CN118766830A - Pharmaceutical composition, pharmaceutical preparation and application thereof for oral mucosal delivery - Google Patents

Abstract

The present application relates to a pharmaceutical composition, a pharmaceutical preparation and its application for oral mucosal delivery. The pharmaceutical composition for oral mucosal delivery comprises the following components by weight: 5 to 40 parts of active pharmaceutical ingredients and 5 to 90 parts of functional oil matrix; wherein the active pharmaceutical ingredients include one or more of butylphthalide and butylphthalide derivatives; and the functional oil matrix includes one or more of fatty acid esters. The above-mentioned pharmaceutical composition for oral mucosal delivery, by using fatty acid esters of fatty acid chains as functional oil matrix, can significantly reduce the pain caused by the strong stimulation of active pharmaceutical ingredients containing butylphthalide and/or its derivatives to the oral mucosa, especially to the sublingual mucosa, and can mask the original strong bad smell of active pharmaceutical ingredients, so that such active pharmaceutical ingredients are suitable for oral mucosal delivery, improve the palatability of medication, and increase the compliance of users.

Description

Pharmaceutical composition, pharmaceutical preparation and application thereof for oral mucosal delivery

Technical Field

The present application relates to the field of pharmaceutical technology, and in particular to a pharmaceutical composition, a pharmaceutical preparation and an application thereof for oral mucosal delivery.

Background Art

Oral mucosal administration, especially sublingual or buccal administration, has the advantages of fast absorption and no first-pass effect in the liver, which can significantly improve the absorption and bioavailability of non-injection administration routes, and is convenient for outpatient administration, avoiding the compliance problem of injection administration. Therefore, the oral mucosal delivery route can improve the defects of some preparations such as injections and oral preparations in the clinical medication process, and is a more ideal route of administration.

However, some active ingredients of drugs, especially volatile active ingredients such as butylphthalide, have strong irritation to the oral mucosa or a bad taste. When such drugs are administered through the oral mucosa, the first issue that needs to be addressed is the palatability during the buccal period.

The currently disclosed butylphthalide compositions are still mainly administered by oral route, injection route, etc. In addition, there is a method to provide a butylphthalide composition for sublingual administration, a composition solubilized by the surfactant Gelucire 44, which has been tried by volunteers of this team and has significant spicy stimulation and bad odor, and a strong bitter taste and extremely poor palatability. At the same time, there are also methods to try to improve the taste of the butylphthalide composition, and develop a butylphthalide composition solubilized by a surfactant with a specific fatty acid chain length, which reduces the strong stimulation and special smell of butylphthalide to the oral mucosa to a certain extent, but during the sublingual administration, there is still a certain burning sensation of the mucosa, or a slight bitter taste and an unpleasant "celery" smell, and patients who are sensitive to spicy stimulation have poor compliance with sublingual administration.

Summary of the invention

Based on this, the present application provides a pharmaceutical composition, a pharmaceutical preparation and its application for oral mucosal delivery which has good palatability and is conducive to long-term medication.

In a first aspect of the present application, there is provided a pharmaceutical composition for delivery via the oral mucosa, characterized in that it comprises the following components in parts by weight:

5 to 40 parts of active pharmaceutical ingredients, and

Functional oil base 5 to 90 parts;

Based on the total weight of the pharmaceutical composition, the moisture content accounts for ≤3%, optionally, the moisture content accounts for ≤2%, and further optionally, the moisture content accounts for ≤1%;

The active pharmaceutical ingredient comprises one or more of butylphthalide and butylphthalide derivatives;

The functional oil matrix includes one or more of fatty acid esters.

In one embodiment, the carbon number of the fatty acid chain in the fatty acid ester is ≥6.

In one embodiment, the carbon number of the fatty acid chain in the fatty acid ester is 6 to 30.

In one embodiment, the functional oil matrix is selected from soybean oil, corn oil, peanut oil, sesame oil, olive oil, coconut oil, castor oil, peppermint oil, medium-chain fatty acid esters and derivatives thereof, polyethylene glycol fatty acid glycerides, structured oils, star anise oil, tea oil, clove basil oil, patchouli oil, perilla leaf oil, clove oil, monolinolein, monoolein, diolein, ethyl linoleate, ethyl oleate, ethyl palmitate, isopropyl myristate, vitamin C palmitate and isopropyl palmitate;

Optionally, the functional oil matrix is selected from one or more of coconut oil, soybean oil, castor oil, peppermint oil, olive oil, medium-chain fatty acid esters and derivatives thereof.

In one embodiment, the butylphthalide is selected from one or more of racemic butylphthalide, levorotatory butylphthalide and dextrorotatory butylphthalide;

The butylphthalide derivative is selected from butylphthalide prodrugs; optionally, the butylphthalide derivative is selected from 2-(α-hydroxypentyl)benzoic acid potassium salt;

The active pharmaceutical ingredient comprises a combination of butylphthalide and other drugs in related therapeutic fields; optionally, the other drugs in related therapeutic fields are selected from a combination of one or more of borneol, dextroborneol and edaravone.

In one embodiment, the pharmaceutical composition for oral mucosal delivery comprises the following components in parts by weight:

5 to 25 parts of active pharmaceutical ingredients, and

Functional oil base 5 to 90 parts.

In one embodiment, the pharmaceutical composition for oral mucosal delivery further comprises 0 to 20 parts of a surfactant;

Optionally, the surfactant includes one or more of polyethylene glycol olein, polyethylene glycol stearin, polyethylene glycol sorbitol oleate, polyethylene glycol sorbitan monostearate/oleate, polyethylene glycol-7-stearate, polyethylene glycol-75-stearate, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyethylene glycol-12-hydroxystearate, polyoxyethylene 35 castor oil and polyoxyethylene (20) sorbitan monooleate.

In one embodiment, the pharmaceutical composition for oral mucosal delivery further comprises 0 to 72 parts of a diluent;

Optionally, the diluent includes one or more of ethanol, propylene glycol, glycerol, isopropanol, polyethylene glycol, benzyl alcohol, diethylene glycol ethyl ether, ethyl acetate, propylene glycol diethyl ester, diethyl malonate, diethanolamine, benzyl benzoate, nitrogen methyl pyrrolidone, dimethylacetamide, polyethylene glycol monomethyl ether and dimethyl sulfoxide.

