阅读说明：本技术 用于伤口愈合的组合物及其生成方法和用途 (Composition for wound healing and its production method and use ) 是由 Z·B·P·M·A·拉扎克 于 2019-02-21 设计创作，主要内容包括：本申请涉及一种用于伤口愈合的组合物,包含壳聚糖或壳聚糖衍生物和透明质酸衍生物以及用于口服和/或局部给药的固体剂型、半固体剂型和/或液体剂型的赋形剂,以及一种生成该组合物的方法。该用于伤口愈合的组合物pH在4.0至6.0之间,包含在3.0％w/v至6.0％w/v范围内的壳聚糖和在1.0％w/v至2.0％w/v范围内的透明质酸。该壳聚糖具有85％的脱乙酰度和150kDa的分子量。该透明质酸的分子量为100kDa。(The present application relates to a composition for wound healing comprising chitosan or a chitosan derivative and a hyaluronic acid derivative together with excipients for oral and/or topical administration in solid, semi-solid and/or liquid dosage forms, and a method of producing the composition. The composition for wound healing has a pH between 4.0 and 6.0, comprises chitosan in the range of 3.0% w/v to 6.0% w/v and hyaluronic acid in the range of 1.0% w/v to 2.0% w/v. The chitosan had a degree of deacetylation of 85% and a molecular weight of 150 kDa. The molecular weight of the hyaluronic acid is 100 kDa.)

1. A composition for wound healing comprising chitosan or a chitosan derivative and a hyaluronic acid derivative, together with excipients for oral and/or topical administration in solid, semi-solid and/or liquid dosage forms.

2. The composition for wound healing of claim 1, wherein the chitosan has a degree of deacetylation between 80-90%.

3. The composition for wound healing of claim 1, wherein the chitosan has a degree of deacetylation of 85%.

4. The composition for wound healing of claim 1, wherein the chitosan has a molecular weight ranging from 100kDa to 300 kDa.

5. The composition for wound healing of claim 1, wherein the chitosan has a molecular weight of 150 kDa.

6. The composition for wound healing of claim 1, wherein the hyaluronic acid has a molecular weight ranging from 50kDa to 300 kDa.

7. The composition for wound healing of claim 1, wherein the hyaluronic acid has a molecular weight of 100 kDa.

8. A composition for use in wound healing according to claim 1, wherein the chitosan is in the range of 3.0% w/v to 6.0% w/v.

9. A composition for use in wound healing according to claim 1, wherein the chitosan is in an amount of 5.0% w/v.

10. The composition for wound healing of claim 1, wherein the hyaluronic acid is in the range of 1.0% w/v to 2.0% w/v.

11. The composition for wound healing of claim 1, wherein the hyaluronic acid has an amount of 1.6% w/v.

12. The composition for wound healing according to claim 1, wherein the solid dosage form composition for topical administration comprises a foam dressing, a hydrocolloid and a fiber.

13. The composition for wound healing of claim 1, wherein the semi-solid dosage form for topical administration comprises pharmaceutically acceptable ointments, creams, lotions, gels, pastes and suppositories.

14. The composition for wound healing of claim 1, wherein the composition for oral administration in liquid dosage form comprises pharmaceutically acceptable emulsions, solutions, dispersions and suspensions.

15. The composition for wound healing of claim 13, wherein the semi-solid dosage form contains an inert diluent.

16. The composition for wound healing according to claim 15, wherein the inert diluent is water or other solvents, solubilizing agents and emulsifiers and mixtures thereof.

17. A method for generating a composition for wound healing, comprising the steps of:

i. mixing chitosan powder with an aqueous solution of lactic acid, wherein the lactic acid is in the range of 1.0% w/v to 1.5% w/v, preferably, in an amount of 1.0% w/v;

ii. (ii) stirring the mixture obtained in step (i) to produce a chitosan solution in an amount in the range of 3.0% w/v to 6.0% w/v, preferably having 5.0% w/v;

iii, preparing an aqueous solution of sodium hyaluronate in the range of 1.0% w/v to 2.0% w/v, preferably, in an amount of 1.6% w/v;

(iv) mixing the chitosan solution obtained in step (ii) with the sodium hyaluronate solution obtained in step (iii) to produce a mixture having a pH between 4.0 and 6.0, preferably a pH of 4.2; and

v, stabilizing the mixture obtained in step (iv) in a cryostat at 0 to 25 ℃ to obtain a wound healing composition.

18. Use of a composition comprising chitosan or a chitosan derivative and a hyaluronic acid derivative, together with an excipient, for wound healing.

