粉针剂，其中步骤(c)中所述补加注射用水至处方全量是指补加注射用水直至活性成分浓度为0.1～5mg/ml(例如0.2～2mg/ml)的量。
根据本发明第一方面任一实施方案的冷冻干燥粉针剂，其中步骤(d)中所述除菌过滤是使用0.22um的聚醚砜滤芯进行除菌过滤。
进一步的，本发明第二方面提供了使特拉唑嗪稳定的方法，该方法包括使特拉唑嗪与赋形剂制成药物组合物的步骤，该药物组合物中特拉唑嗪与赋形剂形成均一混合物。
根据本发明第二方面任一实施方案的方法，其中所述药物组合物是冷冻干燥的组合物。
根据本发明第二方面任一实施方案的方法，其中所述药物组合物是冷冻干燥的可用于注射的粉针剂。
根据本发明第二方面任一实施方案的方法，其中所述药物组合物是冷冻干燥的可用于注射的粉针剂，该粉针剂是用玻璃瓶密封包装的。
根据本发明第二方面任一实施方案的方法，其中所述药物组合物是冷冻干燥的可用于注射的粉针剂，该粉针剂是用玻璃瓶密封包装的，每瓶中的特拉唑嗪的量为0.1mg～5mg，例如每瓶中的特拉唑嗪的量为0.1mg～2.5mg。
根据本发明第二方面任一实施方案的方法，其中所述药物组合物中包括：特拉唑嗪、赋形剂。
根据本发明第二方面任一实施方案的方法，其中所述特拉唑嗪还可以是其药用盐或其溶剂合物例如水合物。
在本发明中，当提及特拉唑嗪时，其不但包括以上结构所示的化合物，还包括上述结构化合物的 药学可接受的盐(例如盐酸盐)，以及上述结构化合物及其盐的溶剂合物例如水合物。在本发明的一个优选实施方案中，所述特拉唑嗪是指盐酸特拉唑嗪二水合物。本发明下文使用作为式I化合物典型示例的特拉唑嗪进行了大量研究以表明本发明出人意料的效果；在下文试验特别是生物学试验中，如未另外指明，所用的试药特拉唑嗪是指盐酸特拉唑嗪二水合物。
根据本发明第二方面任一实施方案的方法，其中所述特拉唑嗪是特拉唑嗪盐酸盐。
根据本发明第二方面任一实施方案的方法，其中所述特拉唑嗪是盐酸特拉唑嗪二水合物。在下文试验中，如未另外指明，所用的试药特拉唑嗪是指盐酸特拉唑嗪二水合物。
根据本发明第二方面任一实施方案的方法，其中所述赋形剂选自：甘露醇、乳糖、山梨醇、木糖醇、葡萄糖、麦芽糖、甘氨酸、可溶性糊精、黄原胶、明胶、水解明胶、阿拉伯胶、果胶、瓜尔胶、桃胶、黄芪胶、金合欢胶、羧甲基纤维素钠、聚乙烯吡咯烷酮、卡波姆、羟丙基纤维素、羟丙基甲基纤维素、海藻酸盐、或其组合。
根据本发明第二方面任一实施方案的方法，其中所述特拉唑嗪与赋形剂的重量比为1：10～1000。
根据本发明第二方面任一实施方案的方法，其中所述特拉唑嗪与赋形剂的重量比为1：20～750。
根据本发明第二方面任一实施方案的方法，其中所述特拉唑嗪与赋形剂的重量比为1：25～500。
根据本发明第二方面任一实施方案的方法，其中所述赋形剂选自：甘露醇、乳糖、山梨醇、木糖醇、葡萄糖、麦芽糖、甘氨酸。
根据本发明第二方面任一实施方案的方法，其中所述赋形剂选自：甘露醇、乳糖、甘氨酸。已经出人意料地发现，在特拉唑嗪与特定量的特定赋形剂组合时，可以有效地抑制组合物中与特拉唑嗪有关的杂质的增长速度。
根据本发明第二方面任一实施方案的方法，其中所述赋形剂不包括明胶或水解明胶。已经出人意料地发现，添加明胶或者水解明胶对于组合物的制备是不利的。
根据本发明第二方面任一实施方案的方法，其使得该药物组合物在密封条件下、在40℃避光放置6个月的时间内，杂质A增加率小于100％，特别是小于75％，更特别是小于50％。
根据本发明第二方面任一实施方案的方法，其中所述药物组合物是由西林瓶密封包装。
根据本发明第二方面任一实施方案的方法，其中所述药物组合物是由西林瓶密封包装，并且在西林瓶中呈圆饼状。
根据本发明第二方面任一实施方案的方法，其中所述药物组合物水分含量低于10％，优选低于8％，优选低于7％，更优选低于5％。
根据本发明第二方面任一实施方案的方法，其中所述药物组合物中还包括酸碱调节剂。在一个实施方案中，所述的酸碱调节剂选自氢氧化钠、氢氧化钾、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、盐酸、磷酸、硝酸、硫酸、或其组合。在一个实施方案中，所述的酸碱调节剂是盐酸溶液或者氢氧化钠溶液，例如1M盐酸溶液或者1M氢氧化钠溶液。
众所周知，经低温冷冻-真空干燥而获得的冷冻干燥粉针剂(通常简称为冻干粉针剂或冻干粉针)，其是首先将各物料用溶剂溶解(通常而言是用水溶解)，配制成一溶液，然后使该溶液进行低温冷冻， 再进行抽真空、升华、干燥而获得的一种基本无水(通常而言水含量低于8％，特别是通常低于7％，特别是通常低于5％)的粉末状物或块状物。因此，该固体冻干物的酸碱度通常通过配制过程调节溶液的pH值来控制；或者可以通过处方调整以使获得的固体冻干物在规定的溶解/稀释程度下控制该溶解/稀释液的pH值来控制(此称为控制固体冻干物的酸碱度)；后一方式通常更为普遍使用，例如药典中所载的诸多冻干粉针剂均以此方式控制制品的酸碱度，而这种方式控制产品的酸碱度通常可以不具体规定酸碱调节剂的处方量，而仅规定终产品的酸碱度即可。同样适用于本发明的是，根据本发明第一方面任一实施方案所述的冻干粉针剂，其中所述任选的酸碱调节剂的量是，使所述冻干粉针剂用注射用水溶解成含特拉唑嗪0.5mg/ml浓度的溶液时该溶液的pH值在3.0～5.0范围内的量，例如该溶液的pH值在3.5～4.5范围内的量。
根据本发明第一方面任一实施方案的药物组合物，其中还包括枸橼酸。在一个实施方案中，特拉唑嗪和枸橼酸的重量比为1：1～10。在一个实施方案中，特拉唑嗪和枸橼酸的重量比为1：2～5。