In one embodiment, the pharmaceutical composition for oral mucosal delivery further comprises 0 to 6 parts of a flavoring agent;

Optionally, the flavoring agent includes one or more of a sweetener, a cooling agent, an essence, and a sesame oil;

Further optionally, the flavoring agent includes one or more of saccharin sodium, stevioside, aspartame, nutame, cyclamate, acesulfame potassium, mogroside, xylitol, mannitol, lactose, glucose, sucrose, sucralose, honey, peppermint oil, menthol, thymol, eucalyptus oil, WS-5, WS-23, apple flavor, vanillin, lemon flavor, tea flavor, strawberry flavor, pineapple flavor, hawthorn flavor, glucosyl steviol glycoside, jasmine absolute, lemon oil, sweet orange oil, winter vanilla oil, sweet orange juice oil, rose absolute, grapefruit oil, red grapefruit oil, borneol, sodium caseinate, alanine, citric acid, acetic acid, malic acid and trisodium citrate.

In one embodiment, the pharmaceutical composition for oral mucosal delivery further comprises 0 to 1 part of an antioxidant and/or 0 to 1 part of a preservative;

Optionally, the antioxidant includes one or more of tocopherol, tocopherol acetate, vitamin E, sodium metabisulfite, cysteine hydrochloride, sodium sulfite, sodium metabisulfite, sodium bisulfite, ascorbic acid, thioglycerol, ascorbyl palmitate, butylated hydroxytoluene and butylated hydroxyanisole;

Optionally, the preservative includes one or more of benzalkonium bromide, benzoic acid and its sodium salt, benzyl benzoate, sorbic acid and its potassium salt, and parabens (eg, paraben).

The second aspect of the present application provides a pharmaceutical preparation, comprising the pharmaceutical composition for delivery through the oral mucosa described in the first aspect, wherein the dosage form of the pharmaceutical preparation is sublingual drops, sublingual spray, oral spray, buccal mucosal spray, buccal mucosal aerosol, sublingual aerosol or oral aerosol.

The above-mentioned pharmaceutical composition for oral mucosal delivery, by using fatty acid esters of fatty acid chains as functional oil matrix, can significantly reduce the pain caused by the strong stimulation of the active pharmaceutical ingredients containing butylphthalide and/or its derivatives to the oral mucosa, especially the sublingual mucosa, and can mask the original strong unpleasant smell of the active pharmaceutical ingredients, making such active pharmaceutical ingredients suitable for oral mucosal delivery, improving the palatability of the medication, and increasing the compliance of the user.

Furthermore, the above-mentioned pharmaceutical composition for delivery via oral mucosa also has high bioavailability.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a drug-time curve of the comparative example, the example and the commercially available preparation after oral administration to dogs.

DETAILED DESCRIPTION

The pharmaceutical composition, pharmaceutical preparation and application thereof for oral mucosal delivery of the present application are further described in detail below in conjunction with specific examples. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

In this application, "first aspect", "second aspect", "third aspect", etc. are used only for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range of instrument control.

As used herein, the terms "include", "comprising", "having", "containing" or any other similar terms are open-ended transitional phrases, which are intended to cover non-exclusive inclusions. For example, a composition or article containing multiple elements is not limited to the elements listed herein, but may also include other elements that are not explicitly listed but are generally inherent to the composition or article. In addition, unless otherwise expressly stated, the term "or" refers to an inclusive "or" rather than an exclusive "or". For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist). In addition, as used herein, the terms "include", "comprising", "having", and "containing" should be interpreted as having been specifically disclosed and simultaneously covering closed or semi-closed transitional phrases such as "consisting of" and "consisting essentially of".

In this article, all features or conditions defined in the form of numerical ranges or percentage ranges are only for simplicity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be deemed to have covered and specifically disclosed all possible secondary ranges and individual values within the range, especially integer values. For example, the range description of "6 to 30" should be deemed to have specifically disclosed all secondary ranges such as 6 to 10, 6 to 15, 6 to 20, 6 to 25, 6 to 30, etc., especially secondary ranges defined by all integer values, and should be deemed to have specifically disclosed individual values such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, etc. Unless otherwise specified, the above interpretation method applies to all contents of the entire application, regardless of whether the scope is broad or not.

If the quantity or other numerical value or parameter is expressed as a range, a preferred range or a series of upper and lower limits, it should be understood that all ranges consisting of any upper limit or preferred value of the range and the lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, if a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

In this document, under the premise of achieving the purpose of the invention, numerical values should be understood to have the accuracy of the number of significant digits of the numerical value. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

In this document, for situations where Markush groups or optional terms are used to describe features or examples of the present invention, those skilled in the art should understand that all subgroups of elements in the Markush group or optional list or any individual element can also be used to describe the present invention. For example, if X is described as "selected from the group consisting of _X1 , _X2 , and _X3 ", it also means that the claim that X is _X1 and the claim that X is _X1 and/or _X2 have been fully described. Furthermore, for situations where Markush groups or optional terms are used to describe features or examples of the present invention, those skilled in the art should understand that any combination of all subgroups of elements in the Markush group or optional list or individual elements can also be used to describe the present invention. Accordingly, for example, if X is described as “selected from the group consisting of _X1 , _X2 , and _X3 ” and Y is described as “selected from the group consisting of _Y1 , _Y2 , and _Y3 ”, it means that the claim that X is _X1 or _X2 or _X3 and Y is _Y1 or _Y2 or _Y3 has been fully described.

The following detailed description is merely illustrative in nature and is not intended to limit the present invention and its use. In addition, this document is not limited by any theory described in the above prior art or invention summary or the following detailed description or examples.

At present, although oral mucosal delivery is known to have many advantages, some active pharmaceutical ingredients have poor palatability due to strong oral mucosal irritation or bad taste, resulting in poor compliance of oral mucosal administration and difficulty in drug development. Without limitation, examples of such active pharmaceutical ingredients include butylphthalide or its derivatives.

3-n-butylphthalide, also known as apigenin A, is the first domestic innovative drug with independent intellectual property rights for stroke in China. Stroke is a major disease that threatens national health. It can cause limb paralysis, language disorders, cognitive disorders and mental depression in patients. It has the characteristics of high incidence, high recurrence rate, high disability rate and high mortality rate. According to statistics from the World Health Organization, one person dies from stroke or becomes permanently disabled due to stroke every 6 seconds in the world. In recent years, the incidence of stroke has shown an upward trend. About three-quarters of patients have lost their ability to work or cannot take care of themselves to varying degrees, which has placed a heavy burden on families and society. The prevention and treatment of stroke is urgent. Studies have shown that butylphthalide has the effect of promoting brain microcirculation in clinical practice. The butylphthalide sodium chloride injection and butylphthalide soft capsules that have been launched on the market have been used to improve the neurological deficits of acute ischemic stroke and the treatment of stroke. However, the prescription of sodium chloride butylphthalide injection contains a high proportion of cyclodextrin, and the medication cycle is long, requiring frequent injections, causing pain and irritation at the injection site, and requiring professional medical staff to operate and accompany. There are potential risks of renal toxicity or injection safety, and its application is subject to certain medical restrictions. The medication compliance is poor for conscious patients, and it is not suitable for patients with diseases outside the hospital. As an oral preparation, butylphthalide soft capsules have severe first-pass liver metabolism, low bioavailability, and a large dosage. For patients with dysphagia, medication compliance is poor.