19. A composition for wound healing produced according to any one of claims 1-18.

Technical Field

The present application relates to a wound healing composition comprising chitosan or a chitosan derivative and a hyaluronic acid derivative together with excipients for oral and/or topical administration in solid, semi-solid and/or liquid dosage forms.

Background

The treatment and therapy of external and internal wounds is an area of intense research and commercial interest because it significantly improves the quality of life of patients. Thus, traditional wound healing agents have been widely replaced by newer and more advanced dressings.

Chronic wounds remain one of the most difficult and expensive chronic conditions in therapy. Furthermore, chronic wounds have a potential impact on the life of people suffering from them, as patients will often be isolated and have limited mobility. Thus, most chronic wound patients exit life and most of them feel isolated from the surrounding environment. Thus, in addition to the economic burden placed on these patients and healthcare systems, there is a significant psychosocial cost associated with chronic wounds.

Accordingly, a wide range of inert and bioactive wound dressing materials with various medical properties are continually being developed. Generally, the wound dressing material should be permeable to moisture and oxygen, and the material should adhere to dry skin. In addition, the healing wound must have a stable and sufficient supply of oxygen, nutrients, enzymes and cells. Once the above factors are controlled and a wound bed with proper debridement and moisture control is prepared, the wound is ready for healing. Products aimed at achieving a well-prepared wound bed suitable for healing are widely studied.

In addition, cellular and biochemical components with enzymatic activity are key components in wound tissue repair and restoration. There are many natural polymers that exhibit suitable structural and physicochemical properties for various applications in wound treatment. For example, various neutral materials (i.e., cellulose), basic materials (i.e., chitin and chitosan), acidic materials (i.e., alginic acid and Hyaluronic Acid (HA)), and sulfated polysaccharides (i.e., heparin, chondroitin, dermatan, and keratin sulfate) have been the focus of attention in wound care applications.

Chitosan is a derivative of chitin, which is extracted from the exoskeletons of marine crustaceans. Chitosan is one of the most important biopolymers in biomedical applications. Chitosan is a biopolymer, which is a deacetylated derivative of chitin, consisting of glucosamine and N-acetylglucosamine. When the number of N-acetyl-glucosamine or N-glucosamine units, respectively, is higher than 50%, the biopolymer is called chitin or chitosan.

The low toxicity of chitosan in combination with various biological activities, such as antibacterial and antifungal effects, hemostatic effect, low immunogenicity, scar prevention, and the ability to effectively release drugs from the matrix, provides ample opportunity for further development. It is also a hydrophilic high molecular weight cationic polysaccharide, with biocompatibility and safety. Its bioadhesive and biodegradable characteristics have attracted interest to researchers in the clinical industry. Furthermore, chitosan and different materials based on chitosan have proven to have advantageous properties for promoting rapid dermal regeneration and for accelerating wound healing.

In addition, chitosan has been extensively studied due to its ready solubility in dilute acids, making it easier to use and to chemically react. However, it is generally insoluble in aqueous solutions above pH7 because its rigid crystal structure and deacetylation limit its wide application. To overcome this drawback, various chemical modifications of the chitosan backbone to obtain covalently grafted or crosslinked chitosan are carried out to improve its water solubility and gelling properties, which generally require the use of toxic reagents.

Hyaluronic Acid (HA) is one of the biopolymers with important biomedical applications, such as increasing cell proliferation and migration, angiogenesis, tissue healing and as inflammatory response control. It is a high molecular weight (104- & ltSUB & gt, 107kDa) non-sulfated glycosaminoglycan (GAG) that is a component of the extracellular matrix (ECM) of many tissues, such as the skin, synovial joints, and periodontal tissues.

US4572906 discloses a surgical dressing which protects a wound during the healing process. The dressing comprises about 3: 1 to 1: 3 and 0-40% w/w of a compatible plasticizer based on the total weight of the gelatin and chitosan.

EP1955693a1 discloses a composition comprising an aqueous solvent and a conjugate of at least one hydrophilic polymer having primary amine functional groups, derivatives or monomers thereof and at least one acidic drug. It also discloses a preparation method and application thereof.

EP3151872B1 discloses a wound dressing, in particular a stimulus-responsive wound dressing, comprising: a lyophilized Hyaluronic Acid (HA) hydrogel and a plurality of devices embedded within the lyophilized hyaluronic acid hydrogel, wherein each device of the plurality of devices comprises chitosan and hypromellose.