根据本发明第二方面任一实施方案的方法，其中所述药物组合物基本上是按包括如下的步骤制备的：
(a)称取处方量的特拉唑嗪和赋形剂(以及任选的枸橼酸)，加入适量注射用水，搅拌使溶解，
(b)向上一步骤所得药液中加入活性炭，搅拌，过滤脱炭；
(c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或者任选地)用酸碱调节剂调节至pH3.0～5.0，优选pH3.5～4.5；
(d)将药液除菌过滤，灌装于西林瓶中；
(e)冷冻干燥除去水分，压塞，即得。
根据本发明第二方面任一实施方案的方法，其中步骤(a)中所述适量注射用水是处方全量的60～70％量的注射用水。
根据本发明第二方面任一实施方案的方法，其中步骤(b)中所述活性炭的添加量是在药液中活性炭浓度达到0.05～0.15％的量。
根据本发明第二方面任一实施方案的方法，其中步骤(b)中所述搅拌是搅拌吸附10～20min，例如搅拌吸附15min。
根据本发明第二方面任一实施方案的方法，其中步骤(b)中所述过滤脱炭的方式是：用孔径为1um的钛棒脱碳过滤后，再用0.45um的聚醚砜滤芯将药液粗滤。
根据本发明第二方面任一实施方案的方法，其中步骤(c)中所述补加注射用水至处方全量是指补加注射用水直至活性成分浓度为0.1～5mg/ml(例如0.2～2mg/ml)的量。
根据本发明第二方面任一实施方案的方法，其中步骤(d)中所述除菌过滤是使用0.22um的聚醚砜滤芯进行除菌过滤。
根据本发明第二方面任一实施方案的方法，其还包括降低所述药物组合物在冷冻干燥过程中喷瓶发生率的处理步骤。在一个实施方案中，该步骤是与赋型剂一起向组合物中添加枸橼酸。在一个实施方案中，特拉唑嗪和枸橼酸的重量比为1：1～10。在一个实施方案中，特拉唑嗪和枸橼酸的重量比为 1：2～5。
进一步地，本发明第三方面提供了制备药物组合物的方法，该药物组合物中包括：特拉唑嗪、赋形剂，该药物组合物是通过冷冻干燥工艺制成的。
根据本发明第三方面任一实施方案的方法，其中所述特拉唑嗪还可以是其药用盐或其溶剂合物例如水合物。
在本发明中，当提及特拉唑嗪时，其不但包括以上结构所示的化合物，还包括上述结构化合物的药学可接受的盐(例如盐酸盐)，以及上述结构化合物及其盐的溶剂合物例如水合物。在本发明的一个优选实施方案中，所述特拉唑嗪是指盐酸特拉唑嗪二水合物。本发明下文使用作为式I化合物典型示例的特拉唑嗪进行了大量研究以表明本发明出人意料的效果；在下文试验特别是生物学试验中，如未另外指明，所用的试药特拉唑嗪是指盐酸特拉唑嗪二水合物。
根据本发明第三方面任一实施方案的方法，其中所述特拉唑嗪是特拉唑嗪盐酸盐。
根据本发明第三方面任一实施方案的方法，其中所述特拉唑嗪是盐酸特拉唑嗪二水合物。在下文试验中，如未另外指明，所用的试药特拉唑嗪是指盐酸特拉唑嗪二水合物。
根据本发明第三方面任一实施方案的方法，其中所述赋形剂选自：甘露醇、乳糖、山梨醇、木糖醇、葡萄糖、麦芽糖、甘氨酸、可溶性糊精、黄原胶、明胶、水解明胶、阿拉伯胶、果胶、瓜尔胶、桃胶、黄芪胶、金合欢胶、羧甲基纤维素钠、聚乙烯吡咯烷酮、卡波姆、羟丙基纤维素、羟丙基甲基纤维素、海藻酸盐、或其组合。
根据本发明第三方面任一实施方案的方法，其中所述特拉唑嗪与赋形剂的重量比为1：10～1000。
根据本发明第三方面任一实施方案的方法，其中所述特拉唑嗪与赋形剂的重量比为1：20～750。
根据本发明第三方面任一实施方案的方法，其中所述特拉唑嗪与赋形剂的重量比为1：25～500。
根据本发明第三方面任一实施方案的方法，其中所述赋形剂选自：甘露醇、乳糖、山梨醇、木糖醇、葡萄糖、麦芽糖、甘氨酸。
根据本发明第三方面任一实施方案的方法，其中所述赋形剂选自：甘露醇、乳糖、甘氨酸。已经出人意料地发现，在特拉唑嗪与特定量的特定赋形剂组合时，可以有效地抑制组合物中与特拉唑嗪有关的杂质的增长速度。
根据本发明第三方面任一实施方案的方法，其中所述赋形剂不包括明胶或水解明胶。已经出人意料地发现，添加明胶或者水解明胶对于组合物的制备是不利的。
根据本发明第三方面任一实施方案的方法，其中所述药物组合物是冷冻干燥的可用于注射的粉针剂。
根据本发明第三方面任一实施方案的方法，其中所述药物组合物是冷冻干燥的可用于注射的粉针剂，该粉针剂是用玻璃瓶密封包装的。
根据本发明第三方面任一实施方案的方法，其中所述药物组合物是冷冻干燥的可用于注射的粉针剂，该粉针剂是用玻璃瓶密封包装的，每瓶中的特拉唑嗪的量为0.1mg～5mg，例如每瓶中的特拉唑嗪的量为0.1mg～2.5mg。
根据本发明第三方面任一实施方案的方法，其中所述药物组合物在密封条件下、在40℃避光放置6个月的时间内，杂质A增加率小于100％，特别是小于75％，更特别是小于50％。
根据本发明第三方面任一实施方案的方法，其中所述药物组合物由西林瓶密封包装。
根据本发明第三方面任一实施方案的方法，其中所述药物组合物由西林瓶密封包装，并且在西林瓶中呈圆饼状。
根据本发明第三方面任一实施方案的方法，其中所述药物组合物中水分含量低于10％，优选低于8％，优选低于7％，更优选低于5％。
根据本发明第三方面任一实施方案的方法，其中所述药物组合物中还包括酸碱调节剂。在一个实施方案中，所述的酸碱调节剂选自氢氧化钠、氢氧化钾、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、盐酸、磷酸、硝酸、硫酸、或其组合。在一个实施方案中，所述的酸碱调节剂是盐酸溶液或者氢氧化钠溶液，例如1M盐酸溶液或者1M氢氧化钠溶液。
