Topical formulations for wound healing

Abstract

A topical preparation comprising an extract of Pogostemonis Herba (PA), an extract of Centella Asiatica (CA), a moisturizing polymeric biomaterial, and a pharmaceutically effective excipient. The present disclosure also relates to the use of the topical preparation for promoting wound healing.

Description

[0001] Cross-reference to related applications This application claims the benefit of U.S. Provisional Application No. 63 / 610,742, filed on December 15, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] Arrival Fragrance ( Plectranthus amboinicus (formerly known as or also called hairy throat coleopterus) Coleus amboinicus Lour., fragrant tea vegetable ( Coleus aromaticus Benth., fragrant tea vegetable ( Coleus aromaticus auct.), aromatic tea vegetables ( Plectranthus aromaticus Roxb., aromatic tea vegetable ( Plectranthus aromaticus Benth.) and Maohouxiang Tea Vegetable ( Plectranthus amboinicus (Lour.) Spreng. is a perennial medicinal herb native to southern and eastern Africa, belonging to the Lamiaceae family (also known as Labiatae). It is also called patchouli, Cuban oregano, Indian borage, Indian mint, Mexican mint, Mexican oregano, country borage, and Spanish thyme.

[0003] Centella asiatica ( Centella asiatica (formerly known as or also called Centella asiatica) Centella asiatica Urban), Centella asiatica ( Centella asiatica (L.) Urban), watercress ( Hydrocotyle asiatica L.) and Indian coriander ( Trisanthus cochinchinensis Centella asiatica (also known as Asian asiatica) is a perennial medicinal plant native to Asia, Africa, and South America, belonging to the Mackinlayaceae or Apiaceae (also known as Umbelliferae) subfamily of Mackinlayoideae. It is also called European water miracle, centella asiatica, kola nut, saxifrage, Indian saxifrage, swamp saxifrage, moneywort, Indian ginseng, horse hoof grass, pegaga, mandookaparni, tiger grass, spadeleaf, or Tono. Extracts of Centella asiatica typically contain two main compounds: asiaticoside and hydroxyasiaticoside. Summary of the Invention

[0004] This disclosure is based, at least in part, on the development of topical formulations comprising plant extracts that exhibit good moisturizing properties, which at least partially contribute to the therapeutic efficacy claimed by the topical formulations (e.g., promoting wound healing). In some examples, the topical formulations provided herein may comprise plant extracts (e.g., *Hedyotis diffusa* (PA) extract, and / or *Centella asiatica* (CA) extract) and the moisturizing polymeric biomaterials described herein.

[0005] Therefore, this article provides a topical formulation comprising: (i) a PA extract; (ii) a CA extract; (iii) a moisturizing polymeric biomaterial; and optionally (iv) a pharmaceutically effective excipient.

[0006] In some embodiments, the topical formulation may comprise (i) about 0.1 to 20% (w / w) of a PA extract; (ii) about 0.1 to 40% (w / w) of a CA extract; and / or (iii) about 0.1 to 90% (w / w) (e.g., about 0.1 to 70%) of a moisturizing polymeric biomaterial.

[0007] In some embodiments, the moisturizing polymeric biomaterial may comprise collagen, keratin, hyaluronic acid or its salts (e.g., sodium hyaluronate), or combinations thereof. In some specific examples, the moisturizing polymeric biomaterial is collagen derived from fish, pigs, or cattle.

[0008] In some embodiments, the topical preparation may be in the form of a cream, gel, ointment, or sheet dressing.

[0009] In one embodiment, the topical formulation is a cream formulation that may comprise pharmaceutically effective excipients, as well as PA extracts, CA extracts, and moisturizing polymeric biomaterials (e.g., collagen). The pharmaceutically effective excipients may comprise an oil base, an emulsifier, and water. In some examples, the oil base comprises fatty acid esters, aliphatic higher alcohols, paraffin oils, lanolin oils, silicone oils, medium-chain oils, and / or silicone polymers. As a non-limiting example, the oil base may comprise petrolatum and / or dimethicone. In some examples, the emulsifier comprises anionic surfactants, cationic surfactants, amphoteric surfactants, and / or nonionic surfactants. As a non-limiting example, the emulsifier may comprise polysorbate compounds, dehydrated sorbitol compounds, or combinations thereof.

[0010] In any cream formulation described herein, a pharmaceutically effective excipient may further comprise one or more of the following: (a) a skin conditioning agent; (b) a skin emollient; (c) a stiffening agent; (d) a moisturizing agent; and (e) a preservative.

[0011] In a specific example, the topical formulation provided herein is in the form of a cream, which may contain about 0.1 to 10% by weight of PA extract, about 0.1 to 24% by weight of CA extract, and / or about 0.1 to 20% by weight of collagen. This cream formulation may further contain white petrolatum and water.

[0012] In another embodiment, the topical formulation is a gel formulation, wherein the pharmaceutically effective excipient comprises a gelling agent and water. In some examples, the gelling agent comprises a cellulose derivative, carbomer, or a combination thereof. As a non-limiting example, the gelling agent may be carboxymethyl cellulose. In any gel formulation described herein, the pharmaceutically effective excipient may further comprise an emollient and / or a preservative.

[0013] In another embodiment, the topical formulation is an ointment formulation in which a pharmaceutically effective excipient comprises an ointment base. In some examples, the ointment base comprises polyethylene glycol, an oil base, or a combination thereof. As a non-limiting example, the ointment base may comprise petrolatum and / or dimethicone. In any ointment formulation described herein, the pharmaceutically effective excipient may further comprise a preservative. In some embodiments (e.g., for multiple uses after opening), the topical formulation may contain one or more antimicrobial preservatives to prevent any microbial growth. Optionally, the topical formulation (e.g., for single-use packaging) may be preservative-free.

[0014] In a specific example, the ointment formulation provided herein may contain about 0.1 to 20% by weight of PA extract; about 0.1 to 40% by weight of CA extract; and / or about 0.1 to 70% by weight of collagen. This ointment formulation may further contain white petrolatum.

[0015] In another embodiment, the topical formulation is a sheet dressing, wherein a pharmaceutically effective excipient comprises the dressing. In some examples, the dressing may be a bandage, membrane, synthetic or bio-hydrogel, hydrocolloid, film, foam, gauze, dermal patch, tape, skin substitute, paste, powder, or fiber. In any sheet dressing described herein, the pharmaceutically effective excipient may further comprise antioxidants, growth factors, and / or extracellular matrix.

[0016] In a specific example, the sheet dressing provided herein may contain approximately 2 to 4% PA extract, approximately 8 to 15% CA extract, and / or approximately 80 to 90% collagen by weight.

[0017] In another aspect, this disclosure provides a method for wound healing, comprising applying a topical preparation disclosed herein to a wound site of a subject in need. In one embodiment, the topical preparation may be applied at least once daily, for example, twice daily.

[0018] In one example, the subject is a human patient with an acute or open wound (e.g., abrasion, incision, laceration, puncture, or avulsion). In another example, the subject is a human patient with a chronic wound, which may be a surgical wound, traumatic wound, pressure ulcer, venous ulcer, diabetic ulcer, or a wound caused by cancer, burns, atopic dermatitis, or bedsores.

[0019] The following also fall within the scope of this disclosure: (i) the use of the topical formulations described herein for promoting wound healing, and (ii) the use of the topical formulations provided herein in the preparation of medicaments for promoting wound healing.

[0020] Details of one or more embodiments of the present invention are set forth in the following description. Other features or advantages of the invention will become apparent from the following drawings and detailed descriptions of various embodiments, as well as from the appended claims. Detailed Implementation

[0021] This disclosure is based, at least in part, on the development of a topical formulation comprising a senna (PA) extract, a centella asiatica (CA) extract, a moisturizing polymeric biomaterial, and a pharmaceutically effective excipient. Performance testing has shown that the topical formulation provided herein has good moisturizing properties (e.g., 97.1% to 100.0% in cream or ointment form), which is superior to commercially available topical formulations for treating skin conditions (which do not contain moisturizing polymeric biomaterials, such as collagen), such as ALHYDRAN. ® (94.5%) and BIAFINE ® (93.8%). This excellent moisturizing ability of the topical formulations provided in this article suggests that they can be used to alleviate skin damage (e.g., promote wound healing) by, for example, effectively retaining moisture and / or inhibiting inflammation.

[0022] Therefore, this article provides a topical formulation comprising PA extract, CA extract, moisturizing polymeric biomaterial and pharmaceutically effective excipient, and a method of using said topical formulation to promote wound healing in subjects requiring treatment.

