WO2022143631A1 - Butylphthalide composition delivered via oral mucosa, and use thereof - Google Patents

Abstract

A butylphthalide composition delivered via oral mucosa, and a use 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 significantly improve the dissolution stability of butylphthalide in saliva, and increases oral mucosa absorption of butylphthalide. The provided butylphthalide composition delivered via oral mucosa may be used to prevent or treat a histopathological damage or nerve cell damage type disease caused by ischemia and hypoxia.

Description

Butylphthalide composition delivered through oral mucosa and use thereof technical field

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

Background technique

Butylphthalide (3-n-butylphthalide, also known as apigenin A), and its two enantiomers (D-butylphthalide and L-butylphthalide), are light yellow and clear oily liquids with strong volatility , There is a special pungent odor in the mouth, and a spicy feeling, insoluble in water.

The patents CN1100097A and CN1623542A of CSPC NBP disclose the composition of the listed NBP soft capsules, which use vegetable oil to solubilize butylphthalide to improve drug solubility. However, oral butylphthalide has a significant hepatic first-pass effect (more than 70% is eliminated by metabolism), low bioavailability, high-dose multiple administration (200 mg (2 soft capsules), TID), and poor patient compliance.

Patent CN1394880A further discloses the composition of the listed NBP injection, which uses cyclodextrin to improve the water solubility of butylphthalide. However, the use of a large amount of cyclodextrin has risks such as nephrotoxicity, and the acute phase is nearly 14 days. It is not suitable for routine medication of patients with out-of-hospital disease and acute late stage.

In addition, a variety of other compositions obtained by using butylphthalide solubilization means have been disclosed: such as emulsion-solubilized butylphthalide injection or oral preparation (CN100367951, CN100361656), synergistic surfactant and cyclodextrin Solubilized butylphthalide oral tablet (CN200710062273), etc. However, none of the above compositions can avoid the first-pass effect of the oral route and the clinical compliance and safety problems of the injection route.

Therefore, in order to meet the needs of clinical medicine, it is necessary to further optimize the existing technology.

Oral mucosal administration has fast absorption and no hepatic first-pass effect, which can significantly improve the absorption and bioavailability under non-injection administration routes, and is convenient for out-of-hospital administration, avoiding the compliance problem of injection routes. Therefore, the oral mucosal delivery route can improve the clinical medication defects of the existing marketed preparations, and is an ideal route of administration.

After retrieval, the butylphthalide composition (CN103169676A) that has been delivered through oral mucosa has been disclosed, but the disclosed butylphthalide sublingual composition technology still has a big defect. The solid dispersion tablets prepared with glycol glycerides as the matrix dissolve slowly in sublingual saliva (>10 minutes), and are prone to drug precipitation (unstable solubilization), resulting in limited absorption and bioavailability. Moreover, after butylphthalide and lauric acid polyethylene glycol glyceride are mixed in the disclosed composition, the effect of adsorption and solidification through lactose and silica gel is not good (the phenomenon of butylphthalide is still precipitated), and the pharmaceutical composition is half Solid-state tableting requires higher technological requirements for continuous production, and is more difficult to actually produce and store.

In addition, the forms of sublingual compositions disclosed in other patents are mostly the administration forms of ordinary solid tablets, such as the sublingual compositions of edaravone disclosed in patents CN201810797624.9 and CN201780048512.7, etc., and sublingual tablets are selected. Conventional excipients, such as mannitol, copovidone or hypromellose, etc., are combined with edaravone and other excipients for sublingual delivery; however, such conventional excipients are not suitable for liquid The mixing and curing of phthalide raw materials cannot realize the continuous production of butylphthalide, nor can it improve the absorption of butylphthalide.

Therefore, it is necessary to further improve the technical scheme of the existing butylphthalide sublingual composition, and develop a better new butylphthalide composition to improve the solubilization stability of butylphthalide, and then improve the butylphthalide through the oral mucosa. Absorption and bioavailability, increase patient compliance and medication safety.

SUMMARY OF THE INVENTION

The inventors of the present disclosure found that butylphthalide has a good dissolution rate in some surfactants with special structures in the study on the mechanism of oral mucosal absorption, and further combined with water-soluble polymers, it can significantly improve the effect of butylphthalide in artificial saliva. Good stability, improve in vitro dissolution permeability, increase oral mucosal absorption of butylphthalide. On this basis, the inventors have completed the present invention.

An object of the present disclosure is to provide a butylphthalide composition for oral mucosal delivery.

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 histopathological damage or neuronal cell damage-like diseases caused by ischemia and hypoxia.

According to one aspect of the present disclosure, there is provided a butylphthalide composition delivered via oral mucosa, comprising: 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. parts by weight.

According to another aspect of the present disclosure, there is provided use of the butylphthalide composition in the preparation of a medicament for preventing or treating histopathological damage or neuronal cell damage-like diseases caused by ischemia and hypoxia.

beneficial effect

According to the butylphthalide composition of the present disclosure, by including the surfactant and the water-soluble polymer, the dilution stability of butylphthalide in saliva can be significantly improved, the rapid precipitation of butylphthalide can be prevented, and the dissolution of the drug can be increased. Permeability, compared with the disclosed solid tablets of CN103169676A, the cumulative permeability of 3h has increased by more than 60%; compared with commercially available oral soft capsules and ordinary sublingual solid tablets, the absorption of butylphthalide has been significantly improved and bioavailability, its absolute bioavailability (relative to the commercially available infusion preparation) can reach more than 55%, so that at a lower dose, that is, non-injection administration, it can achieve anti-ischemic stroke, vascular Prevention and treatment of dementia, muscular spinal atrophy (ALS), angina pectoris and myocardial infarction, and improve medication compliance.