众所周知，经低温冷冻-真空干燥而获得的冷冻干燥粉针剂(通常简称为冻干粉针剂或冻干粉针)，其是首先将各物料用溶剂溶解(通常而言是用水溶解)，配制成一溶液，然后使该溶液进行低温冷冻，再进行抽真空、升华、干燥而获得的一种基本无水(通常而言水含量低于8％，特别是通常低于7％，特别是通常低于5％)的粉末状物或块状物。因此，该固体冻干物的酸碱度通常通过配制过程调节溶液的pH值来控制；或者可以通过处方调整以使获得的固体冻干物在规定的溶解/稀释程度下控制该溶解/稀释液的pH值来控制(此称为控制固体冻干物的酸碱度)；后一方式通常更为普遍使用，例如药典中所载的诸多冻干粉针剂均以此方式控制制品的酸碱度，而这种方式控制产品的酸碱度通常可以不具体规定酸碱调节剂的处方量，而仅规定终产品的酸碱度即可。同样适用于本发明的是，根据本发明第一方面任一实施方案所述的冻干粉针剂，其中所述任选的酸碱调节剂的量是，使所述冻干粉针剂用注射用水溶解成含特拉唑嗪0.5mg/ml浓度的溶液时该溶液的pH值在3.0～5.0范围内的量，例如该溶液的pH值在3.5～4.5范围内的量。
根据本发明第一方面任一实施方案的药物组合物，其中还包括枸橼酸。在一个实施方案中，特拉唑嗪和枸橼酸的重量比为1：1～10。在一个实施方案中，特拉唑嗪和枸橼酸的重量比为1：2～5。
根据本发明第三方面任一实施方案的方法，其基本上包括如下步骤：
(a)称取处方量的特拉唑嗪和赋形剂(以及任选的枸橼酸)，加入适量注射用水，搅拌使溶解，
(b)向上一步骤所得药液中加入活性炭，搅拌，过滤脱炭；
(c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或者任选地)用酸碱调节剂调节至pH3.0～5.0，优选pH3.5～4.5；
(d)将药液除菌过滤，灌装于西林瓶中；
(e)冷冻干燥除去水分，压塞，即得。
根据本发明第三方面任一实施方案的方法，其中步骤(a)中所述适量注射用水是处方全量的60～70％量的注射用水。
根据本发明第三方面任一实施方案的方法，其中步骤(b)中所述活性炭的添加量是在药液中活性炭 浓度达到0.05～0.15％的量。
根据本发明第三方面任一实施方案的方法，其中步骤(b)中所述搅拌是搅拌吸附10～20min，例如搅拌吸附15min。
根据本发明第三方面任一实施方案的方法，其中步骤(b)中所述过滤脱炭的方式是：用孔径为1um的钛棒脱碳过滤后，再用0.45um的聚醚砜滤芯将药液粗滤。
根据本发明第三方面任一实施方案的方法，其中步骤(c)中所述补加注射用水至处方全量是指补加注射用水直至活性成分浓度为0.1～5mg/ml(例如0.2～2mg/ml)的量。
根据本发明第三方面任一实施方案的方法，其中步骤(d)中所述除菌过滤是使用0.22um的聚醚砜滤芯进行除菌过滤。
在本发明上述制备方法的步骤中，虽然其描述的具体步骤在某些细节上或者语言描述上与下文具体实施方式部分的制备例中所描述的步骤有所区别，然而，本领域技术人员根据本发明全文的详细公开完全可以概括出以上所述方法步骤。
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。
下面对本发明作进一步的描述。
本发明所引述的所有文献，它们的全部内容通过引用并入本文，并且如果这些文献所表达的含义与本发明不一致时，以本发明的表述为准。此外，本发明使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本发明仍然希望在此对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本发明所表述的含义为准。
已经发现，本发明方法制备得到的呈冷冻干燥粉针剂形式的药物组合物具有出人意料的优点。例如体现在以下方面的稳定性试验、复溶时间、喷瓶率等：
稳定性试验：下文实施例1至实施例12制备得到的全部组合物，置于40℃处放置6月以进行高温处置试验；对于每一组合物，使用美国药典USP35版第4787页特拉唑嗪片(http://www.drugfuture.com/Pharmacopoeia/usp35/data/v35300/usp35nf30s0m80842.html)之【杂质】检测项中的方法，测定该组合物在0月时以及在6月时的有关物质即杂质A(相对于主成分的)含量，按下式计算杂质A的含量增加百分数(％，可简称为“杂质A增量”)：
Figure PCTCN2016080459-appb-000003
上述全部呈粉针剂形式的组合物使用同一批原料药制备得到，全部粉针剂在0月时的杂质A含量基本相当，均在0.08～0.11％范围内，但是经过上述高温处置后，不同样品呈现明显不同的杂质A变化情况。具体地说：实施例10和实施例12所得全部组合物以及实施例11所得#111至#114四者的的杂质A增量(％)均在114～235％范围内，例如#121和#122的杂质A增量(％)分别为207％和234％；实施例1-9所得全部组合物以及实施例11所得#115至#119五者的杂质A增量(％)均在17～32％范围内，例 如实施例1组合物的杂质A增量(％)为22％。可见，与使用不足量的甘露醇相比，或者与使用其它种类的常规冻干赋形剂相比，使用本发明量甘露醇、乳糖、甘氨酸能够赋予组合物优异的稳定性，特别是杂质A这种据信为水解杂质在组合物长期贮藏过程中增长速度得到抑制。而不足量的甘露醇或者即使是同类的常规冻干赋形剂，却出人意料地显示它们不能赋予组合物的这种效果。