[0023] I. Topical preparations This disclosure provides a topical formulation for alleviating skin damage (e.g., promoting wound healing), said topical formulation may comprise a PA extract, a CA extract, a moisturizing polymeric biomaterial, and optionally a pharmaceutically effective excipient.

[0024] A. Plant extracts Any topical formulation may contain plant extracts, such as PA and / or CA extracts. Topical formulations may contain about 0.1-5%, 0.5-3%, 1-2%, 1-3%, 2-10%, 5-10%, 5-15%, 10-15%, 15-20%, 10-20%, 20-25%, 15-30%, 20-30%, 10-30%, or 25-30% (w / w) of plant extracts. The concentration of plant extracts (or other components disclosed herein) in the topical formulations described herein refers to the percentage of the total weight of the plant extracts in dry form to the total weight of the topical formulation as a whole.

[0025] In some examples, the topical formulations described herein may contain about 0.1% to about 20% (w / w) of a PA extract, for example, about 0.1% to about 15%, about 0.1% to about 10%, about 0.1% to about 5%, or about 0.1% to about 2% by weight of a PA extract. In some examples, the amount of PA extract may be about 0.1% to 1% (e.g., about 0.1% to 0.5%, such as about 0.25% w / w).

[0026] Optionally or additionally, the topical formulations described herein may comprise about 0.1% to about 40% (w / w) of CA extract, for example, about 0.1% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 15%, about 0.1% to about 10%, or about 0.1% to about 5% by weight. In some examples, the amount of CA extract may be about 0.1% to 3% (e.g., about 0.1% to 2% or about 0.1% to 1.5%, such as about 1% w / w).

[0027] As used herein, the term “approximately” refers to a strict numerical boundary (including upper and lower limits) of a specified parameter. Those skilled in the art will understand the meaning of “approximately” in the context of a particular parameter. In some examples, the term “approximately” refers to a specific value + / - 5% (e.g., + / - 3% or + / - 2%).

[0028] In some examples, the ratio of *Hedyotis diffusa* extract to *Centella asiatica* extract can be approximately 1:10 to 10:1. For example, the ratio of *Hedyotis diffusa* extract to *Centella asiatica* extract in topical formulations can be approximately 1:10 to 1:1, approximately 1:1 to 10:1, approximately 1:10 to 1:5, approximately 1:5 to 1:1, approximately 10:1 to 5:1, approximately 5:1 to 1:1, approximately 1:10 to 1:4, approximately 1:4 to 1:1, approximately 10:1 to 4:1, or approximately 4:1 to 1:1.

[0029] (a) Aconitum carmichaelii (PA) extract Acanthus chinensis (PA) extract refers to an extract obtained from the Acanthus chinensis plant using one or more suitable solvents. In some examples, at least one of the solvents used to prepare the extract has a polarity index of less than 7 (e.g., less than 5). See, for example, US20180015133, the relevant disclosure of which is incorporated herein by reference for the subject matter and purposes described herein. As used herein, a solvent means a substance or mixture of substances that dissolves another substance to form a solution. The PA extract described herein can be prepared using a single solvent. The solvent used in each extraction step of preparing the extracts described herein (including PA and CA extracts) can be a single solvent. Alternatively, it can be a mixture of two or more solvents.

[0030] The PA extract described herein may comprise terpenoids (e.g., monoterpenes, diterpenes, triterpenes, and / or sesquiterpenes), flavonoids, phenolic compounds, essential oils, or combinations thereof. The PA extract may be present in the topical formulation at a concentration of about 0.1-5% (w / w). For example, the topical formulation may comprise about 0.1-0.5%, 0.5-1%, 1-1.5%, 1.5-2%, 2-2.5%, 2.5-3%, 3-3.5%, 3.5-4%, 4-4.5%, or 4.5-5% (w / w) of the PA extract. Optionally, the topical formulation may comprise about 0.1-1%, 0.1-2%, 0.1-3%, 0.1-4%, or 0.1-5% (w / w) of the PA extract. In one specific embodiment, the topical formulation comprises about 0.1-1% or 0.1-0.5% of the PA extract.

[0031] The PA extract described herein can be prepared by extracting the whole PA plant or a portion thereof (e.g., aerial parts) with one or more suitable solvents to produce a solution, followed by drying the solution to obtain the PA extract. Since PA extracts contain flavonoids, terpenoids (e.g., monoterpenes, diterpenes, triterpenes, and / or sesquiterpenes), phenolic compounds, or essential oils, which are nonpolar molecules, at least one of the extraction solvents can have relatively low polarity (e.g., a polarity index below 7) to facilitate the dissolution of nonpolar molecules. “Extraction” can be performed by directly contacting the PA material with a suitable solvent or by eluting the active components of PA from a resin to which the PA active components are attached.

[0032] In some examples, solvents with a polarity index below 7 can be used to extract the active components from *Hymenochloa crus-galli* to produce a *Hymenochloa crus-galli* extract. Such solvents can be ethyl acetate, methyl acetate, propanol, butanol, or chloroform. Alternatively, the solvent can be a mixture of one or more solvents with different polarity indices. Examples include, but are not limited to, mixtures of ethanol and ethyl acetate, ethyl acetate and butanol, ethanol and propanol, and methyl acetate and butanol.

[0033] In some embodiments, PA extracts can be prepared by a process involving the use of a solvent, such as a solvent with a polarity index less than 7 (e.g., <6.5, <6.0, <5.5, <about 5.0, <4.9, <4.8, <4.7, <4.6, or <4.5). Examples include, but are not limited to, methanol, ethanol, acetone, ethyl acetate, butanol, dichloromethane, or combinations thereof.

[0034] PA materials can be prepared using conventional methods, and can be the whole PA plant or a portion thereof (e.g., aerial parts, such as leaves). PA materials can be fresh plants or parts thereof. Optionally, PA materials can be in dried form. PA can optionally be dried to form a powder, which can be used as a PA material for preparing PA extracts.

[0035] Any PA material described herein can be extracted once or multiple times with a suitable solvent to produce a crude extract. The solvent used to prepare the crude extract can be a highly polar solvent, for example, with a polarity index greater than 5 and preferably less than 7 (e.g., >5.2, >5.5, >5.8, >6 or higher and preferably less than 7). Examples include, but are not limited to, ethanol, acetone, methanol, water, or combinations thereof. If necessary, the crude extract can be concentrated using conventional methods to produce a concentrated crude extract.

[0036] The crude extract can then be contacted with a suitable resin (e.g., a nonionic adsorption resin) under appropriate conditions that allow the active ingredients in the crude extract to bind to the resin. Exemplary resins for preparing the hand fragrance extract include, but are not limited to, DIAION. ®HP20, DIAION ® HP20SS, Sepabeds ® SP207, Amberlite TM XAD-2 or Amberlite TM XAD-4.

[0037] The resin can then be washed once or multiple times and eluted with a suitable solvent (e.g., a solvent with a polarity index of less than 7) to produce a PA extract, which can then be dried by conventional methods (e.g., freeze-drying, spray-drying, or concentration-drying) to produce a dried PA extract, which can be in semi-solid or paste form.

[0038] In some embodiments, the resin adsorption step can be performed by mixing the crude extract with resin in a container. In other embodiments, the resin separation step can be performed using a chromatographic column setup.

[0039] Any method disclosed in US20230000941 (which is incorporated herein by reference for the subject matter and purposes cited herein) may also be used to prepare the PA extracts disclosed herein.

[0040] (b) Centella Asiatica (CA) extract The Centella asiatica (CA) extracts described herein refer to extracts obtained from the whole Centella asiatica plant or a portion thereof. CA extracts may contain asiaticoside.

[0041] CA extract can be present in topical formulations at concentrations of about 0.1-20% (w / w). For example, topical formulations may contain about 0.1-0.5%, 0.5-1%, 1-1.5%, 1.5-2%, 2-2.5%, 2.5-3%, 3-3.5%, 3.5-4%, 4-4.5%, 4.5-5%, 5-5.5%, 5.5-6%, 6-6.5%, 6.5-7%, 7-7.5%, 7.5-8%, 8-8.5%, 8.5-9%, 9-9.5%, 9.5-10%, 10-10.5%, 10. 5-11%, 11-11.5%, 11.5-12%, 12-12.5%, 12.5-13%, 13-13.5%, 13.5-14%, 14-14.5%, 14.5-15%, 15-15.5%, 15.5-16%, 16-16.5%, 16.5-17%, 17-17.5%, 17.5-18%, 18-18.5%, 18.5-19%, 19-19.5%, or 19.5-20% (w / w) of CA extract. Optionally, the topical formulation may contain about 0.1-5%, 0.1-10%, 0.1-15%, 0.1-20%, 0.5-5%, 0.5-10%, 0.5-15%, or 0.5-20% (w / w) of CA extract. In specific examples, the topical formulation may contain approximately 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% (w / w) of CA extract.