Description of drawings

FIG. 1 is a graph comparing the drug-time curves of the butylphthalide composition of prescription 1 and the compositions of comparative prescriptions 1 to 4 and commercially available NBP soft capsules according to an embodiment of the present disclosure (dog).

FIG. 2 is a dissolution-permeation curve diagram of the comparative formulation 5 prepared according to the prior art disclosed and the butylphthalide compositions prepared according to the formulation 8, formulation 10 and formulation 11 of the present disclosure.

Fig. 3 is the drug-time curve comparison diagram of the commercially available drip preparation, the comparative prescription 5 prepared according to the prior art and the butylphthalide composition prepared according to the present disclosure prescription 8, prescription 10, prescription 11, and prescription 18 (canine ).

Detailed ways

In order for those with ordinary knowledge in the art to understand the features and effects of the present invention, general descriptions and definitions of terms and terms mentioned in the specification and the scope of the patent application are provided below. Unless otherwise specified, all technical and scientific terms used herein have the ordinary meanings understood by those skilled in the art to the present invention, and in case of conflict, the definitions in this specification shall prevail.

As used herein, the terms "comprising", "including", "having", "containing" or any other similar terms are open-ended transitional phrases intended to encompass non-exclusive inclusions. For example, a composition or article of manufacture containing a plurality of elements is not limited to only those elements listed herein, but can also include other elements not expressly listed, but which are generally inherent to the composition or article of manufacture. Otherwise, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" rather than an exclusive "or". For example, the condition "A or B" is satisfied by any of the following: A is true (or present) and B is false (or absent), A is false (or absent) and B is true (or present), Both A and B are true (or exist). In addition, in this document, the terms "comprising", "including", "having", "containing" should be interpreted as having specifically disclosed and encompassing both "consisting of" and "substantially consisting of" and other closures Formal or semi-closed connectives.

In this document, all features or conditions defined 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 encompass and specifically disclose all possible sub-ranges and individual numerical values within the range, particularly integer numerical values. For example, a range description of "1 to 8" should be deemed 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, etc., particularly are sub-ranges bounded by all integer values, and should be deemed to have specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. Unless otherwise indicated, the foregoing method of interpretation applies to all content throughout this disclosure, whether broad or not.

If a quantity or other value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that any upper or preferred value of the range and the lower limit of the range have been specifically disclosed herein or all ranges of preferred values, whether or not those ranges are disclosed separately. Furthermore, when a range of values is referred to herein, unless otherwise indicated, the range shall include its endpoints and all integers and fractions within the range.

As used herein, numerical values should be understood to have an accuracy of significant digits of the numerical value, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

Where Markush group or alternative terminology is used herein to describe features or examples of the invention, those skilled in the art will understand the Markush group or subgroups of all elements within a list of options Groups or any individual element may also be used to describe the invention. For example, if X is described as "selected from the group consisting of X ₁ , X ₂ and X ₃ ", it also means that the claim that X is X ₁ and that X is X ₁ and/or X ₂ have been fully described claim. Furthermore, where Markush group or option terminology is used to describe features or instances of the invention, those skilled in the art will recognize subgroups or individual elements of all elements within the Markush group or option list Any combination of , can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X ₁ , X ₂ and X ₃ " and Y is described as "selected from the group consisting of Y ₁ , Y ₂ and Y ₃ group of "," means that the claim that X is X ₁ or X ₂ or X ₃ and Y is Y ₁ or Y ₂ or Y ₃ has been fully described.

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 this summary or in the following detailed description or examples.

Due to the small absorption area of oral mucosal drugs and serious saliva flushing, the composition administered through sublingual mucosa must meet the characteristics of low dose, rapid dissolution and absorption, otherwise it will be lost by saliva flushing, resulting in poor absorption and low bioavailability . Oils and fats (fatty acid glycerides) can effectively solubilize poorly soluble compounds, but oil is difficult to digest and absorb in the oral cavity (different from the gastrointestinal tract, there is no lipase that digests oil in the oral cavity, etc.), so it is dissolved in oil. However, CN103169676A has confirmed that butylphthalide solubilized by oils and fats such as glyceryl behenate and glyceryl stearate has a slow dissolution rate 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 its saliva is a necessary condition for its effective sublingual absorption. Amphiphilic surfactants based on fatty acids (eg, PEGylated fatty acid glycerides, which have both hydrophilic and lipophilic properties) are considered to be the best means for promoting oral absorption of poorly soluble drugs. However, the inventor's research found that butylphthalide solubilized solely by amphiphilic surfactants based on medium and short-chain fatty acids below C12 (such as lauric acid polyethylene glycol glyceride, Gelucire 44/14), in saliva After dilution, precipitation will be immediately precipitated, which is not conducive to the rapid absorption of drugs; and the use of an equal amount of amphiphilic surfactants based on long-chain fatty acids above C14, especially C18, can greatly improve butylphthalide. The stability in saliva maintains the dissolution stability of butylphthalide for nearly 1 hour (no significant precipitation), which helps to increase the rapid absorption of the drug through the oral mucosa. Further, the inventors also found that adding a certain amount of polymer to the butylphthalide composition after solubilization of the amphiphilic surfactant based on C14 or above, especially C18 long-chain fatty acid, can not only adjust the composition The dispersion rate of butylphthalide in saliva can be improved, and at the same time, it can cooperate with surfactant to further improve the dissolution stability of butylphthalide in the composition, further improve the oral mucosal 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 oral mucosal delivery, wherein the composition comprises:

100 parts by weight of butylphthalide;

50-1000 parts by weight of the first surfactant, preferably 100-500 parts by weight;

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 the oral mucosa. Based on 100 parts by weight of butylphthalide, the amount of the first surfactant is 50-1000 parts by weight, preferably 100-500 parts by weight, such as 120, 150, 180, 200, 250, 300, 350, 400, 450 parts by weight Wait. 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 will become poor, and the rate of precipitation and precipitation will become faster; and if the amount of the first surfactant is too large, for example, more than 1000 parts by weight, the composition The large volume is not conducive to the delivery of oral mucosa such as sublingual mucosa, and it is difficult to achieve short-term absorption of drugs.

