CN116209437A

CN116209437A - Butylphthalide composition delivered through oral mucosa and application thereof

Info

Publication number: CN116209437A
Application number: CN202180062137.8A
Authority: CN
Inventors: 甘勇; 朱全垒; 郭仕艳
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2020-12-29
Filing date: 2021-12-28
Publication date: 2023-06-02
Also published as: WO2022143631A1; CN114681389A

Abstract

Relates to a butylphthalide composition delivered through oral mucosa and application 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 remarkably 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 can be used for preventing or treating tissue pathological injury or nerve cell injury diseases caused by ischemia and hypoxia.

Description

Butylphthalide composition delivered through oral mucosa and application thereof

Technical Field

The present disclosure relates to a pharmaceutical composition delivered via oral mucosa and uses thereof, and in particular, to a butylphthalide composition delivered via oral mucosa and uses thereof.

Background

Butylphthalide (3-n-butyl phthalide, also known as apigenin A), and its two enantiomers (dextrorotatory butylphthalide and levobutylphthalide) are both pale yellow clear oily liquid, have strong volatility, have special pungent smell in oral cavity, have pungent feel, and are insoluble in water.

Patent CN1100097A, CN1623542a of Dan Yaoen biprop discloses the composition of a marketed enbiprop soft capsule, which solubilizes butylphthalide with vegetable oil, improving the drug solubility. However, oral administration of butylphthalide, with significant liver first pass effect (more than 70% being metabolised, eliminated), low bioavailability, multiple dosing at high doses (200 mg (2-granule soft capsule), TID), and poor patient compliance.

Patent CN1394880a further discloses the composition of the marketed nebivopril 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 like, and the injection administration of the drug for nearly 14 days in the acute phase has poor patient compliance, is limited in application and is not suitable for the conventional administration of patients with nosocomial morbidity and acute later phase.

In addition, various other compositions have been disclosed which are obtained using a butylphthalide solubilisation means: such as emulsion-solubilized butylphthalide injection or oral formulation (CN 100367951, CN 100361656), butylphthalide oral tablet (CN 200710062273) synergistically solubilized with surfactant and cyclodextrin, etc., however, the above compositions are not capable of avoiding the first pass effect of the oral route and the clinical compliance and safety problems of the injection route.

Therefore, to meet the clinical demands of drug use, it is necessary to further optimize the prior art.

The oral mucosa is administrated, the absorption is fast, the first pass effect of liver is avoided, the absorption and the bioavailability under the non-injection administration route can be obviously improved, the administration outside the hospital is convenient, and the problem of compliance of the injection route is avoided. Therefore, the oral mucosa delivery way can improve the clinical medication defect of the existing marketed preparation, and is an ideal administration way.

By searching, butylphthalide compositions (CN 103169676A) delivered through oral mucosa are disclosed at present, however, the disclosed butylphthalide sublingual composition technology still has major defects that solid dispersion tablets prepared by taking semisolid lauric acid polyethylene glycol glyceride as a matrix are slowly dissolved in sublingual saliva (> 10 minutes), and medicines are easy to separate out (solubilization is unstable), so that absorption and bioavailability are limited. In addition, after the butylphthalide and the lauric acid polyethylene glycol glyceride are mixed in the composition, the adsorption and solidification effects of lactose and silica gel are poor (the phenomenon of precipitation of butylphthalide still exists), the pharmaceutical composition is pressed into a semisolid tablet, the technological requirement on continuous production is high, and the practical production and storage difficulty is high.

In addition, the sublingual composition forms disclosed in other patents are mostly administration forms of common solid tablets, such as edaravone sublingual compositions disclosed in patents CN201810797624.9, CN201780048512.7 and the like, conventional auxiliary materials of sublingual tablets, such as mannitol, copovidone or hypromellose and the like, are selected, and the auxiliary materials and the edaravone and the like are combined and tabletted for sublingual delivery; however, the conventional auxiliary materials are not suitable for mixing and curing liquid butylphthalide raw materials, continuous production of butylphthalide cannot be realized, and absorption of butylphthalide cannot be improved.

Therefore, it is necessary to further improve the technical scheme of the existing sublingual composition of butylphthalide, develop a better novel butylphthalide composition, so as to improve the solubilization stability of butylphthalide, further improve the absorption and bioavailability of butylphthalide through oral mucosa, and increase the administration compliance and administration safety 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 in some surfactants with special structures, and further combines with water-soluble polymers, so that the stability of butylphthalide in artificial saliva can be significantly improved, the in vitro dissolution permeability is improved, and the oral mucosa absorption of butylphthalide is increased. On this basis, the inventors completed the present invention.

It is an object of the present disclosure to provide a butylphthalide composition for delivery via the oral mucosa.

Another object of the present disclosure is to provide the use of the butylphthalide composition in the preparation of a medicament for preventing or treating a tissue injury or a nerve cell injury disease caused by ischemia and hypoxia.

According to one aspect of the present disclosure there is provided a butylphthalide composition for delivery via the oral mucosa 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 present disclosure there is provided the use of the butylphthalide composition in the manufacture of a medicament for preventing or treating a disease of the histopathological injury or neuronal injury type caused by ischemia and hypoxia.