[0042] CA extracts can be prepared according to conventional methods, such as those described in U.S. Patent Nos. 5,834,437, 6,417,349, 6,475,536 and 6,267,996, CN 1313124, CN 1089497 and CN 1194154. An example is given below.

[0043] CA materials can be prepared through conventional practices. Such materials can be fresh CA plants or parts thereof, or dried CA. CA materials can be extracted with a suitable solvent (e.g., water, ethanol, or mixtures thereof) to produce a crude extract. The crude extract, which can optionally be concentrated, can be mixed with a suitable resin or loaded onto a resin-filled column. After one or more washes, the resin can be eluted with a suitable solvent. The resulting eluent can be concentrated to form a paste, which can be dried by conventional methods (e.g., vacuum drying) to produce a powder of the CA extract. If necessary, the CA powder can be ground through a sieve (e.g., a 100-mesh sieve).

[0044] B. Moisturizing polymeric biomaterials Any topical formulation disclosed herein may contain a moisturizing polymeric biomaterial (e.g., collagen disclosed herein) in an amount of about 0.1% to about 99% (w / w), for example, about 0.1% to about 20%, about 10% to about 50%, about 20% to about 50%, about 30% to about 50%, about 50% to about 70%, or about 70% to about 90%. In some examples, the amount of moisturizing polymeric biomaterial (e.g., collagen) in the formulation will depend on the form of the formulation. See examples provided elsewhere herein.

[0045] In some embodiments, the moisturizing polymeric biomaterial may comprise collagen, keratin, hyaluronic acid or its salts (e.g., sodium hyaluronate), or combinations thereof.

[0046] Collagen is a major structural protein in the extracellular matrix of various connective tissues in the human body. Collagen has a triple-helix structure formed by elongated fibrils. Various forms of collagen exist that can be used in the topical formulations provided herein, including type I, type II, type III, type IV, type V, or combinations thereof. In some embodiments, the collagen used in the topical formulations provided herein may be derived from humans. Optionally, the collagen used in the topical formulations may be derived from suitable non-human mammals, such as pigs or cattle. In other examples, the collagen may be derived from fish. For example, collagen hydrolysates from fish (e.g., having a molecular weight of about 600–1200 Da) may be used. In other examples, the collagen may be derived from cattle or pigs.

[0047] Keratin is a type of structural fibrous protein, also known as scleroprotein. α-keratin is a type of keratin found in vertebrates. It is a key structural material that makes up the scales, hair, nails, feathers, horns, claws, hooves, and outer layer of skin in vertebrates. Keratin also protects epithelial cells from damage or stress.

[0048] Hyaluronic acid is an anionic, non-sulfated glycosaminoglycan widely distributed in connective tissue, epithelial tissue, and nerve tissue. It is known for its ability to retain 1000 times its weight in water, helping to give skin volume and plumpness. Sodium hyaluronate is the sodium salt form of hyaluronic acid. It penetrates deeper into the skin more easily, making it an excellent alternative to traditional high-molecular-weight hyaluronic acid.

[0049] C. Example forms of topical formulations The topical formulations disclosed herein may be in suitable forms, such as creams, gels, ointments, or sheet dressings.

[0050] (a) Cream formulation In some embodiments, the topical formulations described herein may be in the form of a cream. In some examples, a moisturizing biomaterial (e.g., collagen disclosed herein) may constitute from about 0.1% to about 20% (w / w) of the cream formulation disclosed herein. In some examples, the weight percentage of the moisturizing biomaterial in the cream formulation may be from about 0.5% to about 15%, for example, from about 1% to about 10%. In other examples, the moisturizing biomaterial (e.g., collagen disclosed herein) may constitute from about 0.1% to about 5% by weight in the cream formulation (e.g., from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, or from about 0.1% to about 0.5%).

[0051] In cream formulations, pharmaceutically effective excipients may comprise an oil base, an emulsifier, and an aqueous matrix (e.g., water). Optionally, the cream formulations described herein may further comprise one or more of the following components: skin conditioning agents, emollients, firming agents, moisturizers, and preservatives.

[0052] The cream formulation disclosed in this article has excellent moisturizing ability, with a moisture loss rate of less than 5%.

[0053] (i) Oil-based "Oil-based" or "oil-type ointment" can be any semi-solid formulation or carrier incorporating active agents. The oil base may be pharmacologically inert but may trap water or moisture to provide a moisturizing protective film. In a specific example, the oil base may contain any petrolatum compound (e.g., petrolatum, white petrolatum, white nephrite, liquid petrolatum, liquid paraffin) or any dimethicone compound.

[0054] In some implementations, the oil base may comprise fatty acid esters, aliphatic higher alcohols, paraffin oils, lanolin oils, silicone oils, medium-chain oils, and / or silicone polymers.

[0055] In some examples, fatty acid esters can be synthetic or naturally occurring esters of aliphatic carboxylic acids and aliphatic alcohols. Aliphatic carboxylic acids can include saturated or unsaturated aliphatic monocarboxylic acids or dicarboxylic acids, which are typically lower or higher fatty acids having 2 to 24 carbon atoms. In particular, intermediate or higher fatty acids having 6 to 20 carbon atoms are preferred. As non-limiting examples, acetic acid, propionic acid, hexanoic acid, caprylic acid, octanoic acid, dioctanoic acid, adipic acid, sebacic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and / or myristic acid can be used in cream formulations.

[0056] In some examples, aliphatic higher alcohols can be saturated and unsaturated aliphatic alcohols having 14 to 20 carbon atoms. As a non-limiting example, cetyl alcohol or palmitol, stearyl alcohol, oleyl alcohol and / or cetyl alcohol can be used in cream formulations.

[0057] In some examples, paraffin oils may include those consisting primarily of mixtures of paraffins having 15 or more carbon atoms. As a non-limiting example, fluid paraffins and / or petrolatum (e.g., white petrolatum, squalane, and squalene) may be used in cream formulations.

[0058] In some examples, lanolin oil may include lanolin, lanolin wax, hydrogenated or reduced lanolin, and polymers thereof with ethylene oxide.

[0059] In some examples, silicone oil may comprise a mixture of polymers of dimethylsiloxane. As a non-limiting example, dimethylpolysiloxane and its alkyl esters, methylphenylpolysiloxane and / or ethylene glycol methylsiloxane may be used in cream formulations.

[0060] In some examples, medium-chain oils may have one or more monoglycerides, diglycerides, or triglycerides, or combinations thereof. Exemplary glycerides include, but are not limited to, MIGLYOLs. ® It is caprylic / capric triglyceride (SASOL Germany GMBH, Hamburg). In some specific examples, MIGLYOLs ® Including MIGLYOL ® 810 (Caprylic / Capric Triglycerides), MIGLYOL ® 812 (Caprylic / Capric Triglyceride), MIGLYOL ® 816 (caprylic / capric triglyceride) and MIGLYOL ® 829 (Caprylic / Capric / Succinic Triglycerides). In other examples, the medium-chain oil may contain other caprylic / capric triglycerides, including but not limited to caproic / capric / capric / lauric triglycerides, caprylic / capric / linoleic triglycerides, and caprylic / capric / succinic triglycerides. Exemplary caprylic / capric monoglycerides, diglycerides, or triglycerides include, but are not limited to, CAPMUL. ® MCM, CAPMUL ® MCM C10, CAPMUL ® MCM C8, CAPMUL ® MCM C8 EP and CAPMUL ®708 G (CAPMUL® brand owned by ABITEC, Columbus, Ohio). In other examples, other monoglycerides, diglycerides, and triglycerides of fractionated vegetable fatty acids, and combinations or derivatives thereof, may be used in the cream formulations disclosed herein. For example, the oil phase may be 1,2,3-propanetriol (e.g., glycerol, glycerin, or glycerine) esters of saturated coconut oil and palm kernel oil, and their derivatives.