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). surfactants or ester surfactants based on long-chain fatty alcohols or fatty acids), for example, can be selected from surfactants based on long-chain fatty acid polyoxyethylene (or polyethylene glycol) esters, long-chain fatty acid-based surfactants Polyoxyethylene (or polyethylene glycol) glyceride surfactants, long-chain fatty acid glyceride-based surfactants, long-chain fatty acid sucrose ester-based surfactants, long-chain fatty acid polysorbate-based surfactants one or more of, but not limited to. The long chain refers to a straight or branched carbon chain with 14 or more carbon atoms, that is to say, the long-chain fatty acid or fatty alcohol refers to a straight or branched carbon chain with a carbon number of 14 or more. Branched chain fatty acids or fatty alcohols, such as C14-C22, including but not limited to C15, C16, C17, C18, C19, C20, C21, etc. fatty alcohols or fatty acids. In particular, the surfactant is an amphiphilic surfactant based on C18 fatty acids or fatty alcohols.

More particularly, the first surfactant can be selected from polyethylene glycol glyceryl oleate, polyethylene glycol glyceryl stearate, polyethylene glycol sorbitan oleate (such as Atlas G series surfactants) ), polyethylene glycol sorbitan monostearate/oleate (such as Accosperse series surfactants), polyethylene glycol-7-stearate, polyethylene glycol-75-stearic acid glycerin Esters, Polyoxyethylene 40 Hydrogenated Castor Oil (Kolliphor RH40), Polyoxyethylene (60) Hydrogenated Castor Oil (Cremphor RH60), Polyethylene Glycol-12-Hydroxystearate (Kolliphor HS15), Polyoxyethylene 35 Castor Oil One or more of sesame oil (Kolliphor EL/ELPKolliphor EL), polyoxyethylene (20) sorbitan monooleate (Tween80), but not limited thereto.

The water-soluble polymer can play a synergistic effect of dissolution and stability in the butylphthalide composition, and it can synergize with the first surfactant to improve the dilution stability of the active ingredient and improve the dissolution and dissolution of the drug after oral mucosal administration. , thereby improving the effective utilization rate of active ingredients, and at a lower dose, the blood drug concentration required for the drug effect can be achieved, thereby improving the compliance of patients.

In embodiments, the water-soluble polymer may be 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, poloxa One or more of Poloxamer, gelatin, pectin, sodium alginate and polyethylene glycol, more preferably one or more selected from PVP VA64, Poloxamer 407 and xanthan gum.

Based on 100 parts by weight of butylphthalide, 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, such as 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70 , 80, 90, 100 parts by weight, etc. 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 polymers will be weakened, which is not conducive to the synergistic stability of the composition; Larger amounts of excipients dissolve or disperse the polymer, resulting in a bulkier composition that is not conducive to oral delivery of the composition.

According to one embodiment of the present disclosure, the butylphthalide composition may further comprise a second surfactant, and the second surfactant may be selected from medium-chain fatty acid or fatty alcohol-based surfactants, medium-chain alkane-based surfactants One or more of ionic surfactants based on short chain fatty acids or fatty alcohols. Wherein, based on 100 parts by weight of butylphthalide, the amount of the second surfactant can be 0-200 parts by weight, preferably 0-100 parts by weight, such as 0, 10, 20, 30, 40, 50, 60, 70, 80, 90 parts by weight, etc.

In the case where the butylphthalide composition contains the second surfactant, preferably, based on 100 parts by weight of butylphthalide, the total amount of both the first and second surfactants may be 50˜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, and the like. In addition, the weight ratio of the first and second surfactants may be 1:0.01-5, preferably 1:0.01-1, such as 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, etc. . Within the above weight ratio range, the second surfactant can also play the solubilizing effect of butylphthalide without affecting the solubilizing effect of butylphthalide of the first surfactant.

The medium chain refers to a straight or branched carbon chain with 8 to 12 carbon atoms, and the short chain refers to a straight or branched carbon chain with 2 to 7 carbon atoms. The medium-chain fatty acids or fatty alcohols refer to C8-C12 fatty acids or fatty alcohols. 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-based amphiphilic surfactant). Surfactants of chain fatty alcohols or fatty acid esters or surfactants based on medium chain fatty alcohols or fatty acids), for example, can be selected from polyethylene glycol glyceryl dodecanoate, polyethylene glycol glyceryl caprylate One or more of, but not limited to. Dodecanoic acid is, for example, but not limited to, lauric acid. The medium-chain alkyl-based ionic surfactant refers to an ionic surfactant containing a C8-C12 alkyl group, such as, but not limited to, sodium lauryl sulfate. The short-chain fatty acids or fatty alcohols refer to C2-C7 fatty acids or fatty alcohols. The surfactants based on short-chain fatty acids or fatty alcohols refer to amphiphilic surfactants containing short-chain fatty alcohols or fatty acids (or referred to as short-chain fatty alcohols or fatty acid amphiphilic surfactants or based on short-chain fatty alcohols or fatty acids). Surfactants of short-chain fatty alcohols or fatty acid esters or surfactants based on short-chain fatty alcohols or fatty acids)), for example, can be selected from one or more of sucrose acetate isobutyrate, etc., but not limited to this.

According to one embodiment of the present disclosure, the composition may further comprise excipients. Based on 100 parts by weight of butylphthalide, the amount of the excipient may be 0-1000 parts by weight, preferably 200-800 parts by weight, but not limited thereto.