Despite these advances, there remains a need for a wound healing composition that accelerates wound healing, avoids trauma and healing disturbances due to dressing removal or replacement, and provides for the management of wound exudate, and that can be stored for long periods of time, and is readily available to any patient.

The present application addresses this need. The present application aims to provide a wound healing composition comprising chitosan or a chitosan derivative and a hyaluronic acid derivative.

Disclosure of Invention

A composition for wound healing comprising chitosan or a chitosan derivative and a hyaluronic acid derivative together with excipients for oral and/or topical administration in solid, semi-solid and/or liquid dosage forms.

Optionally, the composition for wound healing has a pH between 4.0 and 6.0, comprises chitosan in the range of 3.0 to 6.0% w/v and hyaluronic acid in the range of 1.0% w/v to 2.0% w/v.

Optionally, the composition has a pH within 4.2 and comprises chitosan in an amount of 5.0% w/v and hyaluronic acid in an amount of 1.6% w/v. The chitosan has a degree of deacetylation of 80% -90%, preferably 85%, and a molecular weight of 100kDa to 300kDa, preferably 150 kDa.

Alternatively, the hyaluronic acid has a molecular weight of 50kDa to 300kDa, preferably, 100 kDa.

A method of generating a composition for wound healing, comprising the steps of: (i) mixing chitosan powder with an aqueous solution of lactic acid, wherein the lactic acid is in the range of 1.0% w/v to 1.5% w/v, preferably, in an amount of 1.0% w/v; (ii) (ii) stirring the mixture obtained in step (i) to produce a chitosan solution in an amount in the range of 3.0% w/v to 6.0% w/v, preferably having 5.0% w/v; (iii) preparing an aqueous solution of sodium hyaluronate in the range of 1.0% w/v to 2.0% w/v, preferably, in an amount of 1.6% w/v; (iv) (iv) mixing the chitosan solution obtained in step (ii) with the sodium hyaluronate solution obtained in step (iii) to produce a mixture having a pH between 4.0 and 6.0, preferably a pH of 4.2; and (v) stabilizing the mixture obtained in step (iv) at a cryostat temperature of 0 to 25 ℃ to obtain a wound healing composition.

Other aspects, features and advantages of the present application will become apparent to those of ordinary skill in the art upon consideration of the following detailed description of the preferred embodiments of the application in conjunction with the accompanying drawings, which are set forth below.

Detailed Description

Detailed descriptions of preferred embodiments of the present application are disclosed herein. However, it is to be understood that the described embodiments are merely examples of the present application, which may be embodied in various forms. Therefore, the specific descriptions disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention.

It is an object of the present application to provide a composition comprising chitosan or a chitosan derivative and a hyaluronic acid derivative for use in wound healing.

Another object of the present application is a method for preparing a composition comprising chitosan or a chitosan derivative and a hyaluronic acid derivative acid for use in wound healing.

The term "chitosan" is intended herein to define polysaccharides derived from deacetylation of chitin, having a degree of deacetylation of 80% to 90%, obtained from cell walls of natural sources, such as fungi and chitin. The molecular weight of chitosan is in the range of 100kDa to 300 kDa.

The term "hyaluronic acid" refers herein to hyaluronic acid extracted from microbial fermentation or animal sources. The molecular weight of hyaluronic acid is in the range of 50kDa to 300 kDa.

Other objects and advantages of the present application will be set forth in the following portions of the specification, wherein the detailed description is for the purpose of fully disclosing preferred embodiments of the application without placing limitations thereon. The preferred embodiments will now be described in detail.

For the purposes of this application, a preferred chitosan has a degree of deacetylation of 85% and a molecular weight of 150 kDa. Further, the chitosan may be in the form of a salt, and may be selected from hydrochloride, sulfate, acetate, lactate, malate, succinate, ascorbate, fumarate, or chitosan adipate salt.

For the purposes of this application, the preferred molecular weight of hyaluronic acid is 100 kDa. Hyaluronic acid is preferably in the form of an alkali metal salt, more preferably in the form of a sodium salt, i.e. sodium hyaluronate.

In one embodiment of the present application, a composition for wound healing is disclosed, having a pH between 4.0 and 6.0, comprising chitosan in the range of 3.0% w/v to 6.0% w/v and hyaluronic acid in the range of 1.0% w/v to 2.0% w/v.

In a preferred embodiment of the present application, a composition for wound healing is disclosed, having a pH of 4.2, comprising chitosan in an amount of 5.0% w/v and hyaluronic acid in an amount of 1.6% w/v.