Advantageous effects

According to the butylphthalide composition disclosed by the invention, the dilution stability of butylphthalide in saliva can be obviously improved by containing the surfactant and the water-soluble polymer, the rapid precipitation of butylphthalide is prevented, the dissolution permeability of the medicine is increased, and compared with a solid tablet disclosed in CN103169676A, the cumulative permeability of 3 hours is improved by more than 60%; compared with the commercial oral soft capsules and common sublingual solid tablets, the absorption and bioavailability of butylphthalide are obviously improved, and the absolute bioavailability (compared with the commercial instillation preparation) of the butylphthalide can reach more than 55%, so that the prevention and treatment of ischemic cerebral apoplexy, vascular dementia, amyotrophic lateral atrophy (freezing syndrome), angina pectoris and myocardial infarction are realized in a non-injection administration mode at a lower dosage, and the administration compliance is improved.

Drawings

Fig. 1 is a graph comparing the drug-time curves of the butylphthalide composition of formula 1 with the comparative compositions of formulas 1-4 and the commercially available entaipu soft capsule (canine) according to one embodiment of the present disclosure.

Fig. 2 is a dissolution-permeation graph of a comparative formulation 5 prepared according to the prior art disclosure and a butylphthalide composition prepared according to formulations 8, 10 and 11 of the present disclosure.

Fig. 3 is a graph comparing drug-time curves of a commercially available instillation formulation, comparative prescription 5 prepared according to the prior art, and butylphthalide compositions prepared according to prescriptions 8, 10, 11, 18 of the present disclosure (canine).

Detailed Description

So that those having ordinary skill in the art can appreciate the features and effects of the present invention, the following general description and definitions apply to the terms and expressions set forth in the specification and claims. Unless otherwise defined, 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, in the event of a conflict, the present specification shall control.

As used herein, the terms "comprising," "including," "having," "containing," or any other similar language, are intended to cover a non-exclusive inclusion, as an open-ended connection (open-ended transitional phrase). For example, a composition or article comprising a plurality of elements is not limited to only those elements listed herein, but may include other elements not explicitly listed but typically inherent to such composition or article. In addition, unless explicitly stated to the contrary, the term "or" refers to an inclusive "or" and not to an exclusive "or". For example, any one of the following conditions satisfies the condition "a or B": a is true (or present) and B is false (or absent), a is false (or absent) and B is true (or present), a and B are both true (or present). Furthermore, the terms "comprising," "including," "having," "containing," and their derivatives, as used herein, are intended to be open ended terms that have been specifically disclosed and encompass both the closed and semi-closed terms, consisting of …, and consisting essentially of ….

All features or conditions defined herein in terms of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "1 to 8" should be taken as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be taken as having specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. The foregoing explanation applies to all matters of the invention throughout its entirety unless indicated otherwise, whether or not the scope is broad.

If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range, whether or not separately disclosed, from any pair of the upper or preferred value for that range and the lower or preferred value for that range is specifically disclosed herein. Furthermore, where 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 accuracy of the numerical significance of the numerical values provided that the objectives of the present invention are achieved. For example, the number 40.0 is understood to cover a range from 39.50 to 40.49.

In this document, where Markush group (Markush group) or option-type language is used to describe features or examples of the present invention, those skilled in the art will appreciate that a sub-group of all elements within a Markush group or option list or any individual element may also be used to describe the present invention. For example, if X is described as "selected from X ₁ 、X ₂ X is X ₃ The group "of which X is X has been fully described ₁ Is claimed and X is X ₁ And/or X ₂ Is claimed. Furthermore, where markush groups or option expressions are used to describe features or examples of the invention, those skilled in the art will appreciate that any combination of sub-groups or individual elements of all elements within a markush group or option list may also be used to describeThe invention relates to a method for manufacturing a semiconductor device. Accordingly, for example, if X is described as "selected from X ₁ 、X ₂ X is X ₃ A group of "and Y is described as" selected from Y ₁ 、Y ₂ Y and Y ₃ The group "of groups indicates that X has been fully described as X ₁ Or X ₂ Or X ₃ And Y is Y ₁ Or Y ₂ Or Y ₃ Is claimed.

The following detailed description is merely exemplary in nature and is not intended to limit the invention and its uses. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or summary or the following detailed description or examples.

Because the oral mucosa medicine has small absorption area and is seriously washed by saliva, the composition which is administrated through sublingual mucosa needs to meet the characteristics of low dosage, dissolution and quick absorption, otherwise, the composition is washed and lost by saliva, so that the absorption is poor and the bioavailability is low. Although the lipid component (fatty glyceride) can effectively solubilize the poorly soluble compound, the lipid is difficult to digest and absorb in the oral cavity (unlike the gastrointestinal tract, lipase without digestive lipid in the oral cavity, etc.), so the lipid-soluble drug cannot be released and absorbed quickly, and CN103169676a has proved that the dissolution rate of the lipid-solubilized butylphthalide such as glyceryl behenate, glyceryl stearate, etc. is slow, and is not suitable for the application of sublingual compositions.