复溶时间测定：取下文各实施例制备得到的组合物粉针剂，向每瓶中加入适量注射用水使固形物浓度均达到5％的程度，静置，计算从加水至完全溶解所需要的时间。结果：实施例1-9所得全部粉针剂以及实施例11所得#111至#117七者的复溶时间均小于20秒，均在9～18秒范围内；但是实施例11所得#118至#119二者的复溶时间分别达132秒和184秒，过大量的甘露醇使得粉针剂复溶时间显著地延长，因此从甘露醇的用量来讲，低于等于500份(相对于1份特拉唑嗪)是有益的。在另外的追加试验中，参照实施例11的配方/制法，不同的是改用乳糖或甘氨酸，结果同样地显示，乳糖或甘氨酸用量大于等于1000份(相对于1份特拉唑嗪)的粉针剂复溶时间均大于110秒，小于等于500份(相对于1份特拉唑嗪)的粉针剂复溶时间均小于30秒；另外，参照实施例11改用乳糖或甘氨酸的粉针，在进行40℃处放置6月时，与实施例11所得结果相似，赋形剂用量大于等于25份(相对于1份特拉唑嗪)的粉针中杂质A增量(％)增量均小于40％，而赋形剂用量小于等于15份(相对于1份特拉唑嗪)的粉针中杂质A增量(％)增量均大于95％。
下文在制备粉针剂的全部实施例中，每批次冻干时至少有500瓶进行冷冻干燥，半加塞的药液冷冻干燥完毕后，观察至少250瓶的粉针是否有喷瓶的问题发生，并统计喷瓶发生率。已经发现，实施例1-8全部批次的粉针剂中，均有2-5％不等的喷瓶发生率，尽管中种发生率不高而且仅仅是影响粉针外观，但是通常来讲这种现象是本领域技术人员期待克服的；但是实施例9所得9批粉针剂的喷瓶组成发生率却均为0，鉴于实施例9的冻干方法与实施例1-3是相同的，因此实施例1-8的喷瓶现象与处方有关，而微量枸橼酸的加入可以克服这种现象。
在本发明中，优选的本发明冻干粉针剂组合物在用水制成每1ml中含活性成分0.5mg的溶液后，再根据中国药典2010年版二部附录VI H项下的方法即pH值测定法测定该冻干粉针的酸碱度。
冷冻干燥粉针剂的制备过程是本领域技术人员公知的制药工艺，例如如下冻干曲线A和冻干曲线B所示的两种示意性的冻干曲线：
Figure PCTCN2016080459-appb-000004
Figure PCTCN2016080459-appb-000005
在下文制备冷冻干燥粉针剂中的具体实例中，如未另外特别说明，所用的冻干曲线是冻干曲线A。
冷冻干燥粉针剂中的水含量是一般在8％以下，优选低于7％，更优选低于5％。水分控制可通过适当调整冷冻干燥程序来控制。该冷冻干燥粉针剂中的水分含量可根据许多已知方法来测定，例如干燥失重法。
在本发明中，为了在必要时调节药液的pH值，可以向组合物中加入适当的pH调节剂。尽管本发明人仅用不具缓冲能力的强酸或强碱溶液例如氢氧化钠水溶液和盐酸水溶液进行调节，然而，本领域技术人员理解，如果用这种不具缓冲能力的pH调节剂处理能满足体系的pH要求，则具有缓冲能力的pH调节剂将更加能够实现本发明目的，因此这些缓冲剂不但能够调节pH值，而且能稳定pH值。因此本发明所列任一pH调节剂或其组合均包括在本发明精神和范围内。
在制备本发明冻干粉针剂时，所配制的药液中，固形物含量是为1～20％(w/v)，优选1～15％(w/v)，再更优选1～10％。由于冻干粉针剂通常是在管状西林瓶中进行冷冻干燥得到，本领域技术人员理解这种产品在获得成品甚至在供医生使用之前，通常均呈现一个圆饼状，尽管该圆饼的体积理论上讲会比原有水溶液的体积少(稍有缩小)，然而通常这种缩小通常不会缩小到原水溶液体积50％，通常会在原水溶液体积的80-120％之间，更通常在原水溶液体积的90-100％之间，而从终产品西林瓶内可观察到原水溶液液面痕迹(主体饼状物因冻干缩小后残留在瓶壁上的液面痕迹，即便西林瓶中的冻干品因各种原因例如碰撞等原因而呈粉末状，通常仍然可以保留原有的液面痕迹)，据此痕迹亦可估计出该冷冻干 燥组合物在冷冻干燥之前的水溶液体积。因此，虽然本发明提供的是一种基本无水的冷冻干燥粉针剂，然而根据该粉针剂仍然可以大致估计出其在配制时，至少在冷冻干燥开始之前的药液体积，根据该估计出的体积以及西林瓶中的干燥终产物的重量，亦可计算到在制备本发明冻干粉针剂时，所配制的药液中的固形物的含量。因此，根据本发明第一方面的冻干粉针剂，其在配制时的药液的固形物含量是为1～20％(w/v)，优选1～15％(w/v)，再更优选1～10％。
在本发明中，符号％，根据其所使用的语境，可以具有本领域技术人员容易理解的含义。例如在提及固形物含量时，该符号表示重量/体积的百分数(w/v，例如g/100ml)；又例如在提及冷冻干燥粉针剂中的“水含量”时，例如水含量在8％以下，此时该符号％表示重量/重量的百分数(w/w，g/100g)。一般而言，在固体分散在液体中时，％表示重量/体积百分数；在固体分散在固体中或者液体分散在固体中(例如粉针的含水量)时，％表示重量/重量百分数。在其它情况下，如无另外说明，符号％表示重量/重量百分数。
在配制本发明的药液时，本领域技术人员公知，可使用例如约0.45um的微孔滤膜进行粗滤过滤，在将药液灌装到西林瓶中之前，可以使用例如约0.22um的微孔滤膜进行精滤过滤以除菌，必要时可以过滤多次。
根据本发明的冻干粉针剂，其用注射用水复溶，通常而言复溶时间在30秒内，优选在20秒内，更优选在15秒内。
根据本发明的呈冻干粉针剂形式的组合物，其用水制成每1ml中含活性化合物0.5mg的溶液并根据中国药典2010年版二部附录VI H项下的方法测定，该溶液的pH值为3.0～5.0。在一个实施方案中，pH值为3.5～4.5。
本发明提供的冻干粉针剂可以在25℃以下干燥处保存至少24个月，可以满足一般的冷冻干燥粉针剂的贮藏要求。
