CN114681389A - Butylphthalide composition delivered through oral mucosa and application thereof - Google Patents
Butylphthalide composition delivered through oral mucosa and application thereof Download PDFInfo
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- CN114681389A CN114681389A CN202011591026.XA CN202011591026A CN114681389A CN 114681389 A CN114681389 A CN 114681389A CN 202011591026 A CN202011591026 A CN 202011591026A CN 114681389 A CN114681389 A CN 114681389A
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- Prior art keywords
- butylphthalide
- weight
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- oil
- surfactant
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- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical compound C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 title claims abstract description 292
- 229950005197 butylphthalide Drugs 0.000 title claims abstract description 147
- 239000000203 mixture Substances 0.000 title claims abstract description 122
- 210000002200 mouth mucosa Anatomy 0.000 title claims abstract description 22
- 239000004094 surface-active agent Substances 0.000 claims abstract description 96
- 238000004090 dissolution Methods 0.000 claims abstract description 19
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
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Abstract
The present disclosure relates to a butylphthalide composition for oral mucosal delivery and uses thereof. The composition comprises 100 parts by weight of butylphthalide, 50-1000 parts by weight of a first surfactant and 0.2-300 parts by weight of a water-soluble polymer. The composition can obviously improve the dissolution stability of the butylphthalide in oral saliva and increase the oral mucosa absorption of the butylphthalide. The butylphthalide composition delivered through the oral mucosa provided by the disclosure can be used for preventing or treating histopathological injury or nerve cell injury diseases caused by ischemia and hypoxia.
Description
Technical Field
The disclosure relates to a pharmaceutical composition delivered through oral mucosa and application thereof, in particular to a butylphthalide composition delivered through oral mucosa and application thereof.
Background
Butylphthalide (3-n-butylphthalide, also known as apigenin) and its two enantiomers (dextrobutylphthalide and levobutylphthalide) are pale yellow clear oily liquids, have strong volatility, have special pungent odor in oral cavity, are pungent, and are insoluble in water.
Patents CN1100097A and CN1623542A of Shiyaobipu disclose the composition of a soft capsule of Shiyaobipu, which is solubilized with butyl phthalide by vegetable oil to improve the solubility of the drug. However, oral butylphthalide has significant hepatic first pass effect (more than 70% is metabolically eliminated), low bioavailability, high dose multiple dosing (200mg (2 soft capsules), TID), and poor patient compliance.
Patent CN1394880A further discloses the composition of marketed embrittle injection, which uses cyclodextrin to improve the water solubility of butylphthalide, however, the use of a large amount of cyclodextrin has the risk of nephrotoxicity, and the administration mode of injection in the acute phase of nearly 14 days has poor patient compliance, and is limited in application, and is not suitable for routine administration of patients with out-of-hospital diseases and in the acute later phase.
In addition, various other means of solubilization of butylphthalide have been disclosed: such as emulsion-solubilized butylphthalide injection or oral preparation (CN100367951, CN100361656), butylphthalide oral tablet (CN200710062273) solubilized by surfactant and cyclodextrin, etc., however, the above compositions can not avoid the first-pass effect of the oral route and the clinical compliance problem of the injection route.
Therefore, there is a need to further optimize the prior art to meet the needs of clinical medication.
The oral mucosa administration is quick in absorption, has no liver first pass effect, can obviously improve the absorption and bioavailability under the non-injection administration way, is convenient for the out-of-hospital administration, and avoids the compliance problem of the injection way. Therefore, the oral mucosa delivery route can improve the clinical medication defect of the existing preparation on the market, and is a more ideal administration route.
Through search, the butylphthalide composition (CN103169676A) for oral mucosal delivery is disclosed at present, however, the disclosed technology of the butylphthalide sublingual composition still has the major defects that the solid dispersion tablet prepared by using semisolid lauric acid polyethylene glycol glyceride as the matrix is slowly dissolved in sublingual saliva (> 10 minutes), and the drug is easy to precipitate (the solubilization is unstable), so that the absorption and the bioavailability are limited. Moreover, the disclosed composition has poor effects of adsorption and solidification by lactose and silica gel (the phenomenon of butylphthalide still separates out) after mixing butylphthalide and lauric acid polyethylene glycol glyceride, has high requirements on tabletting process and has high difficulty in actual preparation or production.
Therefore, there is a need to further improve the technical scheme of the existing butylphthalide sublingual composition and develop a novel butylphthalide composition to improve the solubilization stability of butylphthalide, thereby improving the absorption and bioavailability of butylphthalide through oral mucosa and increasing the drug compliance of patients.
Disclosure of Invention
In the research of oral mucosa absorption promoting mechanism, the inventor of the present disclosure finds that butylphthalide has good dissolution rate in some surfactants with special structures, and further, when the butylphthalide is combined with a water-soluble polymer, the stability of the butylphthalide in artificial saliva can be significantly improved, in vitro dissolution permeability is improved, and oral mucosa absorption of the butylphthalide is increased. On this basis, the inventors have completed the present invention.
It is an object of the present disclosure to provide a butylphthalide composition for oral transmucosal delivery.
The disclosure also provides an application of the butylphthalide composition in preparing a medicament for preventing or treating histopathological injury or nerve cell injury diseases caused by ischemia and anoxia.
According to one aspect of the present disclosure, there is provided an oromucosally delivered butylphthalide composition comprising: 100 parts of butylphthalide, 50-1000 parts of first surfactant and 0.2-300 parts of water-soluble polymer.
According to another aspect of the disclosure, the use of the butylphthalide composition in the preparation of a medicament for preventing or treating pathological tissue damage or nerve cell damage diseases caused by ischemia and hypoxia is provided.
Advantageous effects
According to the butylphthalide composition disclosed by the invention, by containing the surfactant and the water-soluble polymer, the dilution stability of butylphthalide in saliva can be obviously improved, butylphthalide is prevented from being separated out, the dissolution permeability is increased, and the cumulative permeability after 3 hours is improved by more than 60% compared with that of a solid tablet disclosed by CN 103169676A; compared with the commercially available oral soft capsules and common sublingual solid tablets, the absorption and bioavailability of butylphthalide are obviously improved, and the absolute bioavailability (compared with the commercially available instillation preparation) can reach more than 55 percent, so that the prevention and treatment of ischemic cerebral apoplexy, vascular dementia, muscular atrophy (gradually freezing), angina and myocardial infarction can be realized in a non-injection administration mode under a lower dose, and the medicine taking compliance is improved.