Oral mucosal delivery can avoid many defects of the marketed butylphthalide preparations, such as medication compliance and safety.

The following two requirements must be met to achieve oral mucosal administration of butylphthalide: (1) good palatability, suitable for patients to take the drug by mouth; however, butylphthalide has a large mucosal irritation, a strong pungent feeling, and a burning pain during the oral administration, which is difficult to accept. In addition, its strong pungent smell and bitter taste (or "celery" smell) make it difficult to take it by mouth; (2) good bioavailability, which can achieve the ideal blood drug concentration and thus achieve the ideal therapeutic effect; however, butylphthalide or its derivatives have poor water solubility, and it is difficult to dissolve quickly when placed directly in the oral cavity, which is not conducive to absorption. In addition, the oral mucosal drug absorption area is small, and the drug is severely washed by saliva, so the bioavailability is difficult to guarantee. Therefore, the technical threshold for preparing a butylphthalide composition with good compliance, rapid absorption, and high bioavailability is high and difficult.

In order to solve this problem, traditional methods have tried many ways to solve the palatability and absorption problems of butylphthalide, such as using flavoring agents to try to solve the taste problem, or using surfactants or dissolution stabilizers of specific chain lengths to cover up the oral mucosal irritation of butylphthalide or increase absorption. However, these methods are difficult to completely cover up the irritation and special smell of butylphthalide to the oral mucosa. For patients who are sensitive to irritation and odor, the difficulty of medication is still relatively large, which affects the tolerance of the clinical medication process. It can be seen that traditional methods cannot fully meet the clinical demand for oral mucosal delivery of butylphthalide. It is necessary to further optimize the technical solution of the oral mucosal delivery composition of butylphthalide, reduce the side effects of butylphthalide on mucosal irritation, improve patient palatability, increase medication compliance, and then expand the accessibility of oral mucosal delivery drugs of butylphthalide, and increase the population of patients suitable for medication.

In the research of this application, the inventors also conducted a large number of experimental explorations, such as dissolving drugs with small molecule solvents (such as ethanol or propylene glycol commonly used for oral mucosal administration), and trying to add a variety of flavoring agents, such as peppermint oil, orange flavor, jasmine absolute oil, sucralose; and using surfactants to form micelles to encapsulate drugs, etc., all of which could not cover up or reduce the burning sensation of butylphthalide irritating the oral mucosa, and the abnormal unpleasant odor could not be covered up either, and the tolerance of oral mucosal administration was extremely poor. In addition, the small molecule dissolved butylphthalide precipitated in simulated saliva, and the mucosal absorption-promoting effect was poor.

In further research, the inventors accidentally discovered that by using fatty acid esters of special structures, especially fatty acid esters with carbon atoms ≥ 6 in the fatty acid chain, as functional oil matrices and rationally controlling the moisture content of the pharmaceutical composition, the palatability problem of butylphthalide can be effectively solved, the strong oral mucosal irritation of butylphthalide or its derivatives can be masked, there is basically no pungent or burning sensation during the buccal administration process, and the unpleasant odor or bitterness can be significantly reduced. The oral mucosal administration has good tolerance and is suitable for long-term repeated administration.

Based on this, an example of the present application provides a pharmaceutical composition for delivery through the oral mucosa, which comprises the following components in parts by weight:

5 to 40 parts of active pharmaceutical ingredients, and

Functional oil base 5 to 90 parts.

Among them, according to the total weight of the pharmaceutical composition, the water content accounts for ≤3%. During the research process, it was found that the water content in the pharmaceutical composition significantly affects the quality stability of the solution-type composition including the active pharmaceutical ingredient and the functional oil matrix, and also has a more obvious effect on the palatability. When the water content is too high, the spicy and bitter tastes are unstable during the sublingual administration through the quantitative device. Therefore, it is necessary to reasonably control the water content in the pharmaceutical composition to account for ≤3%, further, the water content accounts for ≤2%, and further, the water content accounts for ≤1%. Without limitation, the water content includes but is not limited to: 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.8%, 0.1%, 1.5%, 2%, 2.5%, 3%.

In addition, the control of the moisture content in the pharmaceutical composition is also crucial for the microbial safety of the drug. Generally, the higher the free moisture content, the more likely it is to cause concerns about microbial safety (the higher the free moisture content, the more conducive to the growth of microorganisms). The key combination components involved in this application, such as the functional oil matrix, are all easy to control moisture at the source, controlling the moisture to ≤2%, more preferably ≤1%, and further preferably ≤0.5%, to ensure the moisture content in the pharmaceutical composition prepared by each component, so as to improve the biosafety of the drug.

Wherein, the functional oil matrix includes one or more of fatty acid esters. Further, the carbon number of the fatty acid chain in the fatty acid ester is ≥6. It is understandable that the fatty acid chain may include a saturated fatty acid chain and an unsaturated fatty acid chain, and the unsaturated fatty acid chain may include a monounsaturated fatty acid (containing one double bond) chain, a diunsaturated fatty acid (containing two double bonds) chain or a polyunsaturated fatty acid (containing more than two double bonds) chain. During the research process, it was found that, relative to fatty acid esters with 2 or 4 carbon atoms in the fatty acid chain, butylphthalide or its derivatives solubilized with fatty acid esters with ≥6 carbon atoms in the fatty acid chain have a better masking effect on spicy stimulation and bad taste, and significantly improve palatability. In addition, in some of the examples, compared with the butylphthalide raw material or butylphthalide solubilized by small molecules, the butylphthalide solubilized by the fatty acid ester with a carbon number ≥ 6 has an increased exposure after absorption through the oral mucosa, thereby improving the non-injection bioavailability of the drug. For example, in the specific examples, compared with the commercially available Enbipu soft capsules (oral preparations), the absolute bioavailability of the butylphthalide sublingual preparation is increased by more than 2 times, more by 4 times, and more by more than 6 times.

Wherein, the active pharmaceutical ingredient includes one or more of butylphthalide and butylphthalide derivatives. Without limitation, the butylphthalide is selected from one or more of racemic butylphthalide, levorotatory butylphthalide and dextrorotatory butylphthalide; the butylphthalide derivative is selected from butylphthalide prodrugs such as 2-(α-hydroxypentyl)benzoic acid potassium salt, but is not limited thereto.