For the poorly soluble drug butylphthalide, maintaining the rapid release and solubilization stability of the drug in saliva is a necessary condition for achieving effective sublingual absorption. Amphiphilic surfactants based on fatty acids (e.g. polyglycolized fatty acid glycerides, having both hydrophilic and lipophilic properties) are considered to be the preferred means of oral pro-absorption of poorly soluble drugs. However, the inventors have found that the use of amphiphilic surfactants based on C12 or lower medium and short chain fatty acids alone (such as polyethylene glycol glycerol laurate, gelucire 44/14) solubilizes butylphthalide, which precipitates immediately after saliva dilution, adversely affecting rapid drug absorption; the amphiphilic surfactant based on the long-chain fatty acid with more than C14, particularly C18, can be used independently, so that the stability of the butylphthalide in saliva can be improved to a large extent, and the dissolution stability (no obvious precipitation) of the butylphthalide is maintained for nearly 1h, which is beneficial to the increase of the rapid absorption of the medicament through the oral mucosa. Further, the inventors have found that, in a butylphthalide composition solubilized with an amphiphilic surfactant based on a long-chain fatty acid of C14 or more, particularly C18, adding a certain amount of a polymer not only can adjust the dispersion rate of the composition in saliva, but also can cooperate with the surfactant to further improve the dissolution stability of butylphthalide in the composition, further improve the oral mucosa absorption of butylphthalide after solubilization, and increase the bioavailability of the drug.

According to one embodiment of the present disclosure there is provided a butylphthalide composition for delivery via the oral mucosa, wherein the composition comprises:

100 parts by weight of butylphthalide;

50 to 1000 parts by weight, preferably 100 to 500 parts by weight, of a first surfactant;

the water-soluble polymer is 0.2 to 300 parts by weight, preferably 0.3 to 200 parts by weight.

The first surfactant can improve the absorption and 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 rate of precipitation becomes fast; on the other hand, if the amount is too large, for example, more than 1000 parts by weight, the volume of the composition is large, which is unfavorable for delivery of 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 a long-chain fatty alcohol or fatty acid-based amphiphilic surfactant or a long-chain fatty acid-based ester surfactant), and may be selected from one or more of a long-chain fatty acid polyoxyethylene (or polyethylene glycol) ester-based surfactant, a long-chain fatty acid polyoxyethylene (or polyethylene glycol) 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, for example, 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, for example, C14 to C22, including but not limited to C15, C16, C17, C18, C19, C20, C21, etc., fatty alcohol or fatty acid. In particular, the surfactant is an amphiphilic surfactant based on a C18 fatty acid or fatty alcohol.

More particularly, the first surfactant may be selected from one or more of polyethylene glycol glyceryl oleate, polyethylene glycol glyceryl stearate, polyethylene glycol sorbitol oleate (e.g., atlas G series surfactants), polyethylene glycol sorbitan monostearate/oleate (e.g., accosperase series surfactants), polyethylene glycol-7-stearate, polyethylene glycol-75-glyceryl stearate, polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH 40), polyoxyethylene (60) hydrogenated castor oil (cremophor RH 60), polyethylene glycol-12-hydroxystearate (Kolliphor HS 15), polyoxyethylene 35 castor oil (Kolliphor EL/ELPKolliphor EL), polyoxyethylene (20) sorbitan monooleate (Tween 80), but is not limited thereto.

The water-soluble polymer can play a synergistic effect of dissolution stability in the butylphthalide composition, can synergistically improve the dilution stability of the active ingredient with the first surfactant, improves the dissolution and dissolution of the medicine after oral mucosa administration, further improves the effective utilization rate of the active ingredient, and can reach the blood concentration required by the medicine effect at a lower dosage, thereby improving the compliance of patients.

In embodiments, the water-soluble polymer may be selected from one or more of polyvinylpyrrolidone (PVP, also known as povidone), a 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 selected from one or more of PVP VA64, 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 parts by weight, the synergistic effect of the polymer is impaired, which is detrimental to the exertion of the synergistic stability 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 dissolve or disperse 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 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. 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 the 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, for example 100, 125, 150, 180, 200, 250, 300, 350, 400, 450 parts by weight, etc., based on 100 parts by weight of butylphthalide. In addition, the weight ratio of the first and second surfactants may be 1:0.01 to 5, preferably 1:0.01 to 1, for example 1:0.1,1:0.2,1:0.3,1:0.4,1:0.5, etc. In the above weight ratio range, the second surfactant can also exert the butylphthalide solubilizing effect, while the butylphthalide solubilizing effect of the first surfactant is not affected.