[0061] In some examples, the silicone-based polymer may include dimethicone, cyclodimethylsiloxane, behenyldimethylsiloxane, dioctanoic acid / didecanoic acid dimethylsiloxane copolyol and / or cetyldimethylsiloxane.

[0062] (ii) Emulsifiers An emulsifier is a compound or substance that acts as a stabilizer in a mixture of two or more liquids that are normally immiscible (cannot be mixed or blended).

[0063] In some embodiments, the emulsifier may include anionic surfactants, cationic surfactants, amphoteric surfactants, and / or nonionic surfactants.

[0064] In some examples, anionic surfactants may be based on permanent anions (e.g., sulfates, sulfonates, and phosphates) or pH-dependent anions (e.g., carboxylates). Exemplary sulfates include, but are not limited to, alkyl sulfates and alkyl ether sulfates. In some specific examples, the alkyl sulfate may be ammonium lauryl sulfate or sodium lauryl sulfate (also known as sodium dodecyl sulfate (SDS)). Optionally or additionally, the alkyl ether sulfate may be sodium lauryl ether sulfate (also known as sodium dodecyl ether sulfate (SLES)) or sodium myristyl ether sulfate.

[0065] Exemplary sulfonates include, but are not limited to, docusate salts, sulfonate fluorosurfactants, and alkylbenzene sulfonates. In some specific examples, the docusate salt may be sodium dioctyl sulfosuccinate. Optionally or additionally, the sulfonate fluorosurfactant may be perfluorooctane sulfonate (PFOS) or perfluorobutane sulfonate.

[0066] Exemplary phosphates include, but are not limited to, alkyl aryl ether phosphates and alkyl ether phosphates.

[0067] In some examples, the cationic surfactant can be based on pH-dependent primary, secondary, or tertiary amines. Primary amines are positively charged at pH < 10, secondary amines at pH < 4, and tertiary amines at pH < 9. In one specific example, the cationic surfactant is oteninidine dihydrochloride having a gemini surfactant structure derived from pyridine. Ooteninidine dihydrochloride is active against both Gram-positive and Gram-negative bacteria.

[0068] Alternatively, the cationic surfactant can be a permanently charged quaternary ammonium cation, such as an alkyltrimethylammonium salt. Exemplary alkyltrimethylammonium salts include, but are not limited to, hexadecyltrimethylammonium bromide (CTAB, also known as hexadecyl trimethyl ammonium bromide), hexadecyltrimethylammonium chloride (CTAC), hexadecylpyridine chloride (CPC), polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC), benzyl chloride (BZT), 5-bromo-5-nitro-1,3-dioxane, dimethyl dioctadecyl ammonium chloride, and dioctadecyl dimethyl ammonium bromide (DODAB).

[0069] In some examples, zwitterionic (amphoteric) surfactants may be based on primary, secondary, or tertiary amines or quaternary ammonium cations. Exemplary zwitterionic surfactants include, but are not limited to, sulfonates, sulfobetaines, carboxylates, and phosphates. In one specific example, the sulfonate is CHAPS (3-[(3-cholamidopropyl)dimethylamino]-1-propanesulfonic acid inner salt). Optionally or additionally, a specific example of sulfobetaine is cocamidopropyl hydroxysulfobetaine. Optionally or additionally, specific examples of carboxylates are amino acids and imino acids. Optionally or additionally, a specific example of phosphate is lecithin.

[0070] Nonionic surfactants function by attracting both water and oil simultaneously and are frequently used as emulsifiers in soaps and cosmetics. In some examples, nonionic surfactants include, but are not limited to, alkylamine oxides, monoalkyl and dialkyl alkanolamides, polyethylene glycol fatty acid esters, ethoxylated fatty acid amides, saturated fatty acid alcohols reacted with ethylene oxide, alkyl polyglycosides, and sorbitol ether esters. In some specific examples, the nonionic surfactant may be cetearyl alcohol polyether-2, cetearyl alcohol polyether-3, cetearyl alcohol polyether-4, cetearyl alcohol polyether-5, cetearyl alcohol polyether-6, cetearyl alcohol polyether-7, cetearyl alcohol polyether-8, cetearyl alcohol polyether-9, cetearyl alcohol polyether-10, cetearyl alcohol polyether-11, cetearyl alcohol polyether-12, cetearyl alcohol polyether-13, cetearyl alcohol polyether-14, cetearyl alcohol polyether-15, cetearyl alcohol polyether-16, cetearyl alcohol polyether-17, cetearyl alcohol. Cetearyl alcohol polyether-18, cetearyl alcohol polyether-20, cetearyl alcohol polyether-22, cetearyl alcohol polyether-23, cetearyl alcohol polyether-24, cetearyl alcohol polyether-25, cetearyl alcohol polyether-27, cetearyl alcohol polyether-28, cetearyl alcohol polyether-29, cetearyl alcohol polyether-30, cetearyl alcohol polyether-33, cetearyl alcohol polyether-34, cetearyl alcohol polyether-40, cetearyl alcohol polyether-50, cetearyl alcohol polyether-55, cetearyl alcohol polyether-60, cetearyl alcohol polyether-80, cetearyl alcohol polyether-100. Cetearyl alcohol polyether-n (of which n (The number) refers to a mixture of high molecular weight saturated fatty alcohols (mainly cetyl alcohol). m = 15) and stearyl alcohol ( m = 17)) of polyoxyethylene ether. (Number) n This represents the average number of ethylene oxide residues in the polyoxyethylene chain.

[0071] Emulsifiers suitable for use in the cream formulations described herein may include, but are not limited to, natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth gum, carrageenan, cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, propylene glycol monostearate, and polyvinyl alcohol), carbomers (e.g., carboxylated polymethylene, polyacrylic acid, acrylic polymers, and carboxylated vinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and methyl cellulose), and sorbitol fatty acid esters (e.g., polyoxyethylene sorbitol monolaurate [Tween ® 20], Polyoxyethylene dehydrated sorbitan monostearate [Tween ® 60], polyoxyethylene sorbitan monooleate [Tween® 80], sorbitan monopalmitate [Span ® 40], Sorbitol monostearate [Span ® 60], Sorbitol Tristearate [Span ® 65], glyceryl monooleate and sorbitan monooleate [Span ® 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj]), and polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj]). ® 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), ® ), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [Brij]) ® 30] and poly(vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, hexadecyltrimethylammonium bromide, hexadecylpyridine chloride, benzalkonium chloride and sodium docusate, and / or combinations thereof. In some specific examples, the emulsifier may contain polysorbate compounds (e.g., Tween). ® ) products), dehydrated sorbitol compounds (e.g., Span (Span ® (products) or combinations thereof.

[0072] (iii) Other components of the cream formulation Optionally, the cream formulations described herein may further comprise one or more skin conditioning agents, one or more emollients, one or more firming agents, one or more moisturizing agents, one or more preservatives, or combinations thereof.

[0073] "Skin conditioning agents" refer to a variety of substances that help make skin look and feel smoother, both now and over time. Exemplary skin conditioning agents include, but are not limited to, olive oil, macadamia nut oil, sweet almond oil, grapeseed oil, avocado oil, corn oil, sesame oil, soybean oil, peanut oil, meadowfoam seed oil, safflower seed oil, rosehip (Rosa canis) fruit oil, and argana spinosa kernel oil. Oils, including jojoba (Simundae) seed oil, sunflower seed oil, palmetto fruit oil, squalane, ethylhexyl palmitate, isopropyl myristate, hydrogenated polyisobutylene, isohexadecane, isodecane, diethylhexyl carbonate, dioctyl carbonate, lauroyl sarcosinate isopropyl ester, isononyl isononanoate, hydrogenated polydecene, triisooctyl glycerol, cetyl hexanoate, bis-ethoxydiethylene cyclohexane 1,4-dicarboxylic acid ester, caprylic / capric triglyceride, erucic acid oleyl alcohol ester, octyl dodecyl myristate ester, octyl dodecyl alcohol, dimethicone, octyl polymethylsiloxane, cetyl polydimethylsiloxane (cetyl polydimethylsiloxane), cyclopentamethoxydimethylsiloxane, kojic acid, ascorbic acid, ascorbate glucoside, arbutin, and tranexamic acid. Niacinamide, phytosterols, phytosterol / behenol / octyldodecyl lauroyl glutamate, phenylethyl resorcinol, turmeric extract, birch bark extract, ceramide 2, ceramide 3, acetyl phytosphingosine, resveratrol, Indian rosewood bark extract, coleopterus xanthipes root extract, pepper seed extract, ubiquinone, cholesterol, cholesterol stearate, dipalmitoyl ascorbate, tocopherol (vitamin E), tocopheryl acetate, α-bisabolol, dipalmitoyl ascorbate, tetraisopalmitoyl ascorbate, pyridoxine dioctanoate, pyridoxine dipalmitate, retinyl palmitate, phytosterol / octyldodecyl lauroyl glutamate (phytosteryl / octyldodecyl) Lauroylglutamate, bis-behenyl / isostearyl / phytosteryl dimer dilinoleyl dilinoleate, phytosteryl macadamiate, peptides and plant extracts.