Furthermore, through the delivery of the drug combination, the active ingredients of the drug can still be well absorbed through the oral mucosa. For example, in the specific example, within the dosage range of 5 to 25 mg, the absolute bioavailability (relative to commercially available drip preparations) can reach more than 40%, and up to more than 60%. Therefore, under non-injection administration routes, low doses can achieve good in vivo exposure, and the medication and prevention and treatment of ischemic stroke, vascular dementia, muscular atrophy (ALS), angina pectoris, and myocardial infarction can be realized in non-professional care settings, thereby improving patients' compliance with medication and clinical accessibility.

Specifically, the weight proportions of the active pharmaceutical ingredient include but are not limited to: 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, and 50 parts.

Specifically, the weight proportions of the functional oil matrix include but are not limited to: 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, and 90 parts.

In some examples, the pharmaceutical composition for oral mucosal delivery comprises the following components in parts by weight:

Combination of active ingredients containing butylphthalide 5 to 25 parts, and

Functional oil base: 5 to 90 parts.

Further reasonable control of the weight of each component can obtain better palatability.

In some examples, the number of carbon atoms in the fatty acid chain of the fatty acid ester is 6 to 30. Specifically, the number of carbon atoms in the fatty acid chain of the fatty acid ester includes, but is not limited to: 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30.

In some examples, the functional oil matrix includes soybean oil, corn oil, peanut oil, sesame oil, olive oil, coconut oil, castor oil, peppermint oil, medium chain (6 to 12 carbon atoms) fatty acid esters and their derivatives (without limitation, for example, pharmaceutical grade caprylic acid triglyceride, tricaprylin, cocoyl caprylic acid caprate (Captex 170EP), caprylic acid coconut ester, caprylic acid capric acid mono-, di- and tri-glycerides (Capmul MCM NF), Phosal 53MCT), polyethylene glycol fatty acid glycerides (without limitation, for example, caprylic acid capric acid polyoxyethylene glyceride (Labrasol The invention can include one or more of glyceryl monooleate, glyceryl monooleate, glyceryl monooleate, glyceryl trioleate, ethyl linoleate, ethyl oleate, ethyl palmitate, isopropyl myristate, vitamin C palmitate and isopropyl palmitate.

As mentioned above, the functional oil matrix with a carbon number of ≥6 in the fatty acid chain and a shorter chain (such as 2 and 4 carbon atoms) can better cover the bad taste of butylphthalide and obtain acceptable palatability. Specifically, diolein, monoolein, isopropyl myristate, etc. can better cover the bad taste of butylphthalide, have better palatability, and can be accepted for long-term administration. Soybean oil, olive oil or medium-chain triglycerides can better cover the bad taste of butylphthalide, have better palatability, and can be accepted for long-term administration. Further, the functional oil matrix preferably includes one or more of coconut oil, soybean oil, castor oil, peppermint oil, olive oil and medium-chain (6 to 12 carbon atoms) fatty acid esters and their derivatives.

In some examples, the pharmaceutical composition for oral mucosal delivery may include 0 to 20 parts of a surfactant. Without limitation, the weight parts of the surfactant include, but are not limited to: 0, 0.01, 1, 3, 5, 7, 10, 12, 15, and 20 parts.

Without limitation, the surfactant is an amphiphilic surfactant, including one or more of polyethylene glycol oleic acid glyceryl, polyethylene glycol stearic acid glyceryl, polyethylene glycol sorbitol oleate, polyethylene glycol anhydrous sorbitan monostearate/oleate, polyethylene glycol-7-stearate, polyethylene glycol-75-stearate, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyethylene glycol-12-hydroxystearate, polyoxyethylene 35 castor oil and polyoxyethylene (20) anhydrous sorbitan monooleate. The addition of a certain proportion of surfactants can adjust the in vitro permeation rate of the drug in the system, but the effects of reducing irritation and taste masking will decrease to a certain extent, so in some examples, the pharmaceutical composition for oral mucosal delivery may not include a surfactant.

In addition, without limitation, the pharmaceutical composition for oral mucosal delivery may further include an excipient. The excipient may be any excipient of a medicament suitable for oral mucosal administration in the art. In some examples, the excipient may be one or more selected from a diluent, an antioxidant, a preservative, a flavoring agent, an adsorbent, and a lubricant.

In some examples, the pharmaceutical composition for oral mucosal delivery may include 0 to 72 parts of a diluent. Without limitation, the weight parts of the diluent include, but are not limited to: 0, 0.01, 1, 5, 10, 15, 20, 30, 50, 70, 72.

Specifically, the diluent can be selected from one or more small molecule solvents (molecular weight range of 40 to 500), and the small molecule solvent can make the pharmaceutical composition form a uniformly dispersed liquid preparation or semisolid preparation with different fluidity or viscosity, so as to facilitate the use of patients. Optionally, the diluent includes one or more of ethanol, propylene glycol, glycerol, isopropanol, polyethylene glycol, benzyl alcohol, diethylene glycol ethyl ether, ethyl acetate, propylene glycol diethyl ester, diethyl malonate, diethanolamine, benzyl benzoate, nitrogen methyl pyrrolidone, dimethylacetamide, polyethylene glycol monomethyl ether and dimethyl sulfoxide.

In some examples, the pharmaceutical composition for oral mucosal delivery may include 0 to 6 parts of flavoring agents. Without limitation, the weight parts of flavoring agents include, but are not limited to: 0, 0.01, 0.1, 0.5, 0.7, 1, 1.5, 3, and 6.

Flavoring agent is an additive with a mouthfeel correction effect, and there is no particular restriction on the type of flavoring agent, as long as it can be applied to medicine. Optionally, the flavoring agent includes one or more of a sweetener, a cooling agent, an essence and a sesame oil. Further optionally, the flavoring agent includes one or more of saccharin sodium, stevioside, aspartame, nutame, sodium cyclamate, acesulfame potassium, mogroside, xylitol, mannitol, lactose, glucose, sucrose, sucralose, honey, peppermint oil, menthol, thymol, eucalyptus oil, WS-5, WS-23, apple flavor, vanillin, lemon flavor, tea flavor, strawberry flavor, pineapple flavor, hawthorn flavor, glucosyl steviol glycoside, jasmine absolute, lemon oil, sweet orange oil, winter vanilla oil, sweet orange juice oil, rose absolute, grapefruit oil, red grapefruit oil, borneol, sodium caseinate, alanine, citric acid, acetic acid, malic acid and trisodium citrate.

In some examples, the pharmaceutical composition for oral mucosal delivery may include 0 to 1 part of an antioxidant. Without limitation, the weight parts of the antioxidant include, but are not limited to: 0 part, 0.01 part, 0.1 part, 0.25 part, 0.5 part, 0.7 part, 1 part.