Drawings
FIG. 1 is a graph comparing the drug-time curves of a butylphthalide composition of formula 1 according to one embodiment of the present disclosure with comparative formula 1-4 compositions and commercially available Enbipol soft capsules (Canine).
FIG. 2 is a graph of dissolution versus permeation for comparative formulation 5, prepared according to the prior art disclosure, and butylphthalide compositions prepared according to formulations 8, 10, and 11 of the present disclosure.
Fig. 3 is a graph comparing the drug-time curves of a commercial instillation formulation, a comparative formula 5 prepared according to the prior art disclosure, and butylphthalide compositions prepared according to the present disclosure, formula 8, formula 10, formula 11, and formula 18 (canines).
Detailed Description
To make the features and effects of the present invention comprehensible to those having ordinary knowledge in the art, general description and definitions are made with respect to terms and phrases mentioned in the specification and claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the terms "comprising," "including," "having," "containing," or any other similar term, are intended to be open-ended translational phrase and are intended to cover non-exclusive inclusions. For example, a composition or article comprising a plurality of elements is not limited to only those elements recited herein, but may include other elements not expressly listed but generally inherent to such composition or article. In addition, unless expressly stated to the contrary, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or". For example, the condition "a or B" is satisfied in any of the following cases: a is true (or present) and B is false (or not present), a is false (or not present) and B is true (or present), both a and B are true (or present). Furthermore, in this document, the terms "comprising," including, "" having, "" containing, "and" containing "are to be construed as specifically disclosed and to cover both closed and semi-closed conjunctions, such as" consisting of … "and" consisting essentially of ….
All features or conditions defined herein as numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to have covered and specifically disclosed all possible subranges and individual numerical values within the ranges, particularly integer numerical values. For example, a description of a range of "1 to 8" should be considered to have specifically disclosed all subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and so on, particularly subranges bounded by all integer values, and to have specifically disclosed individual values within that range such as 1, 2, 3, 4, 5, 6, 7, 8, and so on. Unless otherwise indicated, the foregoing explanatory methods apply to all matters contained in the entire disclosure, whether broad or not.
If an amount or other value or parameter is expressed as a range, preferred range, or a list of upper and lower limits, it is to be understood that all ranges subsumed therein for any pair of that range's upper or preferred value and that range's lower or preferred value, whether or not such ranges are separately disclosed, are specifically disclosed herein. Further, when a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.
In this context, numerical values should be understood to have the precision of the number of significant digits of the value, provided that the object of the invention is achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.
In this document, where Markush group (Markush group) or Option language is used to describe features or examples of the invention, those skilled in the art will recognize that a sub-group of all elements or any individual element within a Markush group or list of options may also be used to describe the invention. For example, if X is described as "selected from the group consisting of1、X2And X3The group "also indicates that X has been fully described as X1Is claimed with X1And/or X2Claim (5). Furthermore, where Markush group or option terms are used to describe features or examples of the invention, those skilled in the art will recognize that any combination of sub-groups of all elements or individual elements within the Markush group or option list can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of1、X2And X3Group consisting of "and Y is described as" selected from Y1、Y2And Y3The group "formed indicates that X has been fully described as X1Or X2Or X3And Y is Y1Or Y2Or Y3Claim (5).
The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application thereof. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or the summary of the invention or the following detailed description or examples.
Because the oral mucosa drug has small absorption area and is seriously washed by saliva, the composition for administration through the sublingual mucosa needs to meet the characteristics of low dosage, fast dissolution and absorption, otherwise, the composition is washed by the saliva and lost, thereby causing poor absorption and low bioavailability. Although the oil component (fatty glyceride) can effectively solubilize the insoluble compound, the oil is difficult to digest and absorb in the oral cavity (different from the gastrointestinal tract, lipase which does not digest the oil in the oral cavity and the like), so that the medicine dissolved in the oil cannot be rapidly released and absorbed, and CN103169676A proves that the dissolution rate of the butylphthalide solubilized by the oil such as glyceryl behenate, glyceryl stearate and the like is slow, and is not suitable for the application of the sublingual composition.
For the indissolvable medicament butylphthalide, the necessary condition for realizing the effective sublingual absorption is to maintain the solubilization stability in saliva and the quick release of the medicament. Amphiphilic surfactants based on fatty acids (e.g., polyglycolized fatty acid glycerides, which have both hydrophilic and lipophilic properties) are considered to be the preferred means for promoting oral absorption of poorly soluble drugs. However, the inventor researches and discovers that butylphthalide solubilized by using an amphiphilic surfactant (such as lauric acid polyethylene glycol glyceride, Gelucire 44/14) based on C12 or lower medium-short chain fatty acid alone can precipitate immediately after being diluted by saliva, and is not favorable for quick absorption of the medicine; and the single use of the same amount of amphiphilic surfactant based on the long-chain fatty acid of above C14, especially C18, can improve the stability of the butylphthalide in saliva to some extent, and maintain the dissolution stability of the butylphthalide for nearly 1h (without significant precipitation), which is helpful for increasing the absorption of the medicament through oral mucosa. Furthermore, the inventor also finds that when a certain amount of polymer is added into the butylphthalide composition solubilized by the amphiphilic surfactant based on the long-chain fatty acid with the length of more than C14, especially C18, the dispersion rate of the composition in saliva can be adjusted, and simultaneously the surfactant can be cooperated, so that the dissolution stability of butylphthalide in the composition can be further improved, the oral mucosa absorption of solubilized butylphthalide can be further improved, and the bioavailability of the medicament can be increased.
According to one embodiment of the present disclosure, there is provided a butylphthalide composition for oral transmucosal delivery, wherein the composition comprises:
100 parts of butylphthalide;
50-1000 parts by weight of a first surfactant, preferably 100-500 parts by weight;
0.2 to 300 parts by weight, preferably 0.3 to 200 parts by weight of a water-soluble polymer.