临床上，盐酸特拉唑嗪可用于治疗良性前列腺增生症。盐酸特拉唑嗪也可用于治疗高血压，可单独使用或与其它抗高血压药物如利尿剂或β-肾上腺素能阻滞剂合用。
药效学方面，良性前列腺增生(BPH)：与BPH有关的症状涉及膀胱出口阻塞，它包括两个基本组成部分：静态部分和动态部分。静态部分是前列腺增大的结果。一段时间内，前列腺会不断扩大。然而，临床研究表明，前列腺的大小与BPH症状的严重性或尿道阻塞的程度无关。动态部分是前列腺和膀胱颈平滑肌紧张增加的功能，导致膀胱出口的狭窄。平滑肌紧张是由α1-肾上腺素能受体的交感神经刺激作用介导的，该受体在前列腺、前列腺囊和膀胱颈中是丰富的。给予特拉唑嗪后症状减轻和尿流速改善与膀胱颈和前列腺中的α1-肾上腺素能受体阻断所引起的平滑肌松弛有关。因为在膀胱体中有相对少的α1-肾上腺素能受体,因此特拉唑嗪能够减轻膀胱出口的阻塞而不影响膀胱的收缩。对排尿的总体功能和症状进行了综合评价，与空白治疗的病人相比，用特拉唑嗪治疗的病人有明显(p≤0.001)大的总体改善。长期试验中，特拉唑嗪使症状和尿流速最大值分数都有明显改善，提示特拉唑嗪使平滑肌细胞松弛。尽管阻断α1-肾上腺素能受体也降低因外周血管阻力增加而引起的高血压病人的血压，但血压正常的BPH男性病人用特拉唑嗪治疗时未引起临床上明显的血压降低作用。
高血压：在动物中，特拉唑嗪通过减少总外周血管阻力从而使血压降低。特拉唑嗪的血管舒张、血压降低作用似乎主要是由α1-肾上腺素能受体阻断所引起的。在给药后15分钟内，特拉唑嗪使血压逐渐降低。患有轻度(大约77％，舒张压95-105mmHg)或中度(大约23％，舒张压105-115mmHg)高血压的病人，按照5-20mg/天的总剂量，每日一次或两次给予特拉唑嗪进行临床试验。同所有拮抗剂一样，因为特拉唑嗪在首次或前几次给药后可使血压急速下降，因此起始剂量为1mg，然后调整到某一固定剂量或调整到某一特定血压终点(通常仰卧位的舒张压为90mmHg)。在给药间期末(通常24小时)测量血压，结果显示，降压作用持续整个间期，通常，仰卧位的收缩压降低比空白大5-10mmHg，舒张压的降低大3.5-8mmHg。给药后24小时测量，心率未改变。引起血压反应的量与哌唑嗪类似，但低于氢氯噻嗪。特拉唑嗪小剂量组在统计学上明显地减少病人的总胆固醇、低密度和极低密度脂蛋白，但对高密度脂蛋白和甘油三酯没有明显改变。
毒理致癌、致突变和生殖毒性方面，特拉唑嗪没有致突变作用。也无证据支持特拉唑嗪有致癌作用。治疗对睾丸的重量和形态不产生影响。以30和120mg/kg/天剂量给药，子宫涂片与对照涂片相比精子含量减少并且精子的数量与随后的受孕有比较好的相关性。当以40和250mg/kg/天(29和175倍于人推荐最大剂量)的剂量口服给予大鼠一年或两年时，睾丸萎缩的发生率明显增加，但在8mg/kg/天(>人推荐最大剂量的6倍)剂量时没有增加。在狗的实验中，300mg/kg/天(>人推荐最大剂量的500倍)给药3个月时也观察到了睾丸萎缩，但剂量为20mg/kg/天(>人推荐最大剂量的38倍)时没有观察到了睾丸萎缩。怀孕期致畸作用尚未在怀孕妇女中进行足够的和很好的对照性研究并且特拉唑嗪在怀孕期的安全性尚未确定。不推荐在怀孕期使用特拉唑嗪，除非证明有益性高于对产妇和胎儿的危险性。
药代动力学方面，男性患者服药后基本上完全吸收。饭后立即服药对吸收程度的影响极小，但使血浆浓度达峰时间延迟大约40分钟。特拉唑嗪的肝首过代谢很小。服药后约1小时达到峰值，半衰期约为12小时。在年龄对特拉唑嗪药代动力学影响的研究中发现，70岁和20-39岁年龄的病人，其血浆半衰期分别为14.0和11.4小时。血浆蛋白结合率为90-94％。约40％经尿排泄，约60％随粪便排出。
具体实施方式
通过下面的实施例可以对本发明进行进一步的描述，然而，本发明的范围并不限于下述实施例。本领域的专业人员能够理解，在不背离本发明的精神和范围的前提下，可以对本发明进行各种变化和修饰。本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的，但是本发明仍然在此作尽可能详细描述。以下实施例进一步说明本发明，而不是限制本发明。任何依据本发明构思所作出的仅仅为形式上的而非实质性的等效变换都应视为本发明的技术方案范畴。
在下面的例子中，如未另外说明，制备粉针剂时是使用同一批次的特拉唑嗪原料药(为盐酸特拉唑嗪二水合物，本发明对其计量时均是指以游离碱计；经检测，其符合美国药典USP35版第4785页所收载的盐酸特拉唑嗪(二水合物)的质量标准)。
在下面的例子中，使用的pH调节剂(在本发明中亦即酸碱调节剂)，如无另外说明，是1M氢氧化 钠溶液或者1M盐酸溶液，其用量是使制备粉针剂时，使冷冻干燥前所配制的溶液的pH值调节至某一规定值或范围，该规定值或范围是冷冻干燥所得干粉用注射用水稀释成含活性成分0.5mg/ml(如配液中低于此浓度，则不进行调节，本发明上下文均类似地处理)的溶液所测定的pH值的值或范围。下文制备步骤为了举例的目的，并基于各举例的可比较性而作了某些具体描述，本领域技术人员根据已有知识完全可以从中概括得到本发明制备冻干粉针剂的方法。在下面配液制备各种组合物中，如未另外说明，每批的总配液量为1000瓶的量，但是列明配方时，均以每瓶含特拉唑嗪计1mg的量阐明。
实施例1：制备特拉唑嗪冷冻干燥粉针剂
配方：
特拉唑嗪：1mg，
甘露醇：50mg，
酸碱调节剂：必要时使用适量，调节pH至以下制法中的规定值，
注射用水：至1ml。
制法：