Optionally, the antioxidant includes one or more of tocopherol, tocopherol acetate, vitamin E, sodium metabisulfite, cysteine hydrochloride, sodium sulfite, sodium metabisulfite, sodium bisulfite, ascorbic acid, thioglycerol, ascorbyl palmitate, butylated hydroxytoluene and butylated hydroxyanisole.

In some examples, the pharmaceutical composition for oral mucosal delivery may include 0 to 1 part of a preservative. Without limitation, the weight parts of the antioxidant include, but are not limited to: 0 part, 0.01 part, 0.1 part, 0.25 part, 0.5 part, 0.7 part, 1 part.

Optionally, the preservative includes one or more of benzalkonium bromide, benzoic acid and its sodium salt, benzyl benzoate, sorbic acid and its potassium salt, and parabens (such as paraben).

The addition of antioxidants and preservatives can improve the stability and clinical safety of the pharmaceutical composition during long-term storage to prevent oxidation or corruption during long-term storage.

Some other examples of the present application provide a pharmaceutical preparation, including the pharmaceutical composition for oral mucosal delivery as described above. It can be understood that the oral mucosal delivery can select one or more routes of oral mucosal delivery such as sublingual mucosa or buccal mucosa.

In some examples, the dosage form of the drug preparation is sublingual drops, sublingual sprays, oral sprays, buccal sprays, buccal aerosols, sublingual aerosols, oral aerosols, etc. Without limitation, the drug preparation can be quantitatively loaded into a quantitative drug delivery device (such as a quantitative spray or drop device) and then administered through the buccal mucosa or sublingual mucosa, which is suitable for industrial production.

Still other examples of the present application provide a pharmaceutical composition for delivery via the oral mucosa as described above and the use of one or more of the pharmaceutical preparations as described above in the preparation of a drug for preventing or treating diseases such as tissue pathological damage or nerve cell damage caused by ischemia and hypoxia.

In some of the examples, the diseases of tissue pathological damage or nerve cell damage caused by ischemia and hypoxia are ischemic stroke, vascular dementia, muscular atrophy, angina pectoris or myocardial infarction.

In some examples, the active pharmaceutical ingredient with oral mucosal irritation includes butylphthalide. Further, the single dose of butylphthalide in the pharmaceutical composition is 3 to 50 mg, optionally 5 to 40 mg, and further optionally 10 to 30 mg. The number of administrations per day is 1 to 8 times, optionally 2 to 6 times.

The present application uses a specific functional oil matrix, which can significantly improve the taste of butylphthalide and increase the in vitro dissolution-permeability of butylphthalide. It has been proven through dog oral mucosal administration experiments that it can improve the absorption of non-injection routes of administration and has good bioavailability after oral mucosal administration. In some examples, the pharmaceutical composition is compared with the same dose of commercially available sodium chloride butylphthalide injection ( The absolute bioavailability of the injection (25 mg/100 mL) can reach more than 40%, and can reach more than 60% at most. The absolute bioavailability is significantly higher than that of the Enbipu oral soft capsule preparation.

In addition, the active ingredients of the medicine also include one or more other drugs related to the treatment field of butylphthalide. Without limitation, the other drugs in the treatment field related to butylphthalide include one or more of borneol, dapoxetine, and edaravone. The functional oil matrix can significantly improve the oral taste of butylphthalide combined with other drugs, reduce the strong stimulation (spicy feeling) of butylphthalide to the mucosa, reduce the bad smell and bitterness unique to butylphthalide, improve palatability, and increase the compliance of clinical oral medication. Specifically, the active ingredient combination containing butylphthalide described in the present application, wherein the active ingredient combination, in addition to one or more of butylphthalide and its derivatives, may also include other stroke drugs to achieve the treatment of combined medication. However, the traditional method has not yet seen the listing of a composition delivered by butylphthalide and other common stroke treatment drugs such as edaravone, dapoxetine or borneol, mainly due to the bad taste of butylphthalide. The pharmaceutical composition provided in this application can be further used to prepare a combination of butylphthalide and other cardiovascular and cerebrovascular drugs, such as an oral mucosal pharmaceutical composition with borneol, dexamethasone or edaravone. The seemingly complex and diverse pathogenic mechanisms of stroke actually include oxidative stress and inflammatory reactions, and dexamethasone, borneol or edaravone, etc., all have anti-inflammatory or anti-oxidative stress reactions, which provide the possibility of protecting the brain from the above diseases, and can also form a further synergistic treatment combination with butylphthalide to achieve better disease treatment.

The above-mentioned pharmaceutical composition for oral mucosal delivery can be prepared according to the existing methods in the art without particular limitation. In some examples, the preparation method comprises the following steps:

Mix and dissolve the components.

It is understandable that when the components contain solid flavoring agents or insoluble ingredients, they can be dissolved in a diluent first (using ultrasound, heating, stirring, etc.), and then mixed and dissolved with other components.

The present invention is explained below in conjunction with embodiments, comparative examples, test examples, and drawings and appendices of the specification. The following description is merely an illustrative illustration of the technical solutions claimed in the present application, and is not any limitation to these technical invention solutions, and should not limit the scope of protection of the present invention.

In the embodiments, the butylphthalide raw material (racemic butylphthalide) is from Guangdong Longfu Biotechnology Co., Ltd., edaravone is from Hubei Jiuzhou Kangda Biotechnology Co., Ltd., dextromethorphan is from Jiangsu Huiju Pharmaceutical Co., Ltd., borneol is from Hunan Songyuan Biotechnology Co., Ltd., surfactants, functional oils, small molecule solvents, flavoring agents, excipients, etc. are purchased from BASF, Guangdong Baiyunshan, Gattefossé, Anhui Ante Food Co., Ltd., Chuangle Flavors (Shanghai), Nanjing Will, etc.

Examples and Comparative Examples

The compatibility of the components in the pharmaceutical compositions provided in the Examples and Comparative Examples is shown in Tables 1-5 below.

The preparation method is:

a) mixing ethanol and sucralose, performing ultrasound and stirring to dissolve the sucralose (if sucralose does not exist in the components, this step can be omitted); and

b) mixing the remaining components with the solution obtained in step a), stirring and mixing to dissolve, thereby obtaining the product.

Table 1 Examples of different weight portions of compatibility

Table 2 Examples containing different types of components

Table 3 Examples of active ingredient combinations

Table 4 Comparative Examples of Different Fatty Acid Ester or No Fatty Acid Ester

Table 5 Examples and Comparative Examples of Different Moisture Contents

Note: Water content was determined by Karl Fischer method.