The first surfactant can improve the absorption utilization rate of butylphthalide through oral mucosa. The first surfactant is used in an amount of 50 to 1000 parts by weight, preferably 100 to 500 parts by weight, for example, 120, 150, 180, 200, 250, 300, 350, 400, 450 parts by weight, etc., based on 100 parts by weight of butylphthalide. If the amount of the first surfactant is too small, for example, less than 50 parts by weight, the stability of the drug in saliva becomes poor and the precipitation rate becomes fast; however, if the amount is too large, for example, more than 1000 parts by weight, the composition is bulky and unfavorable for delivery to the oral mucosa such as sublingual mucosa, and short-term absorption of the drug is difficult to achieve.
The first surfactant refers to an amphiphilic surfactant containing a long-chain fatty alcohol or fatty acid (or referred to as a long-chain fatty alcohol or fatty acid amphiphilic surfactant or an amphiphilic surfactant based on a long-chain fatty alcohol or fatty acid or an ester surfactant based on a long-chain fatty alcohol or fatty acid), and may be, for example, one or more selected from the group consisting of a surfactant based on a long-chain fatty acid polyoxyethylene (or referred to as polyethylene glycol) ester, a surfactant based on a long-chain fatty acid polyoxyethylene (or referred to as polyethylene glycol) glyceride, a surfactant based on a long-chain fatty acid phosphoglyceride, a surfactant based on a long-chain fatty acid sucrose ester, and a long-chain fatty acid polysorbate, but is not limited thereto. The long chain refers to a linear or branched carbon chain having 14 or more carbon atoms, that is, the long chain fatty acid or fatty alcohol refers to a linear or branched fatty acid or fatty alcohol having 14 or more carbon atoms of the carbon chain, for example, C14 to C22, including, but not limited to, fatty alcohols or fatty acids such as C15, C16, C17, C18, C19, C20, and C21. In particular, the surfactant is selected from amphiphilic surfactants based on C18 fatty acids or fatty alcohols.
More specifically, the first surfactant may be one or more selected from the group consisting of polyethylene glycol glyceryl oleate, polyethylene glycol glyceryl stearate, polyethylene glycol sorbitan oleate (e.g., Atlas G series surfactants), polyethylene glycol sorbitan monostearate/oleate (e.g., Accosperse series surfactants), polyethylene glycol-7-stearate, polyethylene glycol-75-glyceryl stearate, polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH40), polyoxyethylene (60) hydrogenated castor oil (Cremphor RH60), polyethylene glycol-12-hydroxystearate (Kolliphor HS15), polyoxyethylene 35 castor oil (Kolliphor EL/ELPKolliphor EL), polyoxyethylene (20) sorbitan monooleate (Tween80), but is not limited thereto.
The water-soluble polymer can play a synergistic role in dissolving stability in the butylphthalide composition, can be used for improving the dilution stability of active ingredients by cooperating with the first surfactant, improving the dissolution and the dissolution of the medicament after oral mucosa administration, further improving the effective utilization rate of the active ingredients, and can reach the blood concentration required by the medicament effect under lower dosage, thereby improving the compliance of patients.
In embodiments, the water soluble polymer may be one or more selected from polyvinylpyrrolidone (PVP, also known as povidone), vinylpyrrolidone/vinyl acetate copolymer (also known as copovidone), polyvinyl alcohol, carbomer, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, chitosan, carboxymethyl cellulose, xanthan gum, Poloxamer (Poloxamer), gelatin, pectin, sodium alginate and polyethylene glycol, more preferably one or more selected from PVP 64, Poloxamer 407 and xanthan gum.
The water-soluble polymer may be used in an amount of 0.2 to 300 parts by weight, preferably 0.3 to 200 parts by weight, for example, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 parts by weight, etc., based on 100 parts by weight of butylphthalide. If the amount of the water-soluble polymer is too small, for example, less than 0.2 part by weight, the synergistic effect of the polymer is weakened, which is disadvantageous in exerting the synergistic stability effect of the composition; whereas if the amount is too large, e.g., greater than 300 parts by weight, a larger amount of excipient is required to disperse or dissolve the polymer, resulting in a larger volume of the composition, which is detrimental to oral delivery of the composition.
According to one embodiment of the present disclosure, the butylphthalide composition may further comprise a second surfactant, which may be selected from one or more of medium chain fatty acid or fatty alcohol based surfactants, medium chain alkyl based ionic surfactants, short chain fatty acid or fatty alcohol based surfactants. Wherein the second surfactant may be used in an amount of 0 to 200 parts by weight, preferably 0 to 100 parts by weight, for example, 0, 10, 20, 30, 40, 50, 60, 70, 80, 90 parts by weight, etc., based on 100 parts by weight of butylphthalide.
In the case where the butylphthalide composition comprises a second surfactant, preferably, the total amount of both the first and second surfactants may be 50 to 1000 parts by weight, preferably 100 to 500 parts by weight, such as 100, 125, 150, 180, 200, 250, 300, 350, 400, 450 parts by weight, and the like, based on 100 parts by weight of butylphthalide. Further, the weight ratio of the first and second surfactants may be 1:0.01 to 5, preferably 1:0.01 to 1, such as 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, and the like. Within the weight ratio range, the second surfactant can also play a role in solubilizing the butylphthalide, and the effect of the butylphthalide solubilization of the first surfactant cannot be influenced.
The medium chain refers to a straight chain or branched chain carbon chain with 8-12 carbon atoms, and the short chain refers to a straight chain or branched chain carbon chain with 2-7 carbon atoms. The medium-chain fatty acid or fatty alcohol refers to C8-C12 fatty acid or fatty alcohol. The surfactant based on medium-chain fatty acid or fatty alcohol refers to an amphiphilic surfactant containing medium-chain fatty alcohol or fatty acid (or called medium-chain fatty alcohol or fatty acid amphiphilic surfactant or medium-chain fatty alcohol or fatty acid ester based surfactant or medium-chain fatty alcohol or fatty acid based surfactant), for example, one or more selected from polyethylene glycol glyceryl dodecanoate and polyethylene glycol glyceryl caprylate/caprate, but is not limited thereto. The dodecanoic acid is, for example, lauric acid, but not limited thereto. The medium-chain alkyl-based ionic surfactant refers to an ionic surfactant containing a C8-C12 alkyl group, and may be, for example, sodium lauryl sulfate, etc., but is not limited thereto. The short-chain fatty acid or fatty alcohol refers to fatty acid or fatty alcohol of C2-C7. The surfactant based on a short-chain fatty acid or fatty alcohol refers to an amphiphilic surfactant containing a short-chain fatty alcohol or fatty acid (or referred to as a short-chain fatty alcohol or fatty acid amphiphilic surfactant or a surfactant based on a short-chain fatty alcohol or fatty acid ester or a surfactant based on a short-chain fatty alcohol or fatty acid)), and for example, may be one or more selected from sucrose acetate isobutyrate and the like, but is not limited thereto.