The medium chain refers to a straight or branched carbon chain with 8-12 carbon atoms, and the short chain refers to a straight or branched carbon chain with 2-7 carbon atoms. The medium chain fatty acid or fatty alcohol refers to fatty acid or fatty alcohol of C8-C12. The medium-chain fatty acid or fatty alcohol-based surfactant refers to an amphiphilic surfactant containing a medium-chain fatty alcohol or fatty acid (or referred to as a medium-chain fatty alcohol or fatty acid amphiphilic surfactant or a medium-chain fatty alcohol or fatty acid ester-based surfactant or a medium-chain fatty alcohol or fatty acid-based surfactant), and may be, for example, one or more selected from dodecanoic acid polyethylene glycol glyceride and caprylic acid capric acid polyethylene glycol glyceride, but is not limited thereto. The dodecanoic acid is, for example, lauric acid, but is not limited thereto. The ionic surfactant based on a medium chain alkyl group refers to an ionic surfactant containing a C8 to C12 alkyl group, and may be, for example, sodium dodecyl sulfate or the like, 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 short-chain fatty alcohol or fatty acid ester-based surfactant or a short-chain fatty alcohol or fatty acid-based surfactant)), and for example, may be selected from one or more of 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 in the art suitable for a medicament for oromucosal administration, for example, it may be one or more selected from diluents, antioxidants, preservatives, flavoring agents, adsorbents, lubricants, etc., but is not limited thereto. One skilled in the art can select the appropriate excipients as needed and determine the appropriate amounts to use in the butylphthalide compositions of the present disclosure.

The amount of the diluent is not particularly limited and may be a conventional amount in an oral mucosa delivery formulation. 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 selected from one or more of small molecule solvents and oils. The small molecule solvents or oils may cause the composition to form a liquid or semi-solid formulation of uniform dispersion, different fluidity or viscosity for ease of patient use. The small molecule solvent may be selected from one or more of ethanol, propylene glycol, glycerin, isopropyl alcohol, polyethylene glycol, benzyl alcohol, diethylene glycol diethyl ether, ethyl acetate, water, propylene glycol diethyl ester, diethyl malonate, benzyl benzoate, azamethylpyrrolidone, dimethylacetamide, polyethylene glycol monomethyl ether, diethanolamine, and dimethyl sulfoxide, and the small molecule solvent 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 is selected from one or more of soybean oil, corn oil, linoleic acid glyceride, peppermint oil, ethyl linoleate, peanut oil, cotton seed oil, sesame oil, fish oil, almond oil, peach seed 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 grease 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 liquid or semi-solid form suitable for oromucosal delivery can be modulated. It has been found that the liquid and semisolid compositions described significantly improve the dissolution and osmotic absorption of butylphthalide compared to the disclosed sublingual tablet formulations of butylphthalide.

The antioxidant and preservative can improve stability and clinical safety of the composition during long-term storage to prevent oxidation or spoilage during long-term storage. The antioxidant may be selected from one or more of tocopherol, tocopheryl acetate, vitamin E, sodium metabisulfite, cysteine hydrochloride, sodium bisulphite, 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, and parabens (parabens), but is not limited thereto.

The amount of the antioxidant and the preservative is not particularly limited, and may be conventional amounts in oral mucosa 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 are not limited thereto.

The flavoring agent in the composition is an additive with taste correction function, and is mainly used for masking the special smell and spicy taste of butylphthalide. The flavoring agent is not particularly limited as long as it can be applied to the medicine, and one skilled in the art can select it as needed, for example, one or more selected from the group consisting of sweetener, cooling agent, essence and sesame oil, but not limited thereto. The flavoring agent can mask pungent smell or generate special fragrance, and reduce pungent irritation of butylphthalide, so as to improve patient compliance. The flavoring agent may be one or more selected from saccharin sodium, stevioside, aspartame, thaumatin, 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, orange oil, winter vanilla oil, orange juice oil, rose absolute, grapefruit oil, borneol, sodium caseinate, alanine, citric acid, acetic acid, malic acid, trisodium citrate.

The amount of the flavoring agent is not particularly limited, and may be a conventional amount in an oral mucosa delivery formulation. For example, the flavoring 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 selected from one of racemic butylphthalide, levobutylphthalide and dextrorotatory butylphthalide, preferably levobutylphthalide or racemic butylphthalide.

The compositions of the present disclosure may be formulated into soft capsules or devices for delivering drugs quantitatively (e.g., metered spray or drop devices) and then administered via the buccal or sublingual mucosa, and are suitable for commercial production. The composition may be in the form of a dosage form selected from sublingual drops (or solutions), sublingual gels, oral sprays/aerosols, oral gels or soft capsules.

The single administration dose of the butylphthalide composition is 3 to 50mg, preferably 4 to 40mg, more preferably 5 to 30mg. The number of administrations per day is 1 to 8, preferably 2 to 6.

According to the invention, the butylphthalide composition using the water-soluble polymer and the first surfactant can remarkably improve the in vitro dissolution-permeability of butylphthalide, and the administration experiments of oral mucosa and the like of dogs prove that the absorption of the non-injection administration route can be remarkably improved, and the bioavailability of butylphthalide through the oral mucosa can be increased. Thus, the butylphthalide composition described in the present disclosure can achieve effective plasma levels of butylphthalide at lower delivery doses, reducing liver side effects relative to other compositions already disclosed.

According to one embodiment of the present disclosure, wherein the butylphthalide composition has an in vitro dissolution penetration rate of more than 60% in artificial saliva for 3 hours.

According to one embodiment of the present disclosure, wherein the absolute bioavailability of the butylphthalide composition after delivery via the oral mucosa may be increased to 55% or more, preferably 65% or more, more preferably 80% or more.