[0074] Emollients are moisturizers with skin-softening or soothing properties. They are applied directly to the skin to soothe and moisturize it. They create a protective film to lock in moisture. Emollients are commonly used to help manage dry, itchy, or scaly skin conditions such as eczema, psoriasis, and ichthyosis.

[0075] In some examples, suitable emollients include, but are not limited to, PEG 20 almond glyceride, Probutyl DB-10, and Glucam. TM P-20, Glucam TM E-10, Glucam TM P-10, Glucam TM E-20, Glucam TM P-20 distearate, glycerin, propylene glycol, octyl glycerin, cetyl acetate, acetylated lanolin alcohol (e.g., Acetulan) TM Cetyl ethers (e.g., PPG-10), myristyl ethers (e.g., PPG-3), hydroxylated lactic glycerides (e.g., Cremeral HMG), polyquaternium compounds (e.g., U-care compounds), copolymers of dimethyl diallyl ammonium chloride and acrylic acid (e.g., Merquat) TM ), dipropylene glycol methyl ether (e.g., Dowanol) TM DPM, Dow Coming), polypropylene glycol ether (e.g., Ucon) TM 50-HB-600 (Union Carbide) and silicone polymers.

[0076] In some examples, suitable emollients may include, but are not limited to, hydrocarbon-based emollients (e.g., fatty esters, fatty alcohols, or combinations thereof), including but not limited to diisopropyl adipate, oleyl alcohol, lanolin, isopropyl myristate, isopropyl palmitate, caprylic / capric triglyceride, cetyl lactate, cetyl palmitate, hydrogenated castor oil, glycerides, hydroxycetyl isostearate, hydroxycetyl phosphate, isopropyl isostearate, isostearyl isostearate, diisopropyl sebacate, polyoxypropylene polyoxyethylene cetyl ether (PPG-5-Ceteth-20), 2-ethylhexyl isononanoate, 2-ethylhexyl stearate, C12 to C16 fatty alcohols, C12 to C16 fatty alcohol lactates, isopropyl lanolinate, 2-ethylhexyl salicylate, and mixtures thereof.

[0077] In some examples, one or more emollients may be 1-hexadecyl alcohol, acetylated lanolin, behenyl polydimethylsiloxane, C12-15 alkyl benzoate, cetearyl caprylate, glyceryl cocoate, dicaprylic / didecanoic acid polydimethylsiloxane copolyol, dimethicone alcohol, dioctyl adipate, glyceryl stearate, isocetyl alcohol, isohexadecane, isopentylcyclohexanone, isopropyl palmitate, lauryl lactate, mineral oil, methoxy PEG-22 / dodecyl glycol copolymer, myristyl lactate, octyl dodecyl neopentanoate, octyl cocoate, octyl palmitate, octyl stearate, octyl dodecyl neopentanoate, polyglycerol-4 isostearate, polyoxyethylene 40 stearate, polyoxymethylene urea, potassium sorbate, propylene glycol, propylene glycol isocetyl alcohol polyether-3 acetate, and / or propylene glycol myristyl ether acetate.

[0078] "Stiffening agents" are substances that increase the viscosity or hardness of a formulation. Stiffening agents are primarily used in topical products.

[0079] The stiffening agents applicable to the cream formulations described herein include, but are not limited to, cetyl alcohol, stearyl alcohol, cetearyl alcohol, behenyl alcohol, squalane alcohol, lauric acid, myristic acid, palmitic acid, stearic acid, beeswax, candelilla wax, carnauba wax, lanolin, ceresin, jojoba seed wax, paraffin wax, microcrystalline wax, hydrogenated rice bran wax, hydrogenated coconut oil glycerides, eicosapentaenoic acid (glyceryl behenate / eicosapentaenoic acid ester), myristyl myristate, bis-diglyceride polyacryladiate-2, shea butter, and astragalus murumuru seed butter.

[0080] "Moisturizers" are hygroscopic substances used to keep objects moist. In pharmaceuticals and cosmetics, moisturizers can be applied topically to increase the solubility of active ingredients, thereby enhancing their ability to penetrate the skin.

[0081] In some examples, exemplary moisturizers suitable for the cream formulations described herein include, but are not limited to, fructose, glucose, glycerin, propylene glycol, glyceryl polyether-26, mannitol and urea, pyrrolidone carboxylic acid, hydrolyzed lecithin, cocobetaine, cysteine ​​hydrochloride, glutamine, polyoxypropylene, polyoxyethylene (PPG-15), sodium gluconate, potassium aspartate, oil-based betaine, thiamine hydrochloride, sodium lauryl ether sulfate, sodium hyaluronate, hydrolyzed protein, hydrolyzed keratin, amino acids, amine oxides, water-soluble derivatives of vitamins A, E and D, amino-functionalized silicones, ethoxylated glycerin, α-hydroxy acids and their salts, and water-soluble fatty oil derivatives (e.g., PEG-24 hydrogenated lanolin, almond oil, grapeseed oil and castor oil).

[0082] Preservatives may be used in cream formulations (or other topical formulations disclosed herein) to prevent the growth of any microorganisms. An "antimicrobial preservative" is a compound capable of destroying microorganisms, preventing their proliferation or growth, or preventing their pathogenicity. For multiple uses after opening, topical formulations may contain one or more antimicrobial preservatives to prevent the growth of any microorganisms. For single-use packaging, preservatives are optional.

[0083] In some examples, exemplary antimicrobial preservatives suitable for the cream formulations described herein include, but are not limited to, silver salts, povidone-iodine, iodine, benzoic acid, dihydroacetic acid, propionic acid, sorbic acid, methylparaben, ethylparaben, butylparaben, cetrimonium bromide, benzalkonium chloride, desquinium chloride, chlorhexidine, chlorocresol, chloroxylenol, benzyl alcohol, bromide, tert-butanol, phenoxyethanol, phenethyl alcohol, and 2,4-dichlorobenzene. Methanol, thimerosal, clindamycin, erythromycin, benzoyl peroxide, mupirocin, bacitracin, polymyxin B, neomycin, triclosan, chlorometaxylenol, phosphonic acid, miconazole, fluconazole, itraconazole, ketoconazole, silver sulfadiazine, octoxyglycerol, biguanides such as, but not limited to, chlorhexidine free base, chlorhexidine palmitate, chlorhexidine diphosphate, chlorhexidine digluconate, chlorhexidine diacetate, chlorhexidine dihydrochloride, chlorhexidine diphosphate, etc. Chlorhexidine dichloride, chlorhexidine dihydroiodide, chlorhexidine diperchlorate, chlorhexidine dinitrate, chlorhexidine sulfate, chlorhexidine sulfite, chlorhexidine thiosulfate, chlorhexidine diphosphate, chlorhexidine difluorophosphate, chlorhexidine dicarboxylate, chlorhexidine dipropionate, chlorhexidine diiodobutyrate, chlorhexidine dipentanoate, chlorhexidine dihexate, chlorhexidine malonate, chlorhexidine succinate, chlorhexidine ethanol Chloride, chlorhexidine dimonoglycolate, chlorhexidine monodiglycolate, chlorhexidine dilactate, chlorhexidine di-α-hydroxyisobutyrate, chlorhexidine diglucoheponic acid salt, chlorhexidine dihydroxyethyl sulfonate, chlorhexidine dibenzoate, chlorhexidine dicinnamate, chlorhexidine dimandelate, chlorhexidine diisophthalate, chlorhexidine di-2-hydroxynaphthyl carboxylate, chlorhexidine dihydroxynaphthyl carboxylate, and polyhexamethylene biguanide ("PHMB").