According to one embodiment of the present disclosure, the composition may further comprise an excipient. The excipient may be used in an amount of 0 to 1000 parts by weight, preferably 200 to 800 parts by weight, based on 100 parts by weight of butylphthalide, but is not limited thereto.
The excipient may be any excipient suitable for the pharmaceutical agent administered through the oral mucosa in the art, for example, it may be one or more selected from diluents, antioxidants, preservatives, flavors, adsorbents, lubricants, etc., but is not limited thereto. One skilled in the art can select suitable excipients as desired and determine the appropriate amount to use in the butylphthalide composition of the present disclosure.
The amount of the diluent is not particularly limited and may be the amount conventionally used in oral mucosal drug delivery formulations. For example, the diluent may be used in an amount of 0 to 1000 parts by weight, preferably 150 to 800 parts by weight, based on 100 parts by weight of butylphthalide, but is not limited thereto.
The diluent may be one or more selected from small molecule solvents and greases. The small molecule solvent or grease can make the composition form a liquid preparation or a semisolid preparation with uniform dispersion and different fluidity or viscosity, so that the composition is convenient for patients to use. The small molecule solvent may be one or more selected from the group consisting of ethanol, propylene glycol, glycerol, isopropanol, polyethylene glycol, benzyl alcohol, diethylene glycol ethyl ether, ethyl acetate, water, propylene glycol diethyl ester, diethyl malonate, benzyl benzoate, azomethylpyrrolidone, dimethylacetamide, polyethylene glycol monomethyl ether, diethanolamine, and dimethyl sulfoxide, and may be used in an amount of 0 to 1000 parts by weight, preferably 50 to 1000 parts by weight, based on 100 parts by weight of butylphthalide, but is not limited thereto. The oil and fat can be one or more selected from soybean oil, corn oil, linoleic acid glyceride, peppermint oil, ethyl linoleate, peanut oil, cottonseed oil, sesame oil, fish oil, almond oil, peach kernel oil, sunflower seed oil, safflower oil, olive oil, coconut oil, palm oil, cocoa butter, tea oil, castor oil, sesame oil and medium-chain fatty acid glyceride. The oil may be used in an amount of 0 to 500 parts by weight based on 100 parts by weight of butylphthalide, but is not limited thereto. By adding the diluent, the effect of the composition in a liquid or semi-solid form suitable for oromucosal delivery can be adjusted. It has been found that the liquid and semi-solid compositions significantly improve the dissolution, dissolution and osmotic absorption of butylphthalide compared to the disclosed butylphthalide sublingual tablets.
The antioxidant and the preservative can improve the stability and clinical safety of the composition during long-term storage, so as to prevent oxidation or putrefaction during long-term storage. The antioxidant may be one or more selected from tocopherol, tocopherol acetate, vitamin E, sodium metabisulfite, cysteine hydrochloride, sodium bisulfite, ascorbic acid, thioglycerol, ascorbyl palmitate, BHT, BHA, but is not limited thereto. The preservative may be one or more selected from benzalkonium bromide, benzoic acid and its sodium salt, benzyl benzoate, sorbic acid and its potassium salt, parabens (parabens), but is not limited thereto.
The amount of the antioxidant and preservative is not particularly limited and may be the amount conventionally used in oral mucosal drug delivery formulations. For example, the antioxidant and the preservative may be used in an amount of 0 to 100 parts by weight, preferably 0 to 50 parts by weight, based on 100 parts by weight of butylphthalide, but is not limited thereto.
The flavoring agent in the composition is an additive with a taste correction effect, and is mainly used for covering the special smell and spicy taste of butylphthalide. The taste-improving agent is not particularly limited as long as it can be applied to a medicine, and may be selected as needed by those skilled in the art, for example, one or more selected from the group consisting of a sweetener, a cooling agent, a perfume and a sesame oil, but is not limited thereto. The flavoring agent can cover up pungent odor or generate special fragrance, and reduce pungent irritation of butylphthalide, thereby improving patient compliance. The correctant can be one or more selected from saccharin sodium, stevioside, aspartame, thaumatin, sodium cyclamate, acesulfame potassium, mogroside, xylitol, mannitol, lactose, glucose, sucrose, sucralose, honey, peppermint oil, menthol, thymol, eucalyptol, curcumin, WS-5, WS-23, apple essence, lemon essence, vanillin, tea essence, strawberry essence, pineapple essence, hawthorn essence, glucosyl stevioside, jasmine absolute, lemon oil, sweet orange oil, winter vanilla oil, sweet orange juice oil, rose absolute, grapefruit oil, borneol, sodium caseinate, alanine, citric acid, acetic acid, malic acid and trisodium citrate.
The dosage of the flavoring agent is not particularly limited, and can be the conventional dosage in oral mucosa drug delivery preparations. For example, the taste-corrective agent may be used in an amount of 0 to 200 parts by weight, preferably 0 to 150 parts by weight, based on 100 parts by weight of butylphthalide, but is not limited thereto.
In the present disclosure, the butylphthalide is one selected from racemized butylphthalide, levo-butylphthalide and dextro-butylphthalide, and preferably levo-butylphthalide or racemized butylphthalide.
The composition disclosed by the disclosure can be quantitatively loaded into a soft capsule or a device for quantitatively delivering a medicament (such as a quantitative spray or a drop device) and then is administrated through buccal mucosa or sublingual mucosa, and is suitable for industrial production. The composition may be in the form of a dosage form selected from sublingual drops (or solutions), sublingual gels, buccal sprays/aerosols, buccal gels or soft capsules.
The single administration dosage of the butylphthalide composition is 3-50 mg, preferably 4-40 mg, and more preferably 5-30 mg. The administration is performed 1 to 8 times per day, preferably 2 to 6 times per day.