Compared with the equivalent dosage of the commercial butylphthalide soft capsule preparation (Enbiprofen)

Soft capsule (100 mg/granule)), C after oral mucosa administration _max And AUC _0-4h， All can be increased by more than 2 times, and part can be increased by more than 3 times, and the maximum can be increased by more than 4 times.

The butylphthalide composition is prepared by mixing the components of the composition with the sodium butylphthalide chloride injection (Enbiprop

The absolute bioavailability of the injection (25 mg/100 ml) can reach more than 55 percent, more than 65 percent and at most 80 percent.

The butylphthalide composition, C, relative to an equivalent dose of the disclosed sublingual tablet composition (CN 103169676A example 1 composition) _max And AUC _0-4h Can be increased by 10%, and the partial increase can be increased by 20%, and the maximum increase can be increased by 30%.

Another aspect of the present disclosure relates to the use of the butylphthalide composition according to the present disclosure as described above in the preparation of a medicament for preventing or treating a disease of the type of histopathological injury or nerve cell injury caused by ischemia and hypoxia.

Wherein the disease is selected from one or more of ischemic cerebral apoplexy and its sequela, vascular dementia, muscular dystrophy, angina pectoris, and myocardial infarction.

The butylphthalide composition delivered via oral mucosa according to the present disclosure may be prepared as needed using conventional methods in the art without particular limitation. In one embodiment, the method of preparation comprises the steps of:

a) A diluent dissolves a surfactant, butylphthalide and the like to obtain a mixture A;

b) Dissolving a polymer, a flavoring agent and the like in a diluent to obtain a mixture B; and

c) Adding the mixture A obtained in B) to the mixture B obtained in a) under stirring, and further stirring, dissolving and mixing to obtain the butylphthalide composition in a liquid or semisolid form.

Examples

The present invention is illustrated by the following examples, comparative examples, experimental examples, and accompanying drawings and tables, which are given by way of illustration only and not by way of limitation, and the scope of the invention is not limited by the claims.

In the examples, butylphthalide is derived from jinan Chenghuida, surfactants, polymers, flavors, excipients, etc., and is purchased from Basoff, jiafa lion, chuangle essence (Shanghai), nanjing wil, etc.

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, 0.4g of ammonium chloride, and adjusting the pH to 6.8 by 1mol/l of sodium hydroxide with the volume of ultrapure water reaching 1000 ml;

the preparation method of the ethanol-PBS solution of 6% Tween 80 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 is regulated to 7.0 by hydrochloric acid, 200ml of ethanol is added, and finally, pure water is added, and the volume is fixed to 1000ml.

The investigation method of the dilution condition of the artificial saliva is as follows:

30mg of the preparation was placed in a 2ml transparent glass bottle, 1ml of artificial saliva was added, and the mixture was vortexed at 300rpm for 1min, and then allowed to stand, and the presence or absence of precipitation was observed visually.

The method for examining sublingual absorption of dogs is as follows:

beagle dogs weighing about 10kg were randomized and fasted for 12h prior to dosing and were free to drink water.

Commercially available oral soft capsules (Enbipp soft capsules (100 mg/capsule)) were orally administered in an amount of 100 mg/dog, blood was collected for 15min, 30min, 1h, 1.5h, 2h, and 4h before and after administration, placed in heparin-treated blood collection vessels, centrifuged at 4000rpm for 10min, and plasma was separated and analyzed for detection.

The tested preparation is administrated sublingually, water cannot be drunk within 3min after administration, and the mouths of dogs are combined to prevent the loss of medicines caused by tongue spitting, and each dog is opened after administration for 3 min. Blood is taken 5min, 10min, 15min, 30min, 45min, 1h, 1.5h, 2h and 4h before and after administration, placed in heparin-treated blood taking vessels, centrifuged at 4000rpm for 10min, and plasma is separated and analyzed for detection.

Peak value C of blood concentration _max Obtained from the highest blood concentration on the drug-time curve.

AUC _0-4h Refers to the area under the drug-time curve of 0-4 h, and is calculated by a trapezoid method by Excel.

Absolute bioavailability F is the AUC of the test formulation and commercial sodium butylphthalide chloride injection at the same dose _0-4h Is a percentage of (c).

The in vitro permeability examination method is as follows:

the medicinal liquid of each prescription composition is taken, placed in a dialysis bag with proper size, diluted and dispersed by adding 1ml of artificial saliva, sealed, placed in ethanol-PBS solution containing 6% Tween 80 preheated at 37 ℃, incubated in a constant temperature shaking table (37 ℃,100 rpm/min), and sampled for 1ml respectively at 30min, 1h, 1.5h, 2h and 3h (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, and the content of free drug dissolved and permeated into the PBS solution was detected to evaluate the dissolution-permeation efficiency of the drug.

Example 1: butylphthalide composition containing a first surfactant Kolliphor EL and a polymer PVP VA64

TABLE 1

Weighing propylene glycol, kolliphor EL, apple essence and butylphthalide according to the prescription, stirring for dissolving, adding PVP VA64 and other flavoring agents dissolved in the prescription water, and continuously stirring (200 rpm,60 min) for dissolving to obtain clear and transparent solution with special fragrance.