(a)称取处方量的活性成分和固体辅料，加入适量(处方全量的65％)注射用水，搅拌使溶解，
(b)向上一步骤所得药液中加入活性炭(0.1％)，搅拌(使吸附15min)，过滤脱炭(用孔径为1um的钛棒脱碳过滤后，再用0.45um的聚醚砜滤芯将药液粗滤)；
(c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或者任选地)用酸碱调节剂调节至pH4.0(本实施例以及本发明全部实施例，此处步骤(c)直接调节pH值至此规定值，经冻干得到的粉针剂用注射用水溶解成含特拉唑嗪0.5mg/ml浓度的溶液时该溶液的pH值，该值与步骤(c)直接调节pH值相同)；
(d)将药液除菌过滤(用0.22um的聚醚砜滤芯进行除菌过滤)，灌装于西林瓶中；
(e)冷冻干燥除去水分(水分含量低于3％)，压塞，即得。
另外，通过每瓶分装药液量的调节，可以制成每瓶中的特拉唑嗪的量为0.1mg～2.5mg量的粉针剂。
实施例2：制备特拉唑嗪冷冻干燥粉针剂
配方：
特拉唑嗪：1mg，
甘露醇：25mg，
酸碱调节剂：必要时使用适量，调节pH至以下制法中的规定值，
注射用水：至2.5ml。
制法：
(a)称取处方量的活性成分和固体辅料，加入适量(处方全量的70％)注射用水，搅拌使溶解，
(b)向上一步骤所得药液中加入活性炭(0.15％)，搅拌(使吸附10min)，过滤脱炭(用孔径为1um的钛棒脱碳过滤后，再用0.45um的聚醚砜滤芯将药液粗滤)；
(c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或 者任选地)用酸碱调节剂调节至pH4.5；
(d)将药液除菌过滤(用0.22um的聚醚砜滤芯进行除菌过滤)，灌装于西林瓶中；
(e)冷冻干燥除去水分(水分含量低于4％)，压塞，即得。
实施例3：制备特拉唑嗪冷冻干燥粉针剂
配方：
特拉唑嗪：1mg，
甘露醇：500mg，
酸碱调节剂：必要时使用适量，调节pH至以下制法中的规定值，
注射用水：至5ml。
制法：
(a)称取处方量的活性成分和固体辅料，加入适量(处方全量的60％)注射用水，搅拌使溶解，
(b)向上一步骤所得药液中加入活性炭(0.05％)，搅拌(使吸附20min)，过滤脱炭(用孔径为1um的钛棒脱碳过滤后，再用0.45um的聚醚砜滤芯将药液粗滤)；
(c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或者任选地)用酸碱调节剂调节至pH3.5；
(d)将药液除菌过滤(用0.22um的聚醚砜滤芯进行除菌过滤)，灌装于西林瓶中；
(e)冷冻干燥除去水分(水分含量低于5％)，压塞，即得。
实施例4：制备特拉唑嗪冷冻干燥粉针剂
配方：
特拉唑嗪：1mg，
甘露醇：100mg，
酸碱调节剂：必要时使用适量，调节pH至以下制法中的规定值，
注射用水：至2ml。
制法：
(a)称取处方量的活性成分和固体辅料，加入适量(处方全量的65％)注射用水，搅拌使溶解，
(b)向上一步骤所得药液中加入活性炭(0.1％)，搅拌(使吸附15min)，过滤脱炭(用孔径为1um的钛棒脱碳过滤后，再用0.45um的聚醚砜滤芯将药液粗滤)；
(c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或者任选地)用酸碱调节剂调节至pH3.0；
(d)将药液除菌过滤(用0.22um的聚醚砜滤芯进行除菌过滤)，灌装于西林瓶中；
(e)冷冻干燥除去水分(水分含量低于3％)，压塞，即得。本实施例使用冷冻干燥曲线B进行冻干。
实施例5：制备特拉唑嗪冷冻干燥粉针剂
配方：
特拉唑嗪：1mg，
甘露醇：250mg，
酸碱调节剂：必要时使用适量，调节pH至以下制法中的规定值，
注射用水：至5ml。
制法：
(a)称取处方量的活性成分和固体辅料，加入适量(处方全量的65％)注射用水，搅拌使溶解，
(b)向上一步骤所得药液中加入活性炭(0.1％)，搅拌(使吸附15min)，过滤脱炭(用孔径为1um的钛棒脱碳过滤后，再用0.45um的聚醚砜滤芯将药液粗滤)；
(c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或者任选地)用酸碱调节剂调节至pH5.0；
(d)将药液除菌过滤(用0.22um的聚醚砜滤芯进行除菌过滤)，灌装于西林瓶中；
(e)冷冻干燥除去水分(水分含量低于3％)，压塞，即得。
实施例6：制备特拉唑嗪冷冻干燥粉针剂
配方：
特拉唑嗪：1mg，
甘露醇：25mg，
酸碱调节剂：必要时使用适量，调节pH至以下制法中的规定值，
注射用水：至0.5ml。
制法：
(a)称取处方量的活性成分和固体辅料，加入适量(处方全量的65％)注射用水，搅拌使溶解，
(b)向上一步骤所得药液中加入活性炭(0.1％)，搅拌(使吸附15min)，过滤脱炭(用孔径为1um的钛棒脱碳过滤后，再用0.45um的聚醚砜滤芯将药液粗滤)；
(c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或者任选地)用酸碱调节剂调节至pH4.0；
(d)将药液除菌过滤(用0.22um的聚醚砜滤芯进行除菌过滤)，灌装于西林瓶中；
(e)冷冻干燥除去水分(水分含量低于3％)，压塞，即得。
实施例7：制备特拉唑嗪冷冻干燥粉针剂
分别参照实施例1-3的配方和制法，不同的仅是将其中的甘露醇替换为等量的乳糖，得到三批粉针剂分别记为#71、#72、#73。
实施例8：制备特拉唑嗪冷冻干燥粉针剂