According to the disclosure, the in-vitro dissolution-permeability of the butylphthalide is remarkably improved by using the butylphthalide composition of the water-soluble polymer and the first surfactant, and administration experiments such as oral mucosa of dogs prove that the absorption of a non-injection administration way can be remarkably improved, and the bioavailability of the butylphthalide through the oral mucosa is increased. Thus, the butylphthalide compositions described in the present disclosure may achieve an effective blood level of butylphthalide at lower delivered doses, reducing liver side effects, relative to other disclosed compositions.
According to one embodiment of the present disclosure, the cumulative in vitro dissolution permeability of the butylphthalide composition in artificial saliva for 3 hours reaches 60% or more.
According to an embodiment of the present disclosure, the butylphthalide composition can increase the absolute bioavailability to 55% or more, preferably 65% or more, and more preferably 80% or more, after oral mucosal delivery.
The butylphthalide composition is compared with an equal-dose commercial butylphthalide soft capsule preparation (Soft capsules (100 mg/granule)), C after oral mucosal administrationmaxAnd AUC0-4hAll the components are improved by more than 2 times, and part of the components are improved by more than 3 times, and the components can be improved by more than 4 times at most.
The butylphthalide composition is compared with the commercially available butylphthalide sodium chloride injection (with equal dosage), (b) and (c)Injection (25mg/100ml)), the absolute bioavailability can reach more than 55%, more can reach more than 65%, and can reach more than 80%.
The butylphthalide composition is compared with a disclosed sublingual tablet composition (CN103169676A example 1 composition) at equal dosage, CmaxAnd AUC0-4hCan be improved by 10 percent, can be improved by 20 percent partially, and can be improved by 30 percent at most.
Another aspect of the present disclosure relates to a use of the above butylphthalide composition according to the present disclosure in the preparation of a medicament for preventing or treating pathological tissue damage or nerve cell damage diseases caused by ischemia and hypoxia.
Wherein the disease is selected from ischemic cerebral apoplexy, vascular dementia, muscular atrophy, angina pectoris, and myocardial infarction.
The oral transmucosal delivery of butylphthalide compositions according to the present disclosure can be prepared as desired using conventional methods in the art without particular limitation. In one embodiment, the preparation method comprises the following steps:
a) the diluent dissolves the surfactant, butylphthalide and the like;
b) diluents dissolve polymers, flavors, etc.;
c) adding b) into a) with stirring, and mixing, and further stirring to dissolve to obtain the butylphthalide composition in liquid or semisolid form.
Examples
The invention is illustrated below with reference to examples, comparative examples, experimental examples, drawings and accompanying tables, which are merely illustrative of the technical solutions claimed by the invention and are not intended to limit the technical solutions, and the scope of the invention is not limited by these technical solutions.
In the examples, butylphthalide is from denna cheng hui duda, surfactants, polymers, flavors, excipients, and the like, available from basf, jiafa lion, chuanle essence (shanghai), nanjing waler, and the like.
The preparation method of the artificial saliva comprises the following steps:
3.0g of lactic acid, 0.2g of urea, 4.5g of sodium chloride, 0.3g of potassium chloride, 0.3g of sodium sulfate and 0.4g of ammonium chloride, wherein the volume of ultrapure water is fixed to 1000ml, and the pH value is adjusted to 6.8 by 1mol/l of sodium hydroxide;
the preparation method of the ethanol-PBS solution of 6 percent Tween80 comprises the following steps:
8.0g of sodium chloride, 0.2g of potassium chloride, 3.63g of sodium dihydrogen phosphate dodecahydrate and 0.24g of potassium dihydrogen phosphate, 700ml of pure water is added, the pH value is adjusted to 7.0 by hydrochloric acid, 200ml of ethanol is added, and finally, the pure water is added to the solution to reach the constant volume of 1000 ml.
The method for investigating the dilution condition of artificial saliva is as follows:
30mg equivalent of the preparation was taken and placed in a 2ml clear glass bottle, 1ml of artificial saliva was added, vortex-mixed at 300rpm for 1min, and then allowed to stand, and the presence or absence of the generation of the precipitate was visually observed.
The method for investigating sublingual absorption of dogs is as follows:
beagle dogs weighing about 10kg were randomly assigned and fasted for 12h before administration with free access to water.
A commercially available oral soft capsule (Enbip soft capsule (100 mg/capsule)) is orally administered at a dose of 100 mg/dog, and blood is taken before administration and after administration for 15min, 30min, 1h, 1.5h, 2h, and 4h, placed in a blood sampling vessel treated with heparin, centrifuged at 4000rpm for 10min, and plasma is separated and analyzed.
The test preparation is administered sublingually, no water can be drunk within 3min after administration, and the mouth of dog is combined to prevent drug loss due to tongue vomiting, and each dog is opened after 3min administration. Collecting blood before administration and after administration for 5min, 10min, 15min, 30min, 45min, 1h, 1.5h, 2h, and 4h, placing in blood collecting vessel treated with heparin, centrifuging at 4000rpm for 10min, separating plasma, and analyzing and detecting.
Peak blood concentration CmaxResulting from the highest blood concentration on the drug-time curve.
AUC0-4hThe area under the drug-time curve is 0 h-4 h, and is calculated by a trapezoidal method through Excel.
The absolute bioavailability F is the AUC of the tested preparation and the commercially available butylphthalide sodium chloride injection under the same dosage0-4hIs used as a percentage of (c).
The in vitro permeability study method is as follows:
taking the liquid medicine of each prescription composition, placing in a dialysis bag with proper size, adding 1ml artificial saliva for dilution and dispersion, sealing, immediately placing in ethanol-PBS solution of 6% Tween80 preheated to 37 ℃, incubating in a constant temperature shaking table (37 ℃, 100rpm/min), and sampling 1ml in 30min, 1h, 1.5h, 2h and 3h respectively (simultaneously supplementing blank solution with equal volume and equal temperature). The sample solution was centrifuged at 8000rpm for 10min, and the supernatant was taken as a test solution to determine the content of the free drug dissolved and permeated into the PBS solution to evaluate the dissolution-permeation efficiency of the drug.
Example 1: butylphthalide composition comprising a first surfactant Kolliphor EL and a polymer PVP VA64
TABLE 1
Weighing the prescribed amount of propylene glycol, Kolliphor EL, apple essence and butylphthalide, stirring for dissolving, adding PVP VA64 and other correctants dissolved in the prescribed amount of water, and continuously stirring (200rpm, 60min) for dissolving to obtain clear and transparent solution with special fragrance.