The excipient may be any excipient in the art suitable for oral mucosal administration of medicaments, for example, it may be selected from diluents, antioxidants, preservatives, flavoring agents, adsorbents, lubricants One or more of agents, etc., but not limited thereto. Those skilled in the art can select suitable excipients as required, and determine the appropriate amount for use in the butylphthalide composition of the present disclosure.

The amount of the diluent is not particularly limited, and can be a conventional amount in oral mucosal drug delivery preparations. For example, based on 100 parts by weight of butylphthalide, the amount of the diluent may be 0-1000 parts by weight, preferably 150-800 parts by weight, but not limited thereto.

The diluent may be selected from one or more of small molecule solvents and oils. The small-molecule solvent or oil can make the composition form a liquid preparation or semi-solid preparation with uniform dispersion and different fluidity or viscosity, which is convenient for patients to use. The small molecule solvent can be selected from ethanol, propylene glycol, glycerol, isopropanol, polyethylene glycol, benzyl alcohol, diethylene glycol ethyl ether, ethyl acetate, water, propylene glycol diethyl ester, diethyl malonate, One or more of benzyl benzoate, nitrogen methyl pyrrolidone, dimethylacetamide, polyethylene glycol monomethyl ether, diethanolamine, dimethyl sulfoxide, based on 100 parts by weight of butylphthalide, small The amount of molecular solvent used may be 0 to 1000 parts by weight, preferably 50 to 1000 parts by weight, but not limited thereto. The oil can be selected from soybean oil, corn oil, glyceryl linoleate, peppermint oil, ethyl linoleate, peanut oil, cottonseed oil, sesame oil, fish oil, almond oil, peach kernel oil, sunflower oil, safflower oil, One or more of olive oil, coconut oil, palm oil, cocoa oil, camellia oil, castor oil, sesame oil, and medium chain fatty acid glycerides. Based on 100 parts by weight of butylphthalide, the amount of oil and fat may be 0 to 500 parts by weight, but is not limited thereto. By adding the diluent, the effect of the composition in liquid or semi-solid form suitable for oral mucosal delivery can be adjusted. The study found that the liquid and semi-solid compositions significantly improved the dissolution, dissolution and osmotic absorption of butylphthalide compared with the disclosed sublingual tablets of butylphthalide.

The antioxidants and preservatives can improve the stability and clinical safety of the composition during long-term storage, so as to prevent oxidation or spoilage during long-term storage. The antioxidant can be selected from the one in tocopherol, tocopherol acetate, vitamin E, sodium metabisulfite, cysteine hydrochloride, sodium bisulfite, ascorbic acid, thioglycerol, ascorbyl palmitate, BHT, BHA or more, but not limited thereto. The preservative can 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 not limited to this.

The dosages of the antioxidants and preservatives are not particularly limited, and can be conventional dosages in oral mucosal drug delivery preparations. For example, based on 100 parts by weight of butylphthalide, the amount of antioxidant and preservative may be 0-100 parts by weight, preferably 0-50 parts by weight, but not limited thereto.

The flavoring agent in the composition is an additive with a taste-correcting effect, and the main purpose is to mask the special smell and spicy taste of butylphthalide. There is no particular limitation on the flavoring agent, as long as it can be used in medicine, and those skilled in the art can select it as needed, for example, it can be selected from one or more of sweeteners, cooling agents, essences and sesame oils species, but not limited to this. Flavoring agents can mask irritating odors or produce special aromas, and reduce the pungent irritation of butylphthalide, thereby improving patient compliance. The flavoring agent can be selected from sodium saccharin, stevioside, aspartame, nutame, sodium cyclamate, acesulfame potassium, mogroside, xylitol, mannitol, lactose, glucose, sucrose, sucralose, Honey, Peppermint Oil, Menthol, Thymol, Eucalyptol, Curcumin, WS-5, WS-23, Apple Flavor, Lemon Flavor, Vanillin, Tea Flavor, Strawberry Flavor, Pineapple Flavor, Hawthorn Flavor, Glucosyl steviol glycosides, jasmine absolute oil, lemon oil, sweet orange oil, winter vanilla oil, sweet orange juice oil, rose absolute oil, grapefruit oil, red grapefruit oil, borneol, sodium caseinate, alanine, lemon One or more of 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 mucosal drug delivery preparations. For example, based on 100 parts by weight of butylphthalide, the amount of the flavoring agent may be 0-200 parts by weight, preferably 0-150 parts by weight, but not limited thereto.

In the present disclosure, the butylphthalide is selected from one of racemic butylphthalide, L-butylphthalide, and D-butylphthalide, preferably L-butylphthalide or racemic butylphthalide.

The composition of the present disclosure can be dosed into a soft capsule or a device capable of quantitatively delivering a drug (such as a quantitative spray or drop device), and then administered through the buccal mucosa or sublingual mucosa, which is suitable for industrial production. The composition may be selected from the dosage forms of sublingual drops (or solutions), sublingual gels, oral sprays/aerosols, oral gels or soft capsules.

The single administration dose of the butylphthalide composition is 3-50 mg, preferably 4-40 mg, more preferably 5-30 mg. The daily administration frequency is 1 to 8 times, preferably 2 to 6 times.

According to the present disclosure, the butylphthalide composition using a water-soluble polymer and a first surfactant can significantly improve the in vitro dissolution-permeability rate of butylphthalide. It has been proved by administration experiments such as canine oral mucosa that it can significantly improve the non-injection rate. Absorption by route of administration increases the bioavailability of butylphthalide through the oral mucosa. Therefore, compared with other disclosed compositions, the butylphthalide composition described in the present disclosure can achieve the effective blood concentration of butylphthalide at a lower delivery dose and reduce liver side effects.