分别参照实施例1-3的配方和制法，不同的仅是将其中的甘露醇替换为等量的甘氨酸，得到三批粉针剂分别记为#81、#82、#83。
实施例9：制备特拉唑嗪冷冻干燥粉针剂
分别参照实施例1-3的配方和制法，不同的仅是向其中与甘露醇一起再追加枸橼酸(其量是特拉唑嗪的3.5倍)，得到三批粉针剂分别记为#91、#92、#93；分别参照实施例1-3的配方和制法，不同的仅 是向其中再追加枸橼酸(其量是特拉唑嗪的2倍)，得到三批粉针剂分别记为#94、#95、#96；分别参照实施例1-3的配方和制法，不同的仅是向其中再追加枸橼酸(其量是特拉唑嗪的5倍)，得到三批粉针剂分别记为#97、#98、#99。
实施例10：制备特拉唑嗪冷冻干燥粉针剂
分别参照实施例1的配方和制法，不同的仅是将其中的甘露醇替换为等量的山梨醇、木糖醇、葡萄糖、或麦芽糖，得到四批粉针剂分别记为#101、#102、#103、#104。
实施例11：制备特拉唑嗪冷冻干燥粉针剂
分别参照实施例1的配方和制法，不同的仅是将其中的甘露醇的量改为：0mg、5mg、10mg、15mg、25mg、100mg、500mg、1000mg、或2000mg(后四者所加水量适当调整使药液中固形物浓度为10％)，得到四批粉针剂分别记为#111、#112、#113、#114、#115、#116、#117、#118、#119。
实施例12：制备特拉唑嗪冷冻干燥组合物
将2g盐酸特拉唑嗪、7.5g明胶、0.5g水解明胶、14g甘露醇用350ml水溶解，将所得药液分装于西林瓶中，每瓶2ml，然后放入冷冻干燥机内按本发明冻干曲线A进行冷冻干燥，得组合物#121。
将2g盐酸特拉唑嗪加200ml水溶解，形成溶液A；将7.5g明胶、0.5g水解明胶、14g甘露醇、1.5g阿司巴甜、1.4g薄荷醇、0.1g新橙皮苷二氢查尔酮溶于100ml水中，形成溶液B；将溶液A和溶液B混合，并加适量水稀释至350ml，充分搅拌。将所得药液分装于西林瓶中，每瓶2ml，然后放入冷冻干燥机内按本发明冻干曲线A进行冷冻干燥，得组合物#122。
产业适用性
本发明提供了一种具有优异性质的可注射用的特拉唑嗪冷冻干燥粉针剂，以及该特拉唑嗪冷冻干燥粉针剂的制备方法。本发明制备得到的可注射用的特拉唑嗪冷冻干燥粉针剂具有优异的理化性质。

Claims (10)

  1. 一种药物组合物，其中包括：特拉唑嗪、赋形剂。
  2. 根据权利要求1的药物组合物，其特征在于：
    所述特拉唑嗪还可以是其药用盐或其溶剂合物例如水合物；
    所述特拉唑嗪是特拉唑嗪盐酸盐；
    所述特拉唑嗪是盐酸特拉唑嗪二水合物；
    其中所述赋形剂选自：甘露醇、乳糖、山梨醇、木糖醇、葡萄糖、麦芽糖、甘氨酸、可溶性糊精、黄原胶、明胶、水解明胶、阿拉伯胶、果胶、瓜尔胶、桃胶、黄芪胶、金合欢胶、羧甲基纤维素钠、聚乙烯吡咯烷酮、卡波姆、羟丙基纤维素、羟丙基甲基纤维素、海藻酸盐、或其组合；
    所述特拉唑嗪与赋形剂的重量比为1：10～1000，例如1：20～750，例如1：25～500；
    所述赋形剂选自：甘露醇、乳糖、山梨醇、木糖醇、葡萄糖、麦芽糖、甘氨酸；
    所述赋形剂选自：甘露醇、乳糖、甘氨酸；和/或
    所述赋形剂不包括明胶或水解明胶。
  3. 根据权利要求1的药物组合物，其特征在于：
    其是冷冻干燥的组合物；
    其是冷冻干燥的可用于注射的粉针剂；
    其是冷冻干燥的可用于注射的粉针剂，该粉针剂是用玻璃瓶密封包装的；
    其是冷冻干燥的可用于注射的粉针剂，该粉针剂是用玻璃瓶密封包装的，每瓶中的特拉唑嗪的量为0.1mg～5mg，例如每瓶中的特拉唑嗪的量为0.1mg～2.5mg；
    该药物组合物在密封条件下、在40℃避光放置6个月的时间内，杂质A增加率小于100％，特别是小于75％，更特别是小于50％；和/或
    其中水分含量低于10％，优选低于8％，优选低于7％，更优选低于5％。
  4. 根据权利要求1的药物组合物，其特征在于：
    其中还包括酸碱调节剂；
    所述的酸碱调节剂选自氢氧化钠、氢氧化钾、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、盐酸、磷酸、硝酸、硫酸、或其组合；
    所述的酸碱调节剂是盐酸溶液或者氢氧化钠溶液，例如1M盐酸溶液或者1M氢氧化钠溶液；
    所述任选的酸碱调节剂的量是，使所述冻干粉针剂用注射用水溶解成含特拉唑嗪0.5mg/ml浓度的溶液时该溶液的pH值在3.0～5.0范围内的量，例如该溶液的pH值在3.5～4.5范围内的量；
    其中还包括枸橼酸；和/或
    特拉唑嗪和枸橼酸的重量比为1：1～10，例如1：2～5。
  5. 根据权利要求1的药物组合物，其特征在于：
    其基本上是按包括如下的步骤制备的：
    (a)称取处方量的特拉唑嗪和赋形剂，加入适量注射用水，搅拌使溶解，
    (b)向上一步骤所得药液中加入活性炭，搅拌，过滤脱炭；
    (c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或者任选地)用酸碱调节剂调节至pH3.0～5.0，优选pH3.5～4.5；
    (d)将药液除菌过滤，灌装于西林瓶中；
    (e)冷冻干燥除去水分，压塞，即得；
    其中步骤(a)中所述适量注射用水是处方全量的60～70％量的注射用水；
    其中步骤(b)中所述活性炭的添加量是在药液中活性炭浓度达到0.05～0.15％的量；
    其中步骤(b)中所述搅拌是搅拌吸附10～20min，例如搅拌吸附15min；