[0084] (iv) Exemplary cream formulation In some specific examples, this disclosure provides cream formulations comprising the PA and CA extracts disclosed herein, collagen as a moisturizing polymeric material, and pharmaceutically acceptable excipients comprising (e.g., composed of) white petrolatum and water. In some examples, the weight ratio of the PA extract to the CA extract in the cream formulation is from 10:1 to 1:250 (e.g., 10:1, 1:1, or 1:240). Optionally or additionally, the concentration of the PA extract in the cream formulation may be from 0.1% to 10% by weight (e.g., 0.1% to 5%, 0.1% to 2%, 0.1% to 1%, 1% to 5%, or 5% to 10%). The concentration of CA extract in cream formulations can be from 0.1% to 24% by weight (e.g., 0.1% to 20%, 0.1% to 15%, 0.1% to 10%, 0.1% to 5%, 0.1% to 1%, 1% to 5%, 5% to 10%, 10% to 15%, or 15% to 20%).

[0085] Optionally or additionally, the cream formulation contains 0.1% to 20% collagen by weight. In some examples, the amount of collagen may be 0.1% to 15%, 0.1% to 10%, 0.1% to 5%, or 0.1% to 1%. In other examples, the amount of collagen may be 1% to 5%, 5% to 10%, 10% to 15%, or 15% to 20%.

[0086] (b) Gel formulation The topical formulations described herein may be in gel form. In some examples, a moisturizing biomaterial (e.g., collagen disclosed herein) may constitute about 0.1% to about 70% (w / w) of the gel formulation. In some examples, the weight concentration of the moisturizing biomaterial in the gel formulation disclosed herein may be about 0.5% to about 70%, for example, about 1% to about 70%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, about 50% to about 70%, or about 60% to about 70%.

[0087] In gel formulations, pharmaceutically effective excipients comprise a gelling agent and an aqueous matrix (e.g., water). Optionally, the gel formulations described herein may further comprise one or more of the following components: emollients and preservatives. The gel formulations disclosed herein offer excellent stability and feel. Furthermore, the gel formulations can form a film on a wound, thereby protecting the wound from further damage.

[0088] (i) gelling agent A "gelling agent" is a gel-forming agent that, when dissolved in a liquid phase as a colloidal mixture, forms a weakly aggregated internal structure. In some embodiments, the gelling agent may comprise cellulose derivatives, carbomer, or combinations thereof.

[0089] In some examples, the gelling agent comprises a cellulose derivative. Exemplary cellulose derivatives include, but are not limited to, cellulose ethers (e.g., sodium carboxymethyl cellulose), polysaccharide gums (e.g., xanthan gum), and nonionic thickeners (e.g., hydroxyethyl cellulose, hydroxymethyl cellulose, and hydroxypropyl cellulose).

[0090] In some examples, the gelling agent contains carbomer, which is a crosslinked or uncrosslinked poly(acrylic) polymer or copolymer. Exemplary carbomers include, but are not limited to, CARBOPOL. ® Products (e.g., CARBOPOL) ® 934, CARBOPOL ® 940, CARBOPOL ® 941, CARBOPOL ® 980, CARBOPOL ® 981, CARBOPOL ® 1342 and CARBOPOL ® 1382).

[0091] In one specific example, the gelling agent contains carboxymethyl cellulose.

[0092] (ii) Other components of the gel formulation Optionally, the gel formulations described herein may further comprise one or more emollients, one or more preservatives, or a combination thereof.

[0093] Any emollient disclosed herein can be used to prepare gel formulations. In some examples, exemplary emollients suitable for the gel formulations described herein include, but are not limited to, glycerin, glyceryl oleate, caprylyl glycol, triglycerides (e.g., caprylic / capric triglyceride), silicone oils (e.g., cyclomethicone), ester oils (e.g., butyl myristate, isopropyl myristate, cetyl myristate, isopropyl palmitate, isopropyl stearate, octyl stearate, isocetyl stearate), organic fatty alcohols (e.g., oleyl alcohol, linolenic acid alcohol, linoleyl alcohol, isostearyl alcohol, octyl dodecyl alcohol), long-chain fatty acids, liquid water-soluble polyols, propylene glycol, sorbitol, polyethylene glycol, and ethoxylated methylglucose. Oxylated / propoxylated ethers (e.g., methyl glucose polyether-20) and ethoxylated / propoxylated ethers of lanolin alcohol (e.g., Solulan-75), coconut oil and tallow fatty acids, non-blocked liquid water-soluble polyols, essential amino acids, and sodium pyrrolidone carboxylate (or dl-pyrrolidone carboxylate), urea, L-proline, guanidine and pyrrolidone; hexadecyl esters, myristyl esters, isodecanyl esters or isopropyl esters of adipic acid, lactic acid, oleic acid, stearic acid, isostearic acid, myristic acid or linoleic acid and corresponding alcohol esters such as sodium isostearyl-2-lactic acid, sodium capryloyl lactylate, aloe vera gel and acetamide MEA.

[0094] Any preservatives suitable for topical formulations (e.g., those disclosed herein) may be used herein.

[0095] (c) Ointment preparations The topical formulations described herein may be in the form of an ointment. In some examples, a moisturizing biomaterial (e.g., collagen disclosed herein) may constitute from about 0.1% to about 70% (w / w) of the ointment formulation. In some embodiments, the weight percentage of the moisturizing biomaterial in the ointment formulation disclosed herein may be from about 1% to about 10%, from about 10% to about 20%, from about 20% to about 30%, from about 30% to about 40%, from about 40% to about 50%, from about 50% to about 60%, or from about 60% to about 70% by weight. In some examples, the weight percentage of the moisturizing biomaterial in the ointment formulation disclosed herein may be from about 0.5% to about 20%, from about 1% to about 15%, or from about 5% to about 10%.

[0096] In ointment formulations, pharmaceutically effective excipients comprise an ointment base. Optionally, the ointment formulations described herein may further comprise one or more preservatives. The ointment formulations disclosed herein offer excellent stability and moisturizing properties, with a moisture loss rate of less than 1%.

[0097] (i) Ointment base "Ointment base" can be any semi-solid formulation or carrier in which active agents can be incorporated. Exemplary ointment bases include, but are not limited to, oily ointment bases (e.g., white petrolatum or white ointment), absorbent ointment bases (e.g., hydrophilic petrolatum, anhydrous lanolin, Aquabase), etc. TM Aquaphor ® and Polysorb ® ), water / oil emulsion ointment bases (e.g., cold cream, lanolin-containing ointment, rose water ointment, hydrocream) TM Eucerin ® and Nivea ® Oil / water emulsion ointment bases (e.g., hydrophilic ointments, Dermabase) TM Velvachol ® and Unibase ® and water-soluble ointment bases (e.g., polyethylene glycol (PEG) ointments and Polybase). TMThe ointment base may be pharmacologically inert but may trap water to provide a moisturizing protective film. In one specific embodiment, the ointment base may be any petrolatum compound (e.g., petrolatum, white petrolatum, white nephrite, liquid petrolatum, liquid paraffin). In another specific embodiment, the ointment base is white petrolatum (CAS No. 8009-03-8).

[0098] There are two types of ointments that can be used in the ointment formulations described herein. In some embodiments, the ointment base may be a PEG-based ointment. Such ointment bases contain polyethylene glycol. Exemplary PEG-based ointments include, but are not limited to, PEG600, PEG400, PEG300, PEG100, PEG800, PEG1000, PEG3350, PEG3450, PEG4000, PEG-stearate, PEG40-stearate, PEG-laurate, lecithin, phosphatidylcholine, PEG-oleate, and PEG-glycerin.

[0099] Optionally or additionally, the ointment base may be an oil-based ointment. In some embodiments, the oil-based ointment may contain fatty acid esters, aliphatic higher alcohols, paraffin oil, lanolin oil, silicone oil, medium-chain oils, and / or silicone polymers.

[0100] In some examples, fatty acid esters can be synthetic or naturally occurring esters of aliphatic carboxylic acids and aliphatic alcohols. Aliphatic carboxylic acids can include saturated or unsaturated aliphatic monocarboxylic acids or dicarboxylic acids, which are typically lower or higher fatty acids having 2 to 24 carbon atoms. In particular, intermediate or higher fatty acids having 6 to 20 carbon atoms are preferred. As non-limiting examples, acetic acid, propionic acid, hexanoic acid, capric acid, octanoic acid, dioctanoic acid, adipic acid, sebacic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and / or myristic acid can be used in cream formulations.

[0101] In some examples, aliphatic higher alcohols can be saturated and unsaturated aliphatic alcohols having 14 to 20 carbon atoms. As a non-limiting example, cetyl alcohol or palmitol, stearyl alcohol, oleyl alcohol and / or cetyl alcohol can be used in cream formulations.