In another aspect of the present application, a method of preparing a wound healing composition is disclosed. A detailed description of the method is described below, which is not limited to the example used.

The method of producing a wound healing composition comprises a first step of mixing chitosan powder with an aqueous solution of lactic acid. The lactic acid is added in an amount ranging from 1.0% w/v to 1.5% w/v, preferably 1.0% w/v. The mixture is stirred to give a chitosan solution in an amount in the range of 3.0% w/v to 6.0% w/v, preferably having 5.0% w/v. In addition, an aqueous solution of sodium hyaluronate in the range of 1.0% w/v to 2.0% w/v, preferably, in an amount of 1.6% w/v, is prepared. The chitosan solution was mixed with the sodium hyaluronate solution to produce a mixture. The mixture is maintained in a pH range of 4.0 to 6.0, preferably pH4.2, and is stabilized at a cryostat temperature of 0 to 25 ℃ to obtain the wound healing composition.

The following examples are constructed to illustrate the present application in a non-limiting sense.

A method of producing a wound healing composition:

i. mixing chitosan powder with an aqueous solution of lactic acid, wherein the lactic acid is in the range of 1.0% w/v to 1.5% w/v, preferably in an amount of 1.0% w/v;

ii. (ii) stirring the mixture obtained in step (i) to produce a chitosan solution in an amount in the range of 3.0% w/v to 6.0% w/v, preferably having 5.0% w/v;

iii, preparing an aqueous solution of sodium hyaluronate in the range of 1.0% w/v to 2.0% w/v, preferably, in an amount of 1.6% w/v;

(iv) mixing the chitosan solution obtained in step (ii) with the sodium hyaluronate solution obtained in step (iii) to produce a mixture having a pH between 4.0 and 6.0, preferably a pH of 4.2; and

v, stabilizing the mixture obtained in step (iv) in a cryostat at 0 to 25 ℃ to obtain a wound healing composition.

The method of the present application provides a solution to generate a wound healing composition without the use of any toxic agents, and is therefore also more cost effective.

Therapeutic or sub-therapeutic amounts of the above-described composition of ingredients are delivered by topical, enteral and/or parenteral administration, but other suitable routes of administration are not limited. The wound healing formulations of the present application are not substitutes for those ingredients that occur naturally in the body and/or are consumed in the diet. It represents a formulation aimed at accelerating the wound healing process. It may be introduced into a patient in need thereof as a solid dosage form, a semi-solid dosage form, or a liquid dosage form.

Liquid dosage forms for topical administration include, but are not limited to, pharmaceutically acceptable emulsions, solutions, dispersions, and suspensions. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, and mixtures thereof.

Semisolid dosage forms for topical administration include, but are not limited to, pharmaceutically acceptable ointments, creams, lotions, gels, pastes, and suppositories. In addition to the active compounds, the semi-solid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, and mixtures thereof.

Solid dosage forms for topical administration include, but are not limited to, foam dressings, hydrocolloids, and fibers. In the present application, a foam dressing is preferred, wherein it may be applied directly on the wound area. The solid dosage forms of the present application may be produced using any pharmaceutically acceptable excipient, such as a) fillers or extenders, b) binders, c) humectants, d) disintegrants, e) wetting agents, f) lubricants, and mixtures thereof.

In general, the compositions of the wound healing compositions disclosed herein are formulated in such a way that the components thereof are incorporated in optimal dosages to provide the best results for carrying out the wound healing process. Since the compositions of the present application act in various ways to heal wounds, one skilled in the art may argue that the active ingredients may be administered alone to achieve the desired results. However, this will greatly increase the treatment burden on one person and inevitably lead to rejection.

It is to be understood that the terminology used herein is for the purpose of describing particular example embodiments only, and is not intended to be limiting. As used herein, the singular forms "a", "an" and "the" may include the plural forms as well, unless the context clearly indicates otherwise.

The terms "comprises," "comprising," "including," and "having," are inclusive and therefore specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

The method steps, processes, and operations described herein are not to be construed as necessarily requiring their performance in the particular order discussed or illustrated, unless specifically identified as an order of performance. It should also be understood that additional or alternative steps may be employed. The use of the expression "at least" or "at least one" means that one or more elements are used, as the use may exist in one of the embodiments, for accomplishing one or more desired objects or results.

While the foregoing is directed to various embodiments of the present application, other and further embodiments of the application may be devised without departing from the basic scope thereof. The scope of the application is determined by the following claims. This application is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the application in connection with the information and knowledge available to those having ordinary skill in the art.