Stability was observed by diluting a solution of the formulation corresponding to 30mg of butylphthalide with 1ml of artificial saliva. The composition, amount, and dilution observation of artificial saliva for formula 1 are shown in Table 1 above.
Comparative example 1: butylphthalide composition free of first surfactant or polymer
TABLE 2
Weighing the diluent, the apple essence, the surfactant, the butylphthalide and the like according to the prescription amount, stirring, mixing and dissolving, adding the polymer dissolved in water and other flavoring agents according to the prescription amount, and continuing stirring until the solution is clear and transparent and no oily liquid is visible.
Stability was observed by diluting a solution of the formulation corresponding to 30mg of butylphthalide with 1ml of artificial saliva. The results of observing the dilution conditions of the components, the amounts, and the artificial saliva for comparative formulas 1-4 are shown in Table 2 above.
As can be seen from the artificial saliva dilution results in tables 1 and 2, the stability of formula 1 containing the C18 surfactant Kolliphor EL and the polymer PVP VA64 was significantly improved over comparative formula 1 containing no surfactant and polymer, comparative formula 2 containing no polymer, comparative formula 3 and comparative formula 4 containing a short (sucrose acetate isobutyrate) or medium chain (e.g., glycerol laureth 12) surfactant and polymer. It can be seen that the combination of the water-soluble polymer of the present disclosure and the first surfactant can significantly improve the dissolution stability of butylphthalide in saliva.
Experimental example 1:
using formula 1, comparative formula 1-comparative formula 4 in example 1, prepared above, sublingual administration to dogs was performed at a dose of 30 mg/dog to examine the effect of surfactants and polymers on butylphthalide absorption, and the results are shown in FIG. 1 and Table 3 below.
Table 3: pharmacokinetic parameters of butylphthalide compositions comprising surfactant Kolliphor EL and polymer PVPVA64
CmaxRefers to the highest blood concentration, AUC0-4hRefers to the area under the curve of blood concentration-time within 0-4 hours
The results show the AUC of formula 1 with the C18 surfactant Kolliphor EL and the polymer PVP VA640-4hAnd CmaxThis is significantly higher than comparative formula 1, which contains no surfactant and polymer, comparative formula 2, which contains no polymer, comparative formula 3, which contains a short or medium chain surfactant and polymer, and comparative formula 4. It can be seen that the combination of the water-soluble polymer and the first surfactant according to the present disclosure can improve absorption of butylphthalide at sublingual mucosa.
Example 2 Butylphthalide composition containing different first surfactants
TABLE 4
Prescription 2-prescription 6, weighing the diluent, the flavoring agent, the melted surfactant, the polymer, the butylphthalide and the like according to the prescription amount, stirring, mixing and dissolving until the solution is clear and transparent.
Stability was observed by diluting a solution of the formulation corresponding to 30mg of butylphthalide with 1ml of artificial saliva. The composition, content, and dilution of artificial saliva observed for formulas 2-6 are shown in Table 4 above.
The results show that the compositions of formula 2 to formula 6 are stable after artificial saliva, and no obvious precipitate is generated within 3 hours.
Example 3 Butylphthalide compositions for different polymer types and amounts
TABLE 5
And (3) weighing the diluent, the polymer, the flavoring agent, the surfactant and the butylphthalide according to the prescription amount in turn according to the prescription 7-prescription 9, stirring, mixing and dissolving until the solution is clear and transparent and no oily liquid can be seen.
The prescription is 10-12, after the butylphthalide, the surfactant and the apple essence are dissolved by the propylene glycol, the prescription amount of the polymer and other flavoring agents which are dissolved by water are added, and the uniform and transparent gel product is prepared by stirring, mixing, dissolving and degassing.
Stability was observed by diluting a solution of the formulation corresponding to 30mg of butylphthalide with 1ml of artificial saliva. The composition, amount, and dilution observations of artificial saliva for formulas 7-12 are listed in table 5, above.
The results show that the compositions of formula 7 to formula 12 are stable after artificial saliva, and no precipitate is precipitated within 3 hours.
Example 4 Butylphthalide composition containing both first and second surfactants
TABLE 6
Prescription 13-prescription 17, weighing the diluent, the flavoring agent, the polymer, the surfactant, the butylphthalide and the like according to the prescription amount, stirring, mixing and dissolving until the solution is clear and transparent.
Stability was observed by diluting a solution of the formulation corresponding to 30mg of butylphthalide with 1ml of artificial saliva. The components of recipes 13-17, and the results of the dilution observation of artificial saliva, are listed in table 6 above.
The results show that the compositions of formula 13 to formula 17 are stable after artificial saliva, and no precipitate is precipitated within 3 hours.
EXAMPLE 5 Butylphthalide compositions of varying flavor types and amounts
TABLE 7
Prescription 18-prescription 20, weighing the diluent, the flavoring agent, the polymer, the surfactant, the butylphthalide and the like according to the prescription amount, stirring, mixing and dissolving until the solution is clear and transparent.
Stability was observed by diluting a solution of the formulation corresponding to 30mg of butylphthalide with 1ml of artificial saliva. The components of recipes 18-20, and the observation of dilution of artificial saliva, are listed in table 7 above.
The results show that the compositions of formula 18 to formula 20 are stable after artificial saliva, and no precipitate is precipitated within 3 hours.
Comparative example 2:
according to the prescription and process disclosed in patent CN103169676A, example 1, a butylphthalide buccal tablet with Gelucire 44/14 as a matrix and a unit dose of 30mg, comparative prescription 5 composition, was prepared, and the composition of each component is shown in the following Table 7:
TABLE 7
The preparation method comprises the following steps: the butylphthalide, the glycerol polyethylene glycol laurate and the lactose in the prescription amount disclosed in CN103169676A and obtained in example 1 are added into a double-screw extruder, the section temperature of the extruder is set to be 30-60-60-60-45 ℃, and the rotating speed of a screw of a main machine and the rotating speed of a feeding machine are both set to be 25 rpm.
The composition prepared according to the recipe and process of Table 7 above had poor solidification upon cooling at room temperature and was lightly pressed into semi-solid stick tablets after cooling at 4 ℃ for 12 hours to give the composition of comparative recipe 5.