    其中步骤(b)中所述过滤脱炭的方式是：用孔径为1um的钛棒脱碳过滤后，再用0.45um的聚醚砜滤芯将药液粗滤；
    其中步骤(c)中所述补加注射用水至处方全量是指补加注射用水直至活性成分浓度为0.1～5mg/ml(例如0.2～2mg/ml)的量；和/或
    其中步骤(d)中所述除菌过滤是使用0.22um的聚醚砜滤芯进行除菌过滤。
  6. 使特拉唑嗪稳定的方法，该方法包括使特拉唑嗪与赋形剂制成药物组合物的步骤，该药物组合物中特拉唑嗪与赋形剂形成均一混合物。
  7. 根据权利要求6的方法，其特征在于：
    所述药物组合物是冷冻干燥的组合物；
    所述药物组合物是冷冻干燥的可用于注射的粉针剂；
    所述药物组合物是冷冻干燥的可用于注射的粉针剂，该粉针剂是用玻璃瓶密封包装的；
    所述药物组合物是冷冻干燥的可用于注射的粉针剂，该粉针剂是用玻璃瓶密封包装的，每瓶中的特拉唑嗪的量为0.1mg～5mg，例如每瓶中的特拉唑嗪的量为0.1mg～2.5mg；
    所述药物组合物中包括：特拉唑嗪、赋形剂；
    所述特拉唑嗪还可以是其药用盐或其溶剂合物例如水合物；
    所述特拉唑嗪是特拉唑嗪盐酸盐；
    所述特拉唑嗪是盐酸特拉唑嗪二水合物；
    所述赋形剂选自：甘露醇、乳糖、山梨醇、木糖醇、葡萄糖、麦芽糖、甘氨酸、可溶性糊精、黄原胶、明胶、水解明胶、阿拉伯胶、果胶、瓜尔胶、桃胶、黄芪胶、金合欢胶、羧甲基纤维素钠、聚乙烯吡咯烷酮、卡波姆、羟丙基纤维素、羟丙基甲基纤维素、海藻酸盐、或其组合；
    所述特拉唑嗪与赋形剂的重量比为1：10～1000，例如1：20～750，例如1：25～500；
    所述赋形剂不包括明胶或水解明胶。
  8. 根据权利要求6的方法，其特征在于：
    该方法其使得该药物组合物在密封条件下、在40℃避光放置6个月的时间内，杂质A增加率小于100％，特别是小于75％，更特别是小于50％；
    所述药物组合物是由西林瓶密封包装；
    所述药物组合物是由西林瓶密封包装，并且在西林瓶中呈圆饼状；
    所述药物组合物水分含量低于10％，优选低于8％，优选低于7％，更优选低于5％；
    所述药物组合物中还包括酸碱调节剂；
    所述的酸碱调节剂选自氢氧化钠、氢氧化钾、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、盐酸、磷酸、硝酸、硫酸、或其组合；
    所述的酸碱调节剂是盐酸溶液或者氢氧化钠溶液，例如1M盐酸溶液或者1M氢氧化钠溶液；
    所述任选的酸碱调节剂的量是，使所述冻干粉针剂用注射用水溶解成含特拉唑嗪0.5mg/ml浓度的溶液时该溶液的pH值在3.0～5.0范围内的量，例如该溶液的pH值在3.5～4.5范围内的量；
    其中还包括枸橼酸；
    特拉唑嗪和枸橼酸的重量比为1：1～10，例如1：2～5；和/或
    所述药物组合物基本上是按包括如下的步骤制备的：
    (a)称取处方量的特拉唑嗪和赋形剂(以及任选的枸橼酸)，加入适量注射用水，搅拌使溶解，
    (b)向上一步骤所得药液中加入活性炭，搅拌，过滤脱炭；
    (c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或者任选地)用酸碱调节剂调节至pH3.0～5.0，优选pH3.5～4.5；
    (d)将药液除菌过滤，灌装于西林瓶中；
    (e)冷冻干燥除去水分，压塞，即得。
  9. 制备药物组合物例如权利要求1-5任一项的药物组合物的方法，其基本上包括如下步骤：
    (a)称取处方量的特拉唑嗪和赋形剂，加入适量注射用水，搅拌使溶解，
    (b)向上一步骤所得药液中加入活性炭，搅拌，过滤脱炭；
    (c)补加注射用水至处方全量，搅拌均匀，测定溶液pH值和任选的测定活性成分含量，必要时(或者任选地)用酸碱调节剂调节至pH3.0～5.0，优选pH3.5～4.5；
    (d)将药液除菌过滤，灌装于西林瓶中；
    (e)冷冻干燥除去水分，压塞，即得。
  10. 根据权利要求9的方法，其特征在于：
    所述特拉唑嗪是盐酸特拉唑嗪二水合物；
    所述赋形剂选自：甘露醇、乳糖、山梨醇、木糖醇、葡萄糖、麦芽糖、甘氨酸、可溶性糊精、黄原胶、明胶、水解明胶、阿拉伯胶、果胶、瓜尔胶、桃胶、黄芪胶、金合欢胶、羧甲基纤维素钠、聚乙烯吡咯烷酮、卡波姆、羟丙基纤维素、羟丙基甲基纤维素、海藻酸盐、或其组合；
    特拉唑嗪与赋形剂的重量比为1：10～1000，例如1：20～750，例如1：25～500；
    所述赋形剂不包括明胶或水解明胶；
    所述药物组合物是冷冻干燥的可用于注射的粉针剂，该粉针剂是用玻璃瓶密封包装的，每瓶中的特拉唑嗪的量为0.1mg～5mg，例如每瓶中的特拉唑嗪的量为0.1mg～2.5mg；
    所述药物组合物在密封条件下、在40℃避光放置6个月的时间内，杂质A增加率小于100％，特别是小于75％，更特别是小于50％；
    所述药物组合物中水分含量低于10％，优选低于8％，优选低于7％，更优选低于5％；和/或
    该方法进一步如说明书第三方面任一实施方案所述。
PCT/CN2016/080459 2015-06-11 2016-04-28 药物组合物 WO2016197738A1 (zh)

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