A preparation solution corresponding to 30mg of butylphthalide was diluted with 1ml of artificial saliva to observe stability. The components, amounts and observations of the formulation 1 after dilution with artificial saliva are listed in table 1 above.

Comparative example 1: butylphthalide compositions without first surfactant or polymer

TABLE 2

Weighing diluent, apple essence, surfactant, butylphthalide and the like according to the prescription amount, stirring, mixing and dissolving, adding polymer dissolved by prescription water and other flavoring agents, and continuing stirring until the solution is clear and transparent, and the oily liquid is visible.

A preparation solution corresponding to 30mg of butylphthalide was diluted with 1ml of artificial saliva to observe stability. The components, amounts and observations of comparative formulas 1-4 after dilution with artificial saliva are listed in Table 2 above.

As can be seen from the artificial saliva dilution profile results in tables 1 and 2, the stability of formulation 1, containing the C18 surfactant Kolliphor EL and polymer PVP VA64, was significantly improved compared to comparative formulation 1, which did not contain the surfactant and polymer, comparative formulation 2, which did not contain the polymer, comparative formulation 3 and comparative formulation 4, which contained the short (sucrose acetate isobutyrate) or medium chain (e.g., C12 lauric acid polyethylene glycol glyceride) surfactant and polymer. It can be seen that the combination of the water-soluble polymer and the first surfactant of the present disclosure can significantly improve the dissolution stability of butylphthalide in saliva.

Experimental example 1:

sublingual administration to dogs was performed at a dose of 30mg per dog using formulation 1, comparative formulation 1-comparative formulation 4 of example 1 prepared above, and the effect of surfactants and polymers on butylphthalide absorption was examined, the results are shown in fig. 1 and table 3 below. Table 3: pharmacokinetic parameters of butylphthalide composition containing surfactant Kolliphor EL and polymer PVPVA64

C _max Refers to the highest bloodDrug concentration, AUC _0-4h Refers to the area under the curve of blood concentration-time in 0-4 hours

The results show the AUC of formulation 1 containing the C18 surfactant Kolliphor EL and the polymer PVP VA64 _0-4h And C _max Comparative recipe 1, which is less surfactant and polymer, comparative recipe 2, which is a composition without polymer, comparative recipe 3, which contains a short or medium chain surfactant and polymer, and comparative recipe 4 are all significantly higher. It can be seen that the combination of the water-soluble polymer and the first surfactant described in the present disclosure can enhance absorption of the sublingual mucosa of butylphthalide.

EXAMPLE 2 Butylphthalide composition containing varying amounts of first surfactant

TABLE 4 Table 4

Prescription 2 to prescription 6, weighing the diluent, the flavoring agent, the melted surfactant, the polymer, the butylphthalide and the like according to the prescription amount, and stirring, mixing and dissolving until the solution is clear and transparent.

A preparation solution corresponding to 30mg of butylphthalide was diluted with 1ml of artificial saliva to observe stability. The compositions, amounts and observations of prescriptions 2-6 after dilution with artificial saliva are listed in Table 4 above.

The results show that the compositions of prescriptions 2-6 are stable in the presence of artificial saliva and no obvious precipitate is generated within 3 hours.

EXAMPLE 3 Butylphthalide composition with different Polymer types and amounts

TABLE 5

Prescription 7 to prescription 9, the prescription amount of diluent, polymer, flavoring agent, surfactant and butylphthalide are weighed in sequence, stirred, mixed and dissolved until the solution is clear and transparent, and the oily liquid is visible.

After butylphthalide, surfactant and apple essence are dissolved in propylene glycol according to prescription 10-prescription 12, the prescription amount of polymer dissolved in water and other flavoring agents are added, stirred, mixed, dissolved and degassed to prepare a uniform and transparent gel-like product.

A preparation solution corresponding to 30mg of butylphthalide was diluted with 1ml of artificial saliva to observe stability. The components, amounts and observations of formulations 7-12 after dilution with artificial saliva are listed in Table 5 above.

The results showed that the compositions of formulas 7-12 were stable in the presence of artificial saliva and did not precipitate out within 3 hours. EXAMPLE 4 Butylphthalide composition containing both first and second surfactants

TABLE 6

Prescription 13-prescription 17, weighing diluent, corrective, polymer, surfactant, butylphthalide and the like in prescription amount, stirring, mixing and dissolving until the solution is clear and transparent.

A preparation solution corresponding to 30mg of butylphthalide was diluted with 1ml of artificial saliva to observe stability. The components of prescriptions 13-17, as well as the results observed after dilution with artificial saliva, are listed in Table 6 above.

The results showed that the compositions of formulas 13 to 17 were stable in the presence of artificial saliva and did not precipitate within 3 hours.

EXAMPLE 5 Butylphthalide compositions of different taste corrigents types and amounts

TABLE 7

Prescription 18-prescription 22, weighing diluent, corrective, polymer, surfactant, butylphthalide and the like in prescription amount, stirring, mixing and dissolving until the solution is clear and transparent.

A preparation solution corresponding to 30mg of butylphthalide was diluted with 1ml of artificial saliva to observe stability. The components of prescriptions 18-22 and the observations after dilution with artificial saliva are listed in Table 7 above.