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

According to an embodiment of the present disclosure, after the butylphthalide composition is delivered through the oral mucosa, the absolute bioavailability can be increased to more than 55%, preferably more than 65%, more preferably more than 80%.

Described butylphthalide composition, compared with equal dose commercially available butylphthalide soft capsule preparation (NBP

Soft capsule (100mg/capsule)), _Cmax and AUC _0-4h after oral mucosa administration, both increased by more than 2 times, some increased by more than 3 times, and the most can be increased by more than 4 times.

Described butylphthalide composition, with respect to the commercially available butylphthalide sodium chloride injection (NBP) of equal dose.

Injection (25mg/100ml)), the absolute bioavailability can reach more than 55%, more can reach more than 65%, and can reach more than 80% at most.

The described butylphthalide composition, compared with the disclosed sublingual tablet composition (CN103169676A Example 1 composition) under the same dose, both _Cmax and AUC _0-4h can be increased by 10%, and partially increased by 20% , up to 30% higher.

Another aspect of the present disclosure relates to the use of the above-mentioned butylphthalide composition according to the present disclosure in the preparation of a medicament for preventing or treating histopathological damage or neuronal cell damage-like diseases caused by ischemia and hypoxia.

Wherein, the disease is selected from one or more of ischemic stroke and its sequelae, vascular dementia, muscular spinal atrophy, angina pectoris, and myocardial infarction.

The butylphthalide composition for oral mucosal delivery according to the present disclosure can be prepared using conventional methods in the art as required without particular limitation. In one embodiment, the preparation method comprises the steps of:

a) diluent dissolves surfactant, butylphthalide, etc. to obtain mixture A;

b) the diluent dissolves the polymer, flavoring agent, etc. to obtain mixture B; and

c) Under stirring, the mixture A obtained in b) is added to the mixture B obtained in a), and the mixture is further stirred, dissolved and mixed to obtain a butylphthalide composition in liquid or semi-solid form.

Example

The present invention will be described below in conjunction with the examples, comparative examples, experimental examples, the accompanying drawings of the description, and the accompanying tables. The protection scope of the present invention constitutes a limitation.

In the embodiment, butylphthalide is from Jinan Chenghui Shuangda, and surfactants, polymers, flavoring agents, excipients, etc., are purchased from BASF, Jiafa Lion, Chuangle Flavor (Shanghai), Nanjing Weir, etc. .

How to prepare artificial saliva:

Lactic acid 3.0g, urea 0.2g, sodium chloride 4.5g, potassium chloride 0.3g, sodium sulfate 0.3g, ammonium chloride 0.4g, ultrapure water to 1000ml, 1mol/l sodium hydroxide to adjust pH to 6.8;

Preparation method of 6% Tween 80 in ethanol-PBS solution:

Sodium chloride 8.0g, potassium chloride 0.2g, sodium dihydrogen phosphate dodecahydrate 3.63g, potassium dihydrogen phosphate 0.24g, add 700ml of pure water, adjust pH to 7.0 with hydrochloric acid, add 200ml of ethanol, and finally add pure water, Volume to 1000ml.

The investigation method of artificial saliva dilution is as follows:

Take 30 mg of the equivalent preparation, put it in a 2 ml transparent glass bottle, add 1 ml of artificial saliva, vortex and mix for 1 min at 300 rpm, and then let it stand, and visually observe whether there is precipitation.

Sublingual absorption in dogs is investigated as follows:

Beagle dogs weighing about 10 kg were randomly divided into groups, fasted for 12 h before administration, and had free access to water.

Commercially available oral soft capsules (Enbipu soft capsules (100mg/capsule)), orally according to the amount of 100mg/dog, take blood before administration and 15min, 30min, 1h, 1.5h, 2h, 4h after administration In the heparin-treated blood vessel, centrifuge at 4000 rpm for 10 min, and separate the plasma for analysis and detection.

The test preparations were administered sublingually, no drinking water was allowed within 3 minutes after administration, and the dog's mouth was combined to prevent the loss of the drug due to its tongue sticking out, and each dog's mouth was opened 3 minutes after administration. Before administration and 5min, 10min, 15min, 30min, 45min, 1h, 1.5h, 2h, and 4h after administration, blood was collected, placed in heparin-treated blood vessels, centrifuged at 4000rpm for 10min, and plasma was separated and analyzed.

The peak plasma concentration _Cmax was obtained from the highest plasma concentration on the drug-time curve.

AUC _0-4h refers to the area under the drug-time curve from 0h to 4h, which is calculated by the trapezoidal method in Excel.

Absolute bioavailability F is the percentage of AUC _0-4h of the test preparation and the commercially available butylphthalide sodium chloride injection at the same dose.

The in vitro permeability test method is as follows:

Take the medicinal liquid of each prescription composition, put it in a dialysis bag of appropriate size, add 1 ml of artificial saliva to dilute and disperse it, seal it, and place it in a preheated ethanol-PBS solution containing 6% Tween 80 at 37°C. Incubate in a constant temperature shaker (37°C, 100rpm/min), and sample 1ml at 30min, 1h, 1.5h, 2h, and 3h respectively (supplement an equal volume of blank solution at the same temperature at the same time). The sample solution was centrifuged at 8000rpm for 10min, and the supernatant was taken as the test solution to detect the content of free drug dissolved and penetrated into the PBS solution to evaluate the dissolution-penetration efficiency of the drug.

Example 1: Butylphthalide Composition Containing First Surfactant Kolliphor EL and Polymer PVP VA64

Table 1

Weigh the propylene glycol, Kolliphor EL, apple essence and butylphthalide of the recipe quantity, stir and dissolve, add PVP VA64 and other correctives dissolved in the water of the recipe quantity, continue to stir (200rpm, 60min) to dissolve, obtain a clear and transparent solution, with Special aroma.