Experimental example 2
The formulations corresponding to 30mg of butylphthalide were used to perform in vitro dissolution and permeation studies comparing formulation 5 with formulation 8, formulation 10 and formulation 11 gels according to the in vitro permeation test method described above, and the results are shown in table 8 and fig. 2 below.
TABLE 8 in vitro dissolution-penetration results for different compositions
Time (h) | Prescription 8 (%) | Prescription 10 (%) | Prescription 11 (%) | Comparative prescription 5 (%) |
0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
0.50 | 25.91 | 14.36 | 16.36 | 1.48 |
1.00 | 49.88 | 28.03 | 31.03 | 3.69 |
1.50 | 65.88 | 40.37 | 42.37 | 4.29 |
2.00 | 77.18 | 48.26 | 52.26 | 5.48 |
3.00 | 87.09 | 58.51 | 62.51 | 7.64 |
As can be seen from table 8, according to formulations 8, 10, 11 of the present disclosure, the dissolution and penetration-promoting rates were significantly improved, and the 3h penetration was improved by more than 7 times, compared to the comparative formulation 5 tablet, which has been disclosed in the prior art.
Experimental example 3
Comparative sublingual absorption studies in dogs were performed comparing the composition of formula 5 with the solution of formula 8, the gel of formula 10, formula 11 and formula 18, and a 25mg dose (25mg standard, instillation 60min) of a commercially available instillation formulation (enbip injection), the results of which are shown in table 9 and figure 3 below.
TABLE 9
The results show that the composition of comparative formula 5 dissolves slowly (more than about 10min complete dissolution) after sublingual administration to dogs. While the absolute bioavailability of the formula 8, formula 10, formula 11, and formula 18 compositions solubilized using the polymer and long chain fatty acid ester surfactant according to the present disclosure was at least 25.5% higher, formula 8 and formula 18 were even more than 1-fold higher, relative to comparative formula 5 disclosed in CN 103169676A.
The above embodiments are merely exemplary in nature and are not intended to limit the claimed embodiments or the application or uses of such embodiments. In this document, the term "exemplary" represents "as an example, instance, or illustration. Any exemplary embodiment herein is not necessarily to be construed as preferred or advantageous over other embodiments.
In addition, while at least one exemplary embodiment or comparative example has been presented in the foregoing detailed description, it should be appreciated that a vast number of variations are possible. It should also be appreciated that the embodiments described herein are not intended to limit the scope, applicability, or configuration of the claimed subject matter in any way. Rather, the foregoing implementations will provide those of ordinary skill in the art with a convenient road map for implementing the described embodiment or embodiments. Further, various changes may be made in the function and arrangement of elements without departing from the scope defined in the claims, which includes known equivalents and all foreseeable equivalents at the time of filing this patent application.
Claims (10)
1. An oral transmucosal delivery butylphthalide composition comprising:
100 parts of butylphthalide;
50-1000 parts by weight of a first surfactant, preferably 100-500 parts by weight;
0.2 to 300 parts by weight, preferably 0.3 to 200 parts by weight of a water-soluble polymer.
2. The butylphthalide composition according to claim 1, wherein the first surfactant is an amphiphilic surfactant containing a long-chain fatty alcohol or fatty acid, in particular one or more selected from the group consisting of a long-chain fatty acid polyoxyethylene ester-based surfactant, a long-chain fatty acid polyoxyethylene glyceride-based surfactant, a long-chain fatty acid phosphoglyceride-based surfactant, a long-chain fatty acid sucrose ester-based surfactant, and a long-chain fatty acid polysorbate-based surfactant, the long chain being a linear or branched carbon chain having 14 or more carbon atoms, such as a linear or branched carbon chain from C14 to C22;
in particular, the first surfactant is used in an amount of 50 to 1000 parts by weight, preferably 100 to 500 parts by weight, based on 100 parts by weight of butylphthalide.
3. The butylphthalide composition according to claim 1, wherein the first surfactant is selected from the group consisting of C18 fatty acid-or fatty alcohol-based amphiphilic surfactants,
in particular, the first surfactant is one or more selected from the group consisting of polyethylene glycol glyceryl oleate, polyethylene glycol glyceryl stearate, polyethylene glycol sorbitol oleate, polyethylene glycol sorbitan monostearate/oleate, polyethylene glycol-7-stearate, polyethylene glycol-75-glyceryl stearate, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyethylene glycol-12-hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene (20) sorbitan monooleate.
4. The butylphthalide composition according to claim 1, wherein the water-soluble polymer is one or more selected from polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, carbomer, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, sodium alginate, chitosan, xanthan gum, Poloxamer, gelatin, pectin, sodium alginate and polyethylene glycol, preferably one or more selected from PVP VA64, Poloxamer 407 and xanthan gum;
in particular, the water-soluble polymer is used in an amount of 0.2 to 300 parts by weight, preferably 0.3 to 200 parts by weight, based on 100 parts by weight of butylphthalide.
5. The butylphthalide composition according to claim 1, wherein the butylphthalide composition further comprises a second surfactant, the second surfactant being one or more selected from the group consisting of a medium chain fatty acid or fatty alcohol based surfactant, a medium chain alkyl based ionic surfactant, a short chain fatty acid or fatty alcohol based surfactant; the medium chain refers to a straight chain or branched chain carbon chain with 8-12 carbon atoms, and the short chain refers to a straight chain or branched chain carbon chain with 2-7 carbon atoms;
in particular, the second surfactant may be used in an amount of 0 to 200 parts by weight, preferably 0 to 100 parts by weight, based on 100 parts by weight of butylphthalide;
preferably, the total amount of both the first and second surfactants is 50 to 1000 parts by weight, preferably 100 to 500 parts by weight, based on 100 parts by weight of butylphthalide;
particularly, the weight ratio of the first surfactant to the second surfactant is 1: 0.01-5, preferably 1: 0.01-1;
in particular, the surfactant based on medium-chain fatty acids or fatty alcohols refers to an amphiphilic surfactant containing medium-chain fatty alcohols or fatty acids, in particular selected from one or more of macrogolglycerides dodecanoate, caprylic/capric; the medium-chain alkyl group-based ionic surfactant refers to a medicinal ionic surfactant containing medium-chain alkyl groups, and is especially sodium dodecyl sulfate; the surfactant based on short-chain fatty acid or fatty alcohol refers to an amphiphilic surfactant containing short-chain fatty alcohol or fatty acid, and particularly is sucrose acetate isobutyrate.