Test example:

1. Palatability assessment

The palatability of the examples and comparative examples prepared above was investigated at a sublingual dose of 7 mg.

Taste-masking effect evaluation method: A single-blind test method was used to randomly ask 12 volunteers to rate the spiciness, bitterness, and "celery" smell of different prescription preparations. The total score is 10 points. The higher the average score, the easier it is to accept the corresponding taste of the drug for oral administration:

An average score of 9 to 10 points or above (including the lower limit) indicates better palatability, and the corresponding taste is acceptable for long-term oral administration of drugs; an average score of 8 to 9 points (including the lower limit) indicates good palatability, and the taste is acceptable for long-term oral administration of drugs, and there is room for further optimization; an average score of less than 8 points indicates poor taste during oral administration, discomfort during oral administration, and difficulty in accepting the taste of drugs for long-term oral administration, and it is recommended to continue to optimize the taste of the preparation. The results are as follows:

From the palatability evaluation results of Examples 1 to 6 in Tables 6 to 8, it can be seen that the prescriptions containing the functional fatty acid esters disclosed in the present application have scores of 8 or more for unpleasant tastes such as spiciness, bitterness, and celery smell. The average palatability score of some compositions can reach 9 or more. The taste of these compositions is acceptable for long-term buccal administration.

From the palatability evaluation of Example 1 and Example 7 to Example 17 in Tables 9 to 11, it can be seen that the antioxidants, preservatives, etc. in the composition have little effect on the palatability; although several key functional fatty acid esters have different masking effects on bitterness, the overall palatability score of each composition is more than 8 points, and the average palatability score of some compositions can reach more than 9 points. The taste of these compositions can be accepted for long-term buccal administration.

From the palatability evaluation of Examples 18 to 26 in Tables 12 to 14, it can be seen that the composition of butylphthalide and other pharmaceutical compositions, and the composition formed by the functional fatty acid ester, have a good masking effect on bitterness. The average overall palatability score of each composition is more than 8 points, and the higher ones can reach more than 9 points. The taste of these compositions can be accepted for long-term buccal administration.

From the palatability evaluation of Examples 1, 27 and 28 and Comparative Examples 1 to Comparative Examples 4 in Tables 15 to 17, it can be seen that the taste of Comparative Example 3, which is a reference group without active ingredients, is good, and the average score of each taste is above 9.5 points, but the taste of the raw material itself (Comparative Example 4) and the butylphthalide group dissolved in a small molecule solvent (Comparative Example 1) are extremely poor, with a score of less than 5 points, and it is difficult to take orally; the butylphthalide group dissolved in a surfactant (Comparative Example 2) and the butylphthalide group dissolved in a short-chain glyceride such as tributyrin and tributyrin (Examples 27 and 28) have a score of less than 8 points in terms of spicy stimulation, bitterness and other bad odors, and are still difficult to accept for long-term oral administration. Relatively speaking, medium or long-chain fatty acid glycerides with a carbon chain length of ≥6 have a better masking effect on the irritation of butylphthalide.

From the palatability evaluation of Examples 29 to 32 and Comparative Examples 5 to 6 in Tables 18 to 20, it can be seen that the taste of the compositions of Comparative Examples 5 and 6 when the moisture content is greater than 3% is relatively worse, and the score fluctuations of different volunteers are relatively large, and some volunteers have low scores for individual tastes (<8 points, difficult to accept); while the palatability of Examples 29 to 32 with a moisture content of ≤3% is relatively good, especially the taste of the moisture content of ≤1% is relatively better, and the evaluation fluctuations of different volunteers are small and relatively more stable. It can be seen that the control of moisture in the composition plays an important role in the stability of the taste.

The results of Examples 1 to 6 are shown in Tables 6 to 8 below:

Table 6 Evaluation results of spicy sensation of the prescriptions of Examples 1 to 6

Table 7 Bitterness evaluation results of the prescriptions of Examples 1 to 6

Subject number Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 1 8 8 9 8 9 8 2 10 8.5 8 10 8 7.5 3 9 8.5 9 9 8 8 4 9 8 10 9 9 8.5 5 10 8 10 10 9 9 6 8.5 9 9 9 9 7 7 8 8 10 9 8 8 8 10 9 9 9 9 9 9 9 8 10 9 8 7 10 9 8 9 10 8 8.5 11 10 7.5 10 9 9 8 12 10 9 10 10 9 9 13 9 8.5 9.5 9 8.5 8 14 9 8 8 10 8 7 15 10 8.5 9 10 8.5 8 16 9 9 10 9 9 8.5 17 10 7 9 10 10 9 18 8 9 8 9 9 8 19 8 8 10 10 8 8 20 9 9 9 9 9 9 twenty one 10 8.5 9 9 8 7.5 twenty two 9 8 10 10 8 9 twenty three 9 9 10 9.5 9 9 twenty four 10 8 9 9.5 8 8 average value 9.2 8.3 9.3 9.4 8.6 8.2

Table 8 Celery odor evaluation results of Example 1 to Example 6

The palatability test results of Example 1 and Example 7 to Example 17 are shown in Tables 9 to 11 below:

Table 9 Evaluation results of spicy sensation of Example 1 and Examples 7 to 17

Table 10 Bitterness evaluation results of Example 1 and Examples 7 to 17

Table 11 Celery odor evaluation results of Example 1 and Examples 7 to 17

The palatability test results of Examples 18 to 26 are shown in Tables 12 to 14 below:

Table 12 Evaluation results of spicy sensation of Examples 18 to 26

Table 13 Bitterness evaluation results of Examples 18 to 26

Table 14 Celery odor evaluation results of Examples 18 to 26

The palatability test results of Examples 1, 27 and 28 and Comparative Examples 1 to 4 are shown in Tables 15 to 17 below:

Table 15 Evaluation results of spicy sensation of Examples 1, 27 and 28 and Comparative Examples 1 to 4

Table 16 Bitterness evaluation results of Examples 1, 27 and 28 and Comparative Examples 1 to 4

Table 17 Celery taste evaluation results of Examples 1, 27 and 28 and Comparative Examples 1 to 4

Subject number Example 1 Embodiment 27 Embodiment 28 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 1 8 5 5 0 7 10 0 2 10 4 5 1 6 10 1 3 9 7 6 0 8 10 0 4 9 4 5.5 2 5 10 0 5 10 8 4 0 8 9.5 0 6 9 6 7 0 6 10 1 7 8 7 6 2 6 9 1 8 9.5 4 5 1 5 10 0 9 9 5 4.5 0 8 10 1 10 9 7 5 2 6 9 0 11 9.2 5.5 7 0 7 10 0 12 10 7 6 0 8 10 1 13 9 5.5 6 1 6.5 9.8 0 14 9 4 3.5 1 5.5 10 1 15 9 3 5.5 0 7 10 0 16 10 5 6 1.5 5.5 10 0 17 10 7 4 0 7 9.5 0 18 8 6 6 0 7.5 10 0 19 9 7 7 2 6 9 1 20 8.5 3 5 2 6 10 0 twenty one 9 5 4.5 0 8 10 1 twenty two 9 7.5 6 1 6 9 0 twenty three 10 5 5.5 0 8 9 0 twenty four 8.5 6 7 0 7 10 1 average value 9.1 5.6 5.5 0.7 6.7 9.7 0.4