Take the preparation solution equivalent to 30 mg of butylphthalide and dilute it with 1 ml of artificial saliva to observe the stability. The components and dosages of formulation 1 and the observed results after dilution with artificial saliva are listed in Table 1 above.

Comparative Example 1: Butylphthalide composition without first surfactant or polymer

Table 2

Weigh the prescribed amount of diluent, apple essence, surfactant and butylphthalide, etc., stir, mix and dissolve, then add the prescribed amount of water-soluble polymer and other flavoring agents, and continue to stir until the solution is clear and transparent without oily liquid visible.

Take the preparation solution equivalent to 30 mg of butylphthalide and dilute it with 1 ml of artificial saliva to observe the stability. The components, dosages and the observation results after dilution with artificial saliva of the comparative formulations 1 to 4 are listed in Table 2 above.

From the results of artificial saliva dilution in Tables 1 and 2, it can be seen that the stability of formulation 1 containing C18 surfactant Kolliphor EL and polymer PVP VA64 is more stable than that of comparative formulation 1 without surfactant and polymer, without polymerization Composition comparison formulation 2, comparison formulation 3 and comparison formulation 4 containing short (sucrose acetate isobutyrate) or medium chain (such as C12 polyethylene glycol glyceryl laurate) surfactant and polymer, both Significantly increased. 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:

With prescription 1, comparative prescription 1-contrast prescription 4 in the embodiment 1 prepared above, carry out sublingual administration of dog by 30mg/ dog dose, investigate the influence of surfactant and polymer on the absorption of butylphthalide, The results are shown in Figure 1 and Table 3 below. Table 3: Pharmacokinetic parameters of butylphthalide compositions containing surfactant Kolliphor EL and polymer PPVVA64

_Cmax refers to the highest blood drug concentration, AUC _0-4h refers to the area under the curve of blood drug concentration-time in 0-4 hours

The results show that the AUC _0-4h and C _max of formulation 1 containing the C18 surfactant Kolliphor EL and polymer PVP VA64 are better than those of the comparative formulation 1 without surfactant and polymer, and the comparative formulation of the composition without polymer 2. Both Comparative Formulations 3 and 4, containing short or medium chain surfactants and polymers, were significantly higher. It can be seen that the combination of the water-soluble polymer and the first surfactant described in the present disclosure can improve the absorption of the sublingual mucosa of butylphthalide.

Example 2 Butylphthalide Compositions Containing Different Amounts of First Surfactant

Table 4

For prescription 2 to prescription 6, weigh the diluent, flavoring agent, melted surfactant, polymer, butylphthalide, etc. in the prescribed amount, stir, mix and dissolve until the solution is clear and transparent.

Take the preparation solution equivalent to 30 mg of butylphthalide and dilute it with 1 ml of artificial saliva to observe the stability. The compositions and contents of prescriptions 2 to 6 and the observation results after dilution with artificial saliva are listed in Table 4 above.

The results showed that the compositions of prescriptions 2 to 6 were stable when exposed to artificial saliva, and no obvious precipitation occurred within 3 hours.

Example 3 Butylphthalide compositions under different polymer types and dosages

table 5

For prescription 7 to prescription 9, take the prescription amounts of diluent, polymer, flavoring agent, surfactant and butylphthalide in turn, stir, mix and dissolve until the solution is clear and transparent, and no oily liquid is visible.

Recipe 10 to Recipe 12, after propylene glycol dissolves butylphthalide, surfactant and apple essence, add the polymer and other flavoring agents in the recipe amount dissolved in water, stir, mix, dissolve, and degas to prepare a uniform and transparent condensate. Gel-like product.

Take the preparation solution equivalent to 30 mg of butylphthalide and dilute it with 1 ml of artificial saliva to observe the stability. The components, contents and observation results of formulations 7 to 12 after dilution with artificial saliva are listed in Table 5 above.

The results show that the compositions of prescription 7 to prescription 12 are all stable when exposed to artificial saliva, and no precipitation occurs within 3 hours. Example 4 Butylphthalide composition containing both first and second surfactants

Table 6

For prescription 13 to prescription 17, weigh the diluent, flavoring agent, polymer, surfactant, butylphthalide, etc. in the prescribed amount, stir, mix and dissolve until the solution is clear and transparent.

Take the preparation solution equivalent to 30 mg of butylphthalide and dilute it with 1 ml of artificial saliva to observe the stability. The components of prescriptions 13 to 17 and the observed results after dilution with artificial saliva are listed in Table 6 above.

The results showed that the compositions of prescription 13 to prescription 17 were all stable when exposed to artificial saliva, and no precipitation occurred within 3 hours.

The butylphthalide composition of embodiment 5 different types of correctives and dosage

Table 7

For prescription 18 to prescription 22, weigh the prescribed amount of diluent, flavoring agent, polymer, surfactant and butylphthalide, etc., stir, mix and dissolve until the solution is clear and transparent.

Take the preparation solution equivalent to 30 mg of butylphthalide and dilute it with 1 ml of artificial saliva to observe the stability. The components of formulations 18 to 22 and the observed results after dilution with artificial saliva are listed in Table 7 above.

The results show that the compositions of prescription 18 to prescription 22 are all stable when exposed to artificial saliva, and no precipitation occurs within 3 hours.

Comparative Example 2:

According to the prescription and process of the embodiment 1 disclosed by patent CN103169676A, the preparation of the butylphthalide buccal tablet with Gelucire 44/14 as the base unit dosage of 30mg---contrast prescription 5 compositions, each component composition is shown in the following table 8:

Table 8

Preparation method: add butylphthalide, lauric acid polyethylene glycol glyceride and lactose in the recipe amounts of Example 1 disclosed in CN103169676A into a twin-screw extruder, and the temperature of the extruder section is set to 30°C-60°C -60°C-60°C-45°C, the screw speed of the main machine and the speed of the feeder are both set to 25rpm.