[0102] In some examples, paraffin oils may include those consisting primarily of mixtures of paraffins having 15 or more carbon atoms. As a non-limiting example, fluid paraffins and / or petrolatum (e.g., white petrolatum, squalane, and squalene) may be used in cream formulations.

[0103] In some examples, lanolin oil may include lanolin, lanolin wax, hydrogenated or reduced lanolin, and polymers thereof with ethylene oxide.

[0104] In some examples, silicone oil may comprise a mixture of polymers of dimethylsiloxane. As a non-limiting example, dimethylpolysiloxane and its alkyl esters, methylphenylpolysiloxane and / or ethylene glycol methylsiloxane may be used in cream formulations.

[0105] In some examples, medium-chain oils may have one or more monoglycerides, diglycerides, or triglycerides, or combinations thereof. Exemplary glycerides include, but are not limited to, MIGLYOLs. ® These are caprylic / capric triglycerides (SASOL Germany GMBH, Hamburger). In some specific examples, MIGLYOLs... ® Including MIGLYOL ® 810 (Caprylic / Capric Triglycerides), MIGLYOL ® 812 (Caprylic / Capric Triglyceride), MIGLYOL ® 816 (caprylic / capric triglyceride) and MIGLYOL ® 829 (Caprylic / Capric / Succinic Triglycerides). In other examples, the medium-chain oil may contain other caprylic / capric triglycerides, including but not limited to caproic / capric / capric / lauric triglycerides, caprylic / capric / linoleic triglycerides, and caprylic / capric / succinic triglycerides. Exemplary caprylic / capric monoglycerides, diglycerides, or triglycerides include, but are not limited to, CAPMUL. ® MCM, CAPMUL ® MCM C10, CAPMUL ® MCM C8, CAPMUL ® MCM C8 EP and CAPMUL ® 708 G (CAPMUL) ® (The brand is owned by ABITEC, Columbus, Ohio). In other examples, other monoglycerides, diglycerides, and triglycerides of fractionated vegetable fatty acids, and combinations or derivatives thereof, may be used in the cream formulations disclosed herein. For example, the oil phase may be 1,2,3-propanetriol (glycerol, glycerol, glycerine) esters of saturated coconut oil and palm kernel oil, and derivatives thereof.

[0106] In some examples, the silicone-based polymer may comprise dimethicone, cyclodimethylsiloxane, behenyldimethylsiloxane, dioctanoic acid / didecanoic acid dimethylsiloxane copolyol and / or cetyldimethylsiloxane.

[0107] (ii) Other components of the ointment formulation Optionally, the ointment formulations described herein may further contain one or more preservatives. Any preservative suitable for topical formulations (e.g., those disclosed herein) may be used herein.

[0108] (iii) Exemplary ointment formulation In some specific examples, this disclosure provides ointment formulations comprising the PA and CA extracts disclosed herein, collagen as a moisturizing polymeric material, and pharmaceutically acceptable excipients comprising (e.g., composed of) white petrolatum. Such ointment formulations may be anhydrous. In some examples, the weight ratio of the PA extract to the CA extract in the cream formulation is from 1:1 to 1:400 (e.g., 1:1, 1:10, 1:50, 1:100, 1:200, 1:300, or 1:400). Optionally or additionally, the concentration of the PA extract in the cream formulation may be from 0.1% to 1% by weight (e.g., 0.1% to 0.5%). The concentration of CA extract in cream formulations can be from 0.1% to 40% by weight (e.g., 0.1% to 30%, 0.1% to 20%, 0.1% to 15%, 0.1% to 10%, 0.1% to 5%, 0.1% to 1%, 1% to 5%, 5% to 10%, 10% to 15%, or 15% to 20%, 20% to 30%, or 30% to 40%).

[0109] Optionally or additionally, the cream formulation contains 0.1% to 70% collagen by weight. In some examples, the amount of collagen may be 1% to 70%, 5% to 60%, or 10% to 50%.

[0110] (d) Sheet dressings The topical formulations described herein may be in the form of sheet dressings. In some examples, a moisturizing biomaterial (e.g., collagen disclosed herein) may constitute about 25% to about 90% (w / w) of the sheet dressing formulation. In some examples, the weight percentage of the moisturizing biomaterial (e.g., collagen) in any sheet dressing disclosed herein may be about 30% to about 70%, about 40% to about 60%, about 25% to about 50%, or about 50% to about 70%. In other examples, the weight percentage of the moisturizing biomaterial (e.g., collagen) in any sheet dressing disclosed herein may be about 80% to about 90%. In some examples, the weight percentage of the moisturizing biomaterial (e.g., collagen) in any sheet dressing disclosed herein does not exceed 95%. In some examples, the weight percentage of the moisturizing biomaterial (e.g., collagen) in any sheet dressing disclosed herein does not exceed 90%.

[0111] In sheet dressing formulations, the pharmaceutically effective excipient comprises the dressing. Optionally, the sheet dressing formulations described herein may further comprise one or more of the following components: antioxidants, growth factors, and / or extracellular matrix. The sheet dressing formulations disclosed herein are sterile and can maintain long-term efficacy; for example, the dressing can remain on a wound and remain effective for more than 4 days.

[0112] (i) dressings A dressing, or sheet dressing, is a sterile pad placed on a wound to promote healing and protect it from further damage. Dressings are designed to come into direct contact with the wound.

[0113] In some embodiments, dressings suitable for the topical formulations described herein may be bandages, membranes, synthetic or biological (e.g., decellularized or cellular) hydrogels, hydrocolloids, films, foams, gauze, dermal patches, tapes, skin substitutes, pastes, powders, or fibers (e.g., anionic, amphoteric, or hydrophilic polymers).

[0114] (ii) Other components of sheet dressings In some embodiments, the dressing formulations disclosed herein may further comprise one or more antioxidants, one or more growth factors, one or more extracellular matrices, or combinations thereof.

[0115] Antioxidants are compounds that inhibit oxidation, a chemical reaction that produces free radicals (often via auto-oxidation). Auto-oxidation leads to the degradation of organic compounds, including living matter. Antioxidants can be added to topical formulations to extend their shelf life.

[0116] In some embodiments, antioxidants suitable for sheet dressings may include vitamin A and other carotenoid compounds, vitamin E and other tocopherols, and proanthocyanidins and their derivatives.

[0117] In some implementations, the antioxidant may comprise a sulfite. Suitable sulfites include, but are not limited to, sodium bisulfite (a mixture of sodium monosulfite (NaHSO3) and sodium metabisulfite (Na2S2O5)), sodium metabisulfite, potassium metabisulfite (K2SO5), sulfur dioxide, and acids. In some specific examples, the acid may be ascorbic acid and benzoic acid.

[0118] Growth factors can bind to ECM proteins. The binding of growth factors to the ECM is the main mechanism regulating growth factor activity.

[0119] In some embodiments, exemplary growth factors that bind to ECM proteins and are suitable for use in the sheet dressing formulations described herein include, but are not limited to, platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), insulin-like growth factor (IGF), and epidermal growth factor (EGF). Exemplary ECM proteins include, but are not limited to, keratin, fibronectin, and porphyrin.

[0120] (iii) Exemplary sheet dressing In some specific examples, this disclosure provides sheet dressing formulations comprising the PA extract and CA extract disclosed herein, as well as collagen as a moisturizing polymeric material. In some examples, such sheet dressing formulations may be free of other components, such as those pharmaceutically acceptable excipients disclosed herein. In some examples, the weight ratio of the PA extract to the CA extract in the cream formulation is from 1:2 to 1:10 (e.g., 1:2, 1:4, or 1:5). Optionally or additionally, the concentration of the PA extract in the cream formulation may be from 1% to 5% by weight (e.g., 2% to 4%). The concentration of the CA extract in the cream formulation may be from 5% to 20% by weight (e.g., 5% to 18% or 5% to 16%).

[0121] Optionally or additionally, the cream formulation contains 70% to 90% collagen by weight. In some examples, the amount of collagen may be 70% to 80%, 80% to 85%, or 85% to 90%.

[0122] II. Methods for promoting wound healing Any of the topical preparations described herein can be used to promote wound healing in subjects requiring treatment. The topical preparation can be applied to the wound site according to appropriate dosage and treatment regimen. The dosage and administration regimen of the method will depend on the nature and condition of the wound being treated, the patient's age and condition, and any prior or concurrent treatments. In some examples, the topical preparation can be applied once a week, every other day, once daily, twice daily, three times daily, or four times daily for an appropriate period of time. Treatment can be discontinued when the wound has healed. Treatment can be resumed if necessary, for example, if the wound recurs.