The palatability evaluation results of Examples 29 to 32 and Comparative Examples 5 to 6 are shown in Tables 18 to 20:

Table 18 Evaluation results of spicy sensation of Examples 29 to 32 and Comparative Examples 5 to 6

Table 19 Bitterness evaluation results of Examples 29 to 32 and Comparative Examples 5 to 6

Table 20 Celery taste evaluation results of Examples 29 to 32 and Comparative Examples 5 to 6

Subject number Embodiment 29 Embodiment 30 Embodiment 31 Embodiment 32 Comparative Example 5 Comparative Example 6 1 10 9 9 7 8 9 2 10 8 9 9 8 7 3 9 9.5 10 8 7 8 4 9 10 8 9 9 7 5 9 9 7.5 9 7.5 7 6 10 9.5 9 8 5.5 8 7 8 9 10 7 8 8 8 9 9.5 9 8 8 7.5 9 9 8 8 7.5 6.5 9 10 8 9.5 9 7.5 7 9 11 9 8.5 8 8 8 7 12 10 9 9 9 7 6.5 13 9 9 8.5 8 6 7.5 14 10 10 9 9 8 6 15 9 9.5 10 8 7 8 16 9 10 8.5 8 9 8 17 9 9.5 8 8 7.5 8 18 10 9.5 9 8 9 8 19 8 10 9.5 10 8 8 20 9 9 10 8 8 7 twenty one 9 8.5 10 8 6.5 9 twenty two 8 9 9 8 7 8 twenty three 9 10 9 8 9 6 twenty four 10 9.5 10 10 8 7 average value 9.1 9.3 9.0 8.3 7.6 7.6

2. Bioavailability study experiment:

(1) Dog Experiment to Study the Bioavailability of Butylphthalide Composition

Beagle dogs weighing about 10 kg were randomly divided into groups (n=3), fasted for 12 hours before administration, and had free access to water. Food was provided 4 hours after administration.

Commercially available sodium chloride injection (Enbipu sodium chloride injection, 25 mg/100 mL) was administered intravenously at a dose of 25 mg/dog (intravenous injection for 1 hour). Blood was collected at 0 min, 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, and 2 h before and after administration, and placed in a heparin-treated blood collection tube. The blood was centrifuged at 4000 rpm for 10 min to separate the plasma and analyze it.

Commercially available oral soft capsules (Enbipu soft capsules, 100 mg) were orally administered to dogs by gavage at 100 mg/dog. Blood was collected at 0 min, 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, and 2 h before and after administration, and placed in a heparin-treated blood collection tube. The blood was centrifuged at 4000 rpm for 10 min to separate the plasma and analyze it.

15 mg of the test preparation was administered sublingually. The dogs were not allowed to drink water within 5 minutes after administration, and their mouths were closed to prevent them from sticking out their tongues and causing drug loss. Each dog was allowed to open its mouth 2 minutes after administration. Blood was collected before and at 0 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, and 2 hours after administration, and placed in a heparin-treated blood collection tube. The blood was centrifuged at 4000 rpm for 10 minutes to separate the plasma and analyze the test.

The blood drug concentration data were statistically analyzed using Excel to obtain the peak blood drug concentration _Cmax value, and the area under the blood drug concentration curve AUC _0-2h (0h～2h) was calculated by the trapezoidal method.

The absolute bioavailability F is the percentage of AUC _0-2h of the tested sublingual preparation and the commercially available sodium chloride butylphthalide injection at a unit dose, and the calculation formula is: F = (AUC _{sublingual preparation} /14 mg) ÷ (AUC _Enbipu /administered dose) × 100%.

The results are shown in Figure 1 and Table 21 below (n=3):

The butylphthalide dissolved in the functional fatty acid ester (prescriptions of Examples 1, 7, and 8) has good bioavailability, and its absorption is increased compared with the butylphthalide dissolved in the relatively small molecule solvent (Comparative Example 1) and the pure butylphthalide (Comparative Example 4). Compared with the commercially available Enbipu soft capsules for oral administration, the absolute bioavailability is significantly improved. Although the butylphthalide solubilized with a surfactant (Comparative Example 2) has good absorption, it has a poor taste and is difficult to be taken orally.

Table 21

Note: _Cmax refers to the maximum blood drug concentration, and _AUC0-2h refers to the area under the blood drug concentration-time curve within 0 to 2 hours.

(2) Rat experiment to investigate the bioavailability of butylphthalide compound preparation

Male SD rats, weighing 180-200 g, were randomly divided into groups, 3 rats in each group, fasted for 12 h, allowed free access to water, and provided food 4 h after administration.

a. Injection:

① Take commercially available sodium chloride butylphthalide injection (Enbipu 25mg/100mL, Shijiao Pharmaceutical) and intravenously inject 2.5mg/kg butylphthalide. Take blood samples of 100μL at 2min, 5min, 15min, 30min, 1h, 2.5h, and 5h, separate the plasma and analyze the test;

② Take a concentrated solution of edaravone/dexamethasone for injection (30 mg/7.5 mg, diluted with 100 mL of sodium chloride, Innovent Biologics), and administer it intravenously at a dose of 2.5 mg/kg edaravone/0.625 mg dexamethasone. Take 100 μL of blood samples at 2 min, 5 min, 15 min, 30 min, 1 h, 2.5 h, and 5 h, separate the plasma, and analyze and test;

b. Sublingual administration of butylphthalide-edaravone combination

Sublingual administration: chloral hydrate was injected intraperitoneally to place SD rats in a state of light anesthesia, and the composition of Example 21 (5 mg butylphthalide/5 mg edaravone) was dripped under the tongue at a dose of 1.25 mg/kg butylphthalide/1.25 mg/kg edaravone. The rat mouth was fixed for 30 minutes to prevent the drug solution from flowing out. The timing was started from the dripping of the drug solution. 100 μL of blood samples were taken at 2 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2.5 hours, and 5 hours, and the plasma was separated and analyzed.

c. Sublingual administration of butylphthalide-dexamethasone combination

Sublingual administration: chloral hydrate was injected intraperitoneally to put SD rats into a state of light anesthesia. The composition of Example 23 (5 mg butylphthalide/1 mg borneol) was administered sublingually at a dose of 1.25 mg/kg butylphthalide/0.25 mg/kg borneol. Blood samples of 100 μL were taken at 2 min, 5 min, 15 min, 30 min, 1 h, 2.5 h, and 5 h, and the plasma was separated and analyzed.

d. Sublingual administration of butylphthalide composition

Sublingual administration: chloral hydrate was injected intraperitoneally to put SD rats into a state of light anesthesia. The composition of Example 1 at a dose of 1.25 mg/kg butylphthalide was dripped sublingually. Blood samples of 100 μL were taken at 2 min, 5 min, 15 min, 30 min, 1 h, 2.5 h, and 5 h, and the plasma was separated and analyzed.