The results showed that the compositions of prescriptions 18-22 were stable in the presence of artificial saliva and did not precipitate within 3 hours.

Comparative example 2:

according to the prescription and process of example 1 disclosed in patent CN103169676a, a butylphthalide buccal tablet with a unit dose of 30mg based on Gelucire 44/14, a comparative prescription 5 composition, the composition of each component is shown in table 8 below:

TABLE 8

The preparation method comprises the following steps: the prescribed amounts of butylphthalide, polyethylene glycol glycerol laurate, and lactose of example 1 disclosed in CN103169676a were added to a twin screw extruder, the extruder section temperature was set at 30-60-45 ℃, and the host screw speed and feeder speed were both set at 25rpm.

The composition prepared according to the formulation and process of table 7 above was cooled at room temperature and solidified poorly, and after cooling at 4 ℃ for 12 hours, was lightly pressed into a semisolid strip to give a composition of comparative formulation 5.

Experimental example 2

The in vitro dissolution penetration study was performed by comparing the solutions of prescription 5 and prescription 8, and the gels of prescription 10 and prescription 11, taking a preparation corresponding to 30mg butylphthalide, according to the in vitro penetration study method described above, with the results shown in Table 9 and FIG. 2 below.

TABLE 9 in vitro dissolution-permeation results for different classes of 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 9, according to the formulations 8, 10, 11 of the present disclosure, the dissolution and penetration rates were significantly improved, and the 3h penetration rate was improved by more than 7 times, compared to the comparative formulation 5 tablets already disclosed in the prior art.

Experimental example 3

The sublingual absorption comparison study of dogs was performed with the composition of comparative prescription 5 with the solutions of prescription 8, the gels of prescription 10, prescription 11 and prescription 18, and the 25mg dose (25 mg gauge, 60min instilled) of the commercially available instillation formulation (enbipp injection), the results of which are shown in table 10 below and fig. 3.

Table 10

The results show that the comparative formulation 5 composition dissolves slowly (more than about 10 minutes of complete dissolution) after placement under the dog's tongue. Whereas, according to the present disclosure, the absolute bioavailability of the formulation 8, formulation 10, formulation 11 and formulation 18 compositions solubilized using the polymer and long chain fatty acid ester surfactant was improved by at least 25.5%, and formulation 8 and formulation 18 were even improved by more than 1 fold relative to comparative formulation 5 disclosed in CN103169676 a.

The above embodiments are merely auxiliary illustrations in nature and are not intended to limit the embodiments of the application or uses of these embodiments. In this document, the term "exemplary" represents "as an example, instance, or illustration. Any one of the exemplary embodiments herein is not necessarily to be construed as preferred or advantageous over other embodiments.

Furthermore, while at least one exemplary embodiment or comparative example has been presented in the foregoing description, it should be appreciated that a vast number of variations exist for the invention. 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 embodiments will provide a convenient road to those skilled in the art for implementing the described embodiment or embodiments. Furthermore, various changes may be made in the function and arrangement of elements without departing from the scope defined by the claims, which includes known equivalents and all foreseeable equivalents at the time of filing this patent application.

Claims

A butylphthalide composition for delivery via the oral mucosa comprising:

100 parts by weight of butylphthalide;

50 to 1000 parts by weight, preferably 100 to 500 parts by weight, of a first surfactant; and

the water-soluble polymer is 0.2 to 300 parts by weight, preferably 0.3 to 200 parts by weight.
The butylphthalide composition of claim 1, wherein the first surfactant is an amphiphilic surfactant comprising a long chain fatty alcohol or fatty acid, preferably one or more selected from the group consisting of surfactants based on long chain fatty acid polyoxyethylene esters, surfactants based on long chain fatty acid polyoxyethylene glycerides, surfactants based on long chain fatty acid phosphoglycerides, surfactants based on long chain fatty acid sucrose esters, surfactants based on long chain fatty acid polysorbates, the long chain referring to linear or branched carbon chains having 14 or more carbon atoms, such as linear or branched carbon chains of C14 to C22.
The butylphthalide composition of claim 1, wherein the first surfactant is an amphiphilic surfactant based on a C18 fatty acid or fatty alcohol,

preferably, the first surfactant is selected from one or more 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.
The butylphthalide composition of claim 1, wherein the water-soluble polymer is selected from one or more of polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, carbomer, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium alginate, chitosan, xanthan gum, poloxamer, gelatin, pectin, sodium alginate and polyethylene glycol, preferably selected from one or more of PVP VA64, poloxamer 407 and xanthan gum.
The butylphthalide composition of claim 1, wherein the butylphthalide composition further comprises a second surfactant selected from one or more 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 linear or branched carbon chain with 8-12 carbon atoms, and the short chain refers to a linear or branched carbon chain with 2-7 carbon atoms.
The butylphthalide composition of claim 5, wherein the second surfactant is 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.
The butylphthalide composition of claim 6, wherein 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.
The butylphthalide composition of claim 7, wherein the weight ratio of the first and second surfactants is 1:0.01-5, preferably 1:0.01-1.
The butylphthalide composition of claim 5, wherein the medium chain fatty acid or fatty alcohol-based surfactant is an amphiphilic surfactant containing medium chain fatty alcohol or fatty acid, preferably one or more selected from polyethylene glycol dodecanoate glyceride, polyethylene glycol glyceryl caprylate decanoate; the ionic surfactant based on the medium chain alkyl is a medicinal ionic surfactant containing the medium chain alkyl, preferably sodium dodecyl sulfate; the surfactant based on short chain fatty acids or fatty alcohols is an amphiphilic surfactant containing short chain fatty alcohols or fatty acids, preferably sucrose acetate isobutyrate.
The butylphthalide composition of claim 1, wherein the butylphthalide composition further comprises an excipient;