The composition prepared according to the recipe and process in Table 7 above was cooled at room temperature, and the solidification effect was not good. After cooling at 4° C. for 12 hours, it was lightly pressed into a semi-solid strip to obtain the composition of Comparative Recipe 5.

Experimental Example 2

Will compare the gel of prescription 5 and prescription 8 solution, prescription 10 and prescription 11, get the preparation equivalent to 30mg of butylphthalide and carry out in vitro dissolution permeability research according to the above-mentioned in vitro permeability investigation method, the results are shown in Table 9 below and Figure 2.

Table 9 In vitro dissolution of various compositions - permeation results

time (h)	Prescription 8 (%)	Prescription 10 (%)	Prescription 11 (%)	Comparison 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 and 11 of the present disclosure, compared with the comparative formulation 5 tablets disclosed in the prior art, the dissolution rate and the permeation promotion rate are significantly improved, and the permeation amount in 3 hours is increased by more than 7 times.

Experimental Example 3

The composition of prescription 5 will be compared with the solution of prescription 8, the gel of prescription 10, prescription 11 and prescription 18, and the commercially available infusion preparation (Enbipu injection) 25mg dose (25mg specification, instillation 60min) , a comparative study of sublingual absorption in dogs was performed, the results of which are shown in Table 10 below and Figure 3.

Table 10

The results showed that after the composition of Comparative Formulation 5 was placed under the dog's tongue, the dissolution and dissolution were slow (completely dissolved for more than 10 minutes). According to the present disclosure, the absolute bioavailability of the compositions of formulation 8, formulation 10, formulation 11 and formulation 18 solubilized with polymers and long-chain fatty acid ester surfactants is improved by at least the comparative formulation 5 disclosed in CN103169676A. 25.5%, prescription 8 and prescription 18 even more than doubled.

The above embodiments are merely auxiliary descriptions in nature, and are not intended to limit the embodiments of the application target or the applications or uses of these embodiments. As used herein, the term "exemplary" means "serving as an instance, instance, or illustration." Any exemplary embodiment herein is not necessarily to be construed as preferred or advantageous over other embodiments.

Furthermore, while at least one illustrative or comparative example has been presented in the foregoing embodiments, it should be understood that the present invention is capable of numerous variations. It should also be appreciated that the embodiments described herein are not intended to limit the scope, utility, or configuration of the claimed object in any way. Rather, the foregoing embodiments will provide those of ordinary skill in the art with a convenient guide 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 of the claimed scope, which includes known equivalents and all foreseeable equivalents at the time of filing this patent application .

Claims (27)

1. A butylphthalide composition for oral mucosal delivery, comprising:

   100 parts by weight of butylphthalide;

   50-1000 parts by weight of the first surfactant, preferably 100-500 parts by weight; and

   The water-soluble polymer is 0.2 to 300 parts by weight, preferably 0.3 to 200 parts by weight.
2. The butylphthalide composition according to claim 1, wherein the first surfactant is an amphiphilic surfactant containing long-chain fatty alcohol or fatty acid, preferably selected from long-chain fatty acid polyoxyethylene ester-based Surfactant, long-chain fatty acid polyoxyethylene glyceride-based surfactant, long-chain fatty acid phosphoglyceride-based surfactant, long-chain fatty acid sucrose-based surfactant, long-chain fatty acid polysorbate-based surfactant One or more of surfactants, the long chain refers to a straight or branched carbon chain with 14 or more carbon atoms, such as a straight or branched carbon chain of C14-C22.
3. The butylphthalide composition of claim 1, wherein the first surfactant is a C18 fatty acid or fatty alcohol based amphiphilic surfactant,

   Preferably, the first surfactant is selected from polyethylene glycol glyceryl oleate, polyethylene glycol glyceryl stearate, polyethylene glycol sorbitan oleate, polyethylene glycol sorbitan monohydrate Stearic acid/oleate, polyethylene glycol-7-stearate, polyethylene glycol-75-glyceryl stearate, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil , one or more of polyethylene glycol-12-hydroxystearate, polyoxyethylene 35 castor oil, and polyoxyethylene (20) sorbitan monooleate.
4. The butylphthalide composition according to claim 1, wherein the water-soluble polymer is selected from the group consisting 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, alginic acid One or more of sodium and polyethylene glycol, preferably selected from one or more of PVP VA64, Poloxamer 407 and xanthan gum.
5. The butylphthalide composition according to claim 1, wherein the butylphthalide composition further comprises a second surfactant selected from the group consisting of medium chain fatty acid or fatty alcohol based surfactants , one or more of ionic surfactants based on medium-chain alkyl groups, surfactants based on short-chain fatty acids or fatty alcohols; Chain carbon chain, the short chain refers to a straight or branched carbon chain with 2 to 7 carbon atoms.
6. The butylphthalide composition according to claim 5, wherein, based on 100 parts by weight of butylphthalide, the amount of the second surfactant is 0 to 200 parts by weight, preferably 0 to 100 parts by weight.
7. The butylphthalide composition according to claim 6, wherein, based on 100 parts by weight of butylphthalide, the total amount of both the first and second surfactants is 50-1000 parts by weight, preferably 100-1000 parts by weight 500 parts by weight.
8. The butylphthalide composition according to claim 7, wherein the weight ratio of the first and second surfactants is 1:0.01-5, preferably 1:0.01-1.
9. The butylphthalide composition according to claim 5, wherein the medium-chain fatty acid or fatty alcohol-based surfactant refers to an amphiphilic surfactant containing a medium-chain fatty alcohol or fatty acid, preferably selected from dodecane One or more of alkanoic acid macrogol glyceride, caprylic acid capric acid macrogol glyceride; the medium-chain alkyl-based ionic surfactant is a pharmaceutical ionic surfactant containing a medium-chain alkyl group Surfactant, preferably sodium lauryl sulfate; the surfactant based on short-chain fatty acid or fatty alcohol is an amphiphilic surfactant containing short-chain fatty alcohol or fatty acid, preferably sucrose acetate isobutyrate .
10. The butylphthalide composition of claim 1, wherein the butylphthalide composition further comprises an excipient;