6. The butylphthalide composition according to claim 1, wherein the butylphthalide composition further comprises an excipient;
particularly, the excipient is used in an amount of 0 to 1000 parts by weight, preferably 200 to 800 parts by weight, based on 100 parts by weight of butylphthalide;
in particular, the excipient is one or more selected from diluent, antioxidant, preservative and flavoring agent;
particularly, the diluent is one or more selected from small molecule solvents and grease;
in particular, the diluent is used in an amount of 0 to 1000 parts by weight, preferably 150 to 800 parts by weight, based on 100 parts by weight of butylphthalide,
in particular, the small molecule solvent is one or more selected from ethanol, propylene glycol, glycerol, isopropanol, polyethylene glycol, benzyl alcohol, diethylene glycol ethyl ether, ethyl acetate, water, propylene glycol diethyl ester, diethyl malonate, diethanol amine, benzyl benzoate, azomethyl pyrrolidone, dimethyl acetamide, polyethylene glycol monomethyl ether and dimethyl sulfoxide,
particularly, the small molecular solvent is used in an amount of 0 to 1000 parts by weight, preferably 50 to 1000 parts by weight, based on 100 parts by weight of butylphthalide;
in particular, the oil is one or more selected from soybean oil, corn oil, linoleic acid glyceride, peppermint oil, ethyl linoleate, peanut oil, cottonseed oil, sesame oil, fish oil, almond oil, peach kernel oil, sunflower seed oil, safflower oil, olive oil, coconut oil, palm oil, cocoa bean oil, tea oil, castor oil, sesame oil and medium-chain fatty acid glyceride;
particularly, the amount of the oil is 0 to 500 parts by weight based on 100 parts by weight of butylphthalide;
in particular, the antioxidant is one or more selected from tocopherol, tocopherol acetate, vitamin E, sodium metabisulfite, cysteine hydrochloride, sodium sulfite, sodium metabisulfite, sodium bisulfite, ascorbic acid, thioglycerol, ascorbyl palmitate, BHT and BHA;
in particular, the preservative is one or more selected from benzalkonium bromide, chlorhexidine acetate, benzoic acid and its sodium salt, benzyl benzoate, sorbic acid and its potassium salt, parabens;
particularly, the antioxidant and the preservative are used in an amount of 0 to 100 parts by weight, preferably 0 to 50 parts by weight, based on 100 parts by weight of butylphthalide;
particularly, the flavoring agent is one or more selected from sweetening agent, cooling agent, essence and sesame oil, in particular from one or more selected from saccharin sodium, stevioside, aspartame, thaumatin, sodium cyclamate, acesulfame, mogroside, xylitol, mannitol, lactose, glucose, sucrose, sucralose, honey, peppermint oil, menthol, thymol, eucalyptol, WS-5, WS-23, apple essence, vanillin, lemon essence, tea essence, strawberry essence, pineapple essence, hawthorn essence, glucosyl stevioside, jasmine sambac absolute, lemon oil, sweet orange oil, winter vanilla oil, sweet orange oil, rose absolute, grapefruit oil, borneol, sodium caseinate, alanine, citric acid, acetic acid, malic acid and trisodium citrate;
particularly, the amount of the taste-corrective is 0 to 200 parts by weight, preferably 0 to 150 parts by weight, based on 100 parts by weight of butylphthalide.
7. The butylphthalide composition according to claim 1, wherein the butylphthalide is one selected from racemic butylphthalide, levobutylphthalide and dextrobutylphthalide, preferably levobutylphthalide or racemic butylphthalide.
8. The butylphthalide composition according to claim 1, wherein the composition is in a dosage form selected from the group consisting of sublingual drops, sublingual gels, buccal sprays/aerosols, buccal gels, and soft capsules;
particularly, the single administration dose of the butylphthalide composition is 3-50 mg, preferably 4-40 mg, more preferably 5-30 mg, and the administration times per day are 1-8 times, preferably 2-6 times.
9. The butylphthalide composition according to any one of claims 1 to 8, wherein the butylphthalide composition has a cumulative dissolution permeability of 60% or more for 3 hours in artificial saliva; and/or
Wherein, after the butylphthalide composition is delivered by oral mucosa, the absolute bioavailability reaches more than 55%, preferably more than 65%, and more preferably more than 80%.
10. Use of the butylphthalide composition of any one of claims 1-9 in the preparation of a medicament for preventing or treating pathological tissue damage or nerve cell damage caused by ischemia and anoxia,
in particular, the disease is selected from ischemic stroke, vascular dementia, muscular atrophy, angina, myocardial infarction.
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CN100361656C (en) * | 2004-08-27 | 2008-01-16 | 石药集团中奇制药技术(石家庄)有限公司 | Butylbenzene phthalein self emulsifying releasing medicine system, preparation method and application |
CN103505409B (en) * | 2012-06-27 | 2017-12-26 | 石药集团中奇制药技术(石家庄)有限公司 | A kind of 3-n-butylphthalide injection and preparation method thereof |
CN103505414B (en) * | 2012-06-28 | 2017-08-08 | 石药集团恩必普药业有限公司 | Butylphthalide nasal drop and preparation method thereof |
CN105434426B (en) * | 2014-11-10 | 2018-06-15 | 石药集团恩必普药业有限公司 | One kind contains butylphenyl phthaleine pharmaceutical preparations composition and application thereof |
CN105688220A (en) * | 2014-12-15 | 2016-06-22 | 四川曼赛思医药科技有限公司 | Pharmaceutical composition containing butylphthalide and novel solubilizer |
CN105999279A (en) * | 2016-05-30 | 2016-10-12 | 四川曼赛思医药科技有限公司 | Medicine composition comprising butylphthalide and cosolvent |
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2020
- 2020-12-29 CN CN202011591026.XA patent/CN114681389A/en active Pending
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2021
- 2021-12-28 WO PCT/CN2021/141977 patent/WO2022143631A1/en active Application Filing
- 2021-12-28 CN CN202180062137.8A patent/CN116209437A/en active Pending
Also Published As
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CN116209437A (en) | 2023-06-02 |
WO2022143631A1 (en) | 2022-07-07 |
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