The blood drug concentration data were statistically analyzed using Excel to obtain the peak blood drug concentration _Cmax value, and the area under the blood drug concentration curve _AUC0-5h was calculated using the trapezoidal method.

The absolute bioavailability F is the percentage of AUC _0-5h of the tested sublingual preparation and the injection at a unit dose, and is calculated as follows: F = (AUC _sublingual /sublingual dose) ÷ (AUC _injection /injection dose) × 100%.

The results are shown in Table 22 below (n=3):

The compound compositions of butylphthalide or butylphthalide and other drugs (such as edaravone or dextroborneol) dissolved in functional fatty acid esters (prescriptions in Examples 1, 21, and 23) all have good bioavailability when administered sublingually.

Table 22

The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

The above-described embodiments only express several implementation methods of the present application, which is convenient for understanding the technical solution of the present application in detail, but it cannot be understood as limiting the scope of protection of the patent application. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present application, several modifications and improvements can be made, which all belong to the scope of protection of the present application. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the scope of protection of the claims attached to the present application. Therefore, the scope of protection of the patent of this application shall be based on the contents of the attached claims, and the description and drawings may be used to interpret the contents of the claims.

Claims (10)

1. A pharmaceutical composition for delivery via the oral mucosa, comprising the following components in parts by weight:

5 to 40 parts of medicinal active ingredients and

5-90 Parts of functional oil base;

The moisture content is less than or equal to 3%, alternatively less than or equal to 2%, and further alternatively less than or equal to 1% based on the total weight of the pharmaceutical composition;

The medicine active component comprises one or more of butylphthalide and butylphthalide derivatives;

the functional oil base includes one or more of fatty acid esters.

2. The pharmaceutical composition for delivery via oral mucosa according to claim 1, wherein the fatty acid ester has a carbon number of fatty acid chain of 6 or more, optionally the fatty acid ester has a carbon number of 6 to 30.

3. The pharmaceutical composition for delivery via oral mucosa of claim 1, wherein the functional oil base is selected from one or more of soybean oil, corn oil, peanut oil, sesame oil, olive oil, coconut oil, castor oil, peppermint oil, medium chain fatty acid esters and derivatives thereof, polyethylene glycol fatty acid glycerides, structured greases, star anise oil, tea oil, clove basil oil, patchouli oil, perilla leaf oil, clove oil, monolinolein, oleic acid monolinolein, dioleyl, ethyl linoleate, ethyl oleate, ethyl palmitate, isopropyl myristate, vitamin C palmitate, and isopropyl palmitate;

optionally, the functional oil base is selected from one or more of coconut oil, soybean oil, castor oil, sesame oil, peppermint oil, olive oil and medium chain fatty acid esters and derivatives thereof.

4. The pharmaceutical composition for oromucosal delivery according to claim 1, wherein the butylphthalide is selected from one or more of the group consisting of racemic butylphthalide, levobutylphthalide and dextrorotatbutylphthalide;

the butylphthalide derivative is selected from butylphthalide prodrugs; alternatively, the butylphthalide derivative is selected from the group consisting of potassium 2- (α -hydroxypentyl) benzoate;

The pharmaceutical active ingredients comprise butylphthalide and other pharmaceutical combinations in the relevant therapeutic fields; optionally, the other drugs of the relevant therapeutic field are selected from one or more combinations of borneol, dexbornyl alcohol and edaravone.

5. The pharmaceutical composition for delivery via oral mucosa according to claim 1, comprising the following components in parts by weight:

5 to 25 parts of medicinal active ingredients, and

5-90 Parts of functional oil base.

6. The pharmaceutical composition for delivery via oral mucosa according to any one of claims 1 to 5, further comprising 0 to 20 parts of a surfactant;

Optionally, the surfactant comprises 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, and polyoxyethylene (20) sorbitan monooleate.

7. The pharmaceutical composition for delivery via the oral mucosa according to any one of claims 1 to 5, further comprising 0 to 72 parts of a diluent;

Optionally, the diluent comprises one or more of ethanol, propylene glycol, glycerol, isopropanol, polyethylene glycol, benzyl alcohol, diethylene glycol diethyl ether, ethyl acetate, propylene glycol diethyl, diethyl malonate, diethanolamine, benzyl benzoate, azamethylpyrrolidone, dimethylacetamide, polyethylene glycol monomethyl ether, and dimethylsulfoxide.

8. The pharmaceutical composition for delivery via the oral mucosa according to any one of claims 1 to 5, further comprising 0 to 6 parts of a flavoring agent;

optionally, the flavoring agent comprises one or more of sweetener, cooling agent, essence and sesame oil;

further optionally, the flavoring agent comprises one or more of saccharin sodium, stevioside, aspartame, thaumatin, cyclamate, acesulfame potassium, mogroside, xylitol, mannitol, lactose, glucose, sucrose, sucralose, honey, peppermint oil, menthol, thymol, eucalyptus oil, 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, and trisodium citrate.

9. The pharmaceutical composition for delivery via oral mucosa according to any one of claims 1 to 5, further comprising 0 to 1 part of an antioxidant and/or 0 to 1 part of a preservative;

Optionally, the antioxidant comprises one or more of tocopherol, tocopheryl acetate, vitamin E, sodium metabisulfite, cysteine hydrochloride, sodium sulfite, sodium metabisulfite, sodium bisulfite, ascorbic acid, thioglycerol, ascorbyl palmitate, dibutyl hydroxy toluene, and butyl hydroxy anisole;

optionally, the preservative comprises one or more of benzalkonium bromide, benzoic acid and its sodium salt, benzyl benzoate, sorbic acid and its potassium salt, and parabens.

10. A pharmaceutical formulation comprising a pharmaceutical composition for delivery via the oral mucosa according to any one of claims 1 to 9 in the form of sublingual drops, sublingual spray, oral spray, buccal aerosol, sublingual aerosol or oral aerosol.