    Wherein, based on 100 parts by weight of butylphthalide, the dosage of the excipient is 0-1000 parts by weight, preferably 200-800 parts by weight;

    Wherein, the excipient is one or more selected from diluents, antioxidants, preservatives, and flavoring agents.
11. The butylphthalide composition according to claim 10, wherein the diluent is one or more selected from small molecule solvents and oils.
12. The butylphthalide composition according to claim 11, wherein, based on 100 parts by weight of butylphthalide, the amount of the diluent is 0-1000 parts by weight, preferably 150-800 parts by weight.
13. The butylphthalide composition according to claim 11, wherein the small molecule solvent is selected from the group consisting of ethanol, propylene glycol, glycerol, isopropanol, polyethylene glycol, benzyl alcohol, diethylene glycol ethyl ether, ethyl acetate , water, diethyl propylene glycol, diethyl malonate, diethanolamine, benzyl benzoate, nitrogen methyl pyrrolidone, dimethylacetamide, polyethylene glycol monomethyl ether, one of dimethyl sulfoxide one or more.
14. The butylphthalide composition according to claim 13, wherein, based on 100 parts by weight of butylphthalide, the amount of the small molecule solvent used is 0-1000 parts by weight, preferably 50-1000 parts by weight.
15. The butylphthalide composition according to claim 11, wherein the oil is selected from soybean oil, corn oil, glycerol linoleate, peppermint oil, ethyl linoleate, peanut oil, cottonseed oil, sesame oil, and fish oil , one or more of almond oil, peach oil, sunflower oil, safflower oil, olive oil, coconut oil, palm oil, cocoa oil, camellia oil, castor oil, sesame oil, and medium-chain fatty acid glycerides.
16. The butylphthalide composition according to claim 15, wherein, based on 100 parts by weight of butylphthalide, the amount of the oil and fat is 0-500 parts by weight.
17. The butylphthalide composition according to claim 10, wherein the antioxidant is selected from the group consisting of tocopherol, tocopherol acetate, vitamin E, sodium metabisulfite, cysteine hydrochloride, sodium sulfite, sodium metabisulfite, hydrogen sulfite One or more of sodium, ascorbic acid, thioglycerol, ascorbyl palmitate, BHT, BHA.
18. The butylphthalide composition according to claim 10, wherein the preservative is selected from benzalkonium bromide, chlorhexidine acetate, benzoic acid and its sodium salt, benzyl benzoate, sorbic acid and its potassium salt , one or more of parabens.
19. The butylphthalide composition according to claim 10, wherein the excipients comprise antioxidants and preservatives, wherein, based on 100 parts by weight of butylphthalide, the amounts of the antioxidants and preservatives are 0- 100 parts by weight, preferably 0 to 50 parts by weight.
20. The butylphthalide composition according to claim 10, wherein the flavoring agent is one or more selected from sweeteners, cooling agents, essences, and sesame oils, preferably selected from sodium saccharin, stevioside , Aspartame, Nitame, Cyclamate, Acesulfame K, Mogroside, Xylitol, Mannitol, Lactose, Glucose, Sucrose, Sucralose, Honey, Peppermint Oil, Menthol, Thymol, Eucalyptus Oleogen, WS-5, WS-23, apple essence, vanillin, lemon essence, tea essence, strawberry essence, pineapple essence, hawthorn essence, glucosyl steviol glycosides, jasmine absolute oil, lemon oil, sweet orange oil, One or more of winter vanilla oil, sweet orange juice oil, rose absolute, grapefruit oil, red grapefruit oil, borneol, sodium caseinate, alanine, citric acid, acetic acid, malic acid, trisodium citrate kind.
21. The butylphthalide composition according to claim 20, wherein, based on 100 parts by weight of butylphthalide, the dosage of the flavoring agent is 0-200 parts by weight, preferably 0-150 parts by weight.
22. The butylphthalide composition according to claim 1, wherein the butylphthalide is selected from the group consisting of racemic butylphthalide, levorotatory butylphthalide and dextrobutylphthalide, preferably levorotyl butylphthalide or Racemic Butylphthalide.
23. The butylphthalide composition according to claim 1, wherein the dosage form of the composition is selected from the group consisting of sublingual drops, sublingual gel, oral spray/aerosol, oral gel and soft capsule.
24. The butylphthalide composition according to any one of claims 1-23, wherein the single administration dose of the butylphthalide composition is 3-50 mg, preferably 4-40 mg, more preferably 5-30 mg, each The daily administration frequency is 1 to 8 times, preferably 2 to 6 times.
25. The butylphthalide composition according to any one of claims 1 to 23, wherein the cumulative dissolution penetration rate of the butylphthalide composition in artificial saliva for 3 hours reaches more than 60%; and/or

    Wherein, after the butylphthalide composition is delivered through the oral mucosa, the absolute bioavailability is more than 55%, preferably more than 65%, more preferably more than 80%.
26. Use of the butylphthalide composition according to any one of claims 1 to 23 in the preparation of a medicament for preventing or treating histopathological damage or neuronal cell damage diseases caused by ischemia and hypoxia.
27. The use according to claim 26, wherein the disease is selected from the group consisting of ischemic stroke, vascular dementia, muscular spinal atrophy, angina pectoris, myocardial infarction.

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