Wherein, 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;

wherein the excipient is one or more selected from diluent, antioxidant, antiseptic and correctant.
The butylphthalide composition of claim 10, wherein the diluent is one or more selected from a small molecule solvent and a grease.
The butylphthalide composition of claim 11, wherein 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.
The butylphthalide composition of claim 11, wherein the small molecule solvent is one or more selected from ethanol, propylene glycol, glycerol, isopropanol, polyethylene glycol, benzyl alcohol, diethylene glycol diethyl ether, ethyl acetate, water, propylene glycol diethyl ester, diethyl malonate, diethanolamine, benzyl benzoate, azamethylpyrrolidone, dimethylacetamide, polyethylene glycol monomethyl ether, dimethyl sulfoxide.
The butylphthalide composition of claim 13, wherein the small molecule 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.
The butylphthalide composition of claim 11, wherein the grease is one or more selected from soybean oil, corn oil, glycerol linoleate, peppermint oil, ethyl linoleate, peanut oil, cottonseed oil, sesame oil, fish oil, almond oil, peach kernel oil, sunflower oil, safflower oil, olive oil, coconut oil, palm oil, cocoa butter, tea oil, castor oil, sesame oil, medium-chain fatty glyceride.
The butylphthalide composition of claim 15, wherein the amount of the grease is 0 to 500 parts by weight based on 100 parts by weight of butylphthalide.
The butylphthalide composition of claim 10, wherein the antioxidant is one or more selected from the group consisting of tocopherol, tocopheryl acetate, vitamin E, sodium metabisulfite, cysteine hydrochloride, sodium sulfite, sodium metabisulfite, sodium bisulfite, ascorbic acid, thioglycerol, ascorbyl palmitate, BHT, BHA.
The butylphthalide composition of claim 10, wherein the preservative is one or more selected from the group consisting of benzalkonium bromide, chlorhexidine acetate, benzoic acid and its sodium salt, benzyl benzoate, sorbic acid and its potassium salt, parabens.
The butylphthalide composition of claim 10, wherein the excipient comprises an antioxidant and a preservative, wherein the antioxidant and the preservative are used in an amount of 0-100 parts by weight, preferably 0-50 parts by weight, based on 100 parts by weight of butylphthalide.
The butylphthalide composition of claim 10, wherein the flavoring agent is one or more selected from the group consisting of sweetener, cooling agent, essence, sesame oil, preferably one or more selected from the group consisting of saccharin sodium, stevioside, aspartame, thaumatin, cyclamate, acesulfame potassium, mogroside, xylitol, mannitol, lactose, glucose, sucrose, sucralose, honey, peppermint oil, menthol, thymol, eucalyptol, WS-5, WS-23, apple essence, vanillin, lemon essence, tea flavor essence, strawberry essence, pineapple essence, hawthorn essence, glucosyl stevioside, jasmine absolute, lemon oil, orange oil, winter vanilla oil, orange juice oil, rose absolute, grapefruit oil, borneol, sodium caseinate, alanine, citric acid, acetic acid, malic acid, trisodium citrate.
The butylphthalide composition of claim 20, wherein the flavouring agent is used in an amount of 0-200 parts by weight, preferably 0-150 parts by weight, based on 100 parts by weight of butylphthalide.
The butylphthalide composition of claim 1, wherein the butylphthalide is selected from one of racemic butylphthalide, levobutylphthalide, and dextrorotatory butylphthalide, preferably levobutylphthalide or racemic butylphthalide.
The butylphthalide composition of claim 1, wherein the formulation of the composition is selected from the group consisting of sublingual drops, sublingual gels, oral sprays/aerosols, oral gels and soft capsules.
The butylphthalide composition of any one of claims 1-23, wherein the butylphthalide composition is administered in a single dose of 3-50 mg, preferably 4-40 mg, more preferably 5-30 mg, 1-8 times, preferably 2-6 times per day.
The butylphthalide composition of any one of claims 1-23, wherein the butylphthalide composition has a cumulative dissolution permeation rate in artificial saliva of greater than 60% for 3 hours; and/or

Wherein, after the butylphthalide composition is delivered through the oral mucosa, the absolute bioavailability reaches more than 55%, preferably more than 65%, more preferably more than 80%.
Use of the butylphthalide composition of any one of claims 1-23 in the manufacture of a medicament for preventing or treating a disease of the histopathological injury or neuronal injury type caused by ischemia and hypoxia.
The use according to claim 26, wherein the disease is selected from ischemic stroke, vascular dementia, amyotrophic lateral sclerosis, angina pectoris, myocardial infarction.