[0123] The term “wound” refers to damage to living tissue caused by a cut, blow, or other impact (e.g., caused by a medical condition such as a dermatological disease), typically an injury where the skin is cut or broken. Wounds may be associated with medical conditions (e.g., dermatological diseases). The term “wound healing” refers to the dynamic and complex process of replacing inactivated or missing cellular structures and / or tissue layers. The terms “promotion of wound healing” or “promoting wound healing” refer to inducing an increased level or rate of replacement of inactivated or missing cellular structures and / or tissue layers. As an example, promoted wound healing can be indicated by the partial or complete closure of an ulcer, or by an increase in the rate of ulcer healing (including, but not limited to, a more rapid change in ulcer size, area, or severity, faster closure of an ulcer, and / or an increased percentage change from baseline in terms of ulcer size, area, or severity compared to a control ulcer treated with placebo).

[0124] Subjects treated with the topical formulations described herein may be human or non-human mammals. In some embodiments, the subject is a human patient with an open or acute wound, which is defined as damage or destruction of living tissue (e.g., skin) that causes a disruption of the normal continuity of a biological structure. Open wounds may include, but are not limited to, abrasions, incisions, lacerations, puncture wounds, avulsions, cuts, or other similar injuries.

[0125] In other embodiments, the subject is a human patient with a chronic wound, which can be an injury or destruction of living tissue (e.g., skin) that causes a disruption of the normal continuity of biological structures and cannot heal in an ordered set of stages and / or within a predictable timeframe. Chronic wounds can include, but are not limited to, surgical wounds, traumatic wounds, pressure ulcers, venous ulcers, or diabetic ulcers. In other examples, chronic wounds can be associated with diseases or conditions such as cancer, burns, bedsores, or skin diseases such as atopic dermatitis.

[0126] In some implementations, the subject to be treated by the methods described herein has a severe wound, for example, one with an area greater than 2 cm. 2 (For example, 3 cm) 2 4 cm 2 or 5 cm 2 Ulcers on the soles of the feet. In some examples, subjects had one or more plantar ulcers.

[0127] III. Kits for promoting wound healing This disclosure also provides kits for promoting wound healing. Such kits may comprise one or more containers containing the topical formulations described herein, said topical formulations comprising PA extracts, CA extracts, moisturizing polymeric biomaterials, and pharmaceutically effective excipients.

[0128] In some embodiments, the kit may include instructions for use according to any of the methods described herein. The accompanying instructions may include instructions for applying a topical preparation to promote wound healing according to any of the methods described herein. The kit may further include instructions for selecting suitable individuals for treatment based on determining whether an individual has a wound requiring treatment.

[0129] Instructions for use related to topical formulations typically include information on the dosage, dosing regimen, and route of administration for the intended treatment. Containers may be unit dose, bulk packaging (e.g., multi-dose packaging), or subunit dose. Instructions provided with kits of the present invention are typically written instructions on a label or packaging insert (e.g., a piece of paper included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

[0130] The label or packaging insert indicates that the composition is intended to promote wound healing. Instructions for use in carrying out any of the methods described herein may be provided.

[0131] The kit of the present invention is packaged in a suitable manner. Suitable packaging includes, but is not limited to, vials, bottles, wide-mouth bottles, flexible packaging (e.g., sealed polyester film or plastic bags), etc.

[0132] The kit may optionally include additional components, such as explanatory information. Typically, the kit includes a container and labels or packaging inserts on or associated with the container. In some embodiments, the invention provides an article of manufacture containing the contents of the kit described above.

[0133] Without further elaboration, those skilled in the art can utilize the invention to the fullest extent based on the foregoing description. Therefore, the following specific embodiments should be interpreted as illustrative only and do not limit the remainder of this disclosure in any way. All publications cited herein are incorporated by reference for the purposes or subjects described herein.

[0134] Example 1: Water Retention Capacity Test A moist environment has been shown to promote the wound healing process because it prevents dehydration, enhances angiogenesis and collagen synthesis, and increases the breakdown of dead tissue and fibrin. The topical formulations described in this article help maintain a moist environment in the wound.

[0135] The water retention capacity of the topical formulation was tested. The test was conducted using the Automatic Film Applicator Standard (TQC SHEEN, AB4220) for film preparation. The test sample was applied to the film sealed to the rim of a cup. Water retention capacity was determined by placing the cup in a stability test chamber at 32±1°C and 50±2% relative humidity for 21 hours. The total water loss rate was calculated.

[0136] For the five cream formulations tested, water and white petrolatum were used as excipients. For the three ointment formulations tested, white petrolatum was used as an excipient.

[0137] The results showed that the combination of PA extract and CA extract provided a good water retention capacity of 96.2%. The combination of PA extract, CA extract, and collagen provided an excellent water retention capacity of 97.1% to 100.0%. This water retention rate is superior to commercially available skin conditioning products, such as ALHYDRAN. ® (94.5%), BIAFINE ® (93.8%) and Life Fusion ® (93.1%). See Table 1.

[0138] In addition, the water-retention capacity of three sheet formulations containing PA extract, CA extract, and collagen, as shown in Table 1, was tested. Two of the tested sheet formulations demonstrated superior water retention compared to the commercially available collagen sheet product, Life Fusion. ® The water retention rate is 93.1%.

[0139] Table 1: Water Retention Capacity Test Other implementation plans All features disclosed in this specification can be combined in any way. Each feature disclosed in this specification can be replaced by an alternative feature that performs the same, equivalent, or similar function. Therefore, unless otherwise expressly stated, each disclosed feature is merely an example of a general series of equivalent or similar features.

[0140] Based on the above description, those skilled in the art can readily identify the essential features of the present invention, and various changes and modifications can be made to adapt it to various uses and conditions without departing from its spirit and scope. Therefore, other embodiments are also within the scope of the claims.

[0141] Equivalent form In the claims, unless otherwise indicated or clearly apparent from the context, articles such as "a," "an," and "the" may indicate one or more. A claim or description comprising "or" between one or more members of a group is considered satisfied if one, more than one, or all members of that group are present, used in, or associated with a given product or process, unless otherwise indicated or clearly apparent from the context. The invention includes embodiments in which exactly one member of the group is present, used in, or associated with a given product or process. The invention includes embodiments in which more than one or all members of the group are present, used in, or associated with a given product or process.

[0142] Furthermore, this invention covers all variations, combinations, and arrangements in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations appearing in any other claim dependent on the same basic claim. Where elements are presented in a list (e.g., in Markush group form), each subgroup of elements is also disclosed, and any element may be removed from that group. It should be understood that, generally, where an aspect of the invention is referred to as comprising a particular element and / or feature, certain embodiments of the invention or aspects of the invention consist of or are substantially composed of such elements and / or features. For the purpose of simplicity, those embodiments are not described in particular exhaustively herein. It should also be noted that the terms “comprising” and “containing” are intended to be open-ended and allow for the inclusion of additional elements or steps. When a scope is given, the endpoint is included. Furthermore, unless otherwise stated or clearly understood from the context and from the understanding of one of ordinary skill in the art, values ​​expressed as ranges may represent any specific value or subrange within the range in different embodiments of the invention, accurate to one-tenth of the lower limit unit of the range, unless the context clearly indicates otherwise.

[0143] This application references various granted patents and published patent applications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, the specification shall prevail. Furthermore, any specific embodiments of the invention that are prior art may be expressly excluded from any one or more claims. Because such embodiments are considered to be known to one of ordinary skill in the art, they may be excluded even if not expressly stated otherwise herein. Any specific embodiment of the invention may be excluded from any claim for any reason (whether or not related to the existence of prior art).

[0144] Those skilled in the art will recognize that many equivalent forms of the specific embodiments described herein can be determined, or through experiments not exceeding conventional methods. The scope of the embodiments described herein is not intended to be limited to the foregoing description, but rather as set forth in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this specification without departing from the spirit or scope of the invention as defined in the claims.

Claims

1. A topical formulation comprising: (i) Incense in hand Plectranthus amboinicus (PA) extract; (ii) Centella asiatica Centella asiatica (CA) extract; (iii) Moisturizing polymeric biomaterials.

2. The topical formulation according to claim 1, further comprising (iv) a pharmaceutically effective excipient.

3. The topical formulation according to claim 1, wherein in the topical formulation: (i) The amount of PA extract is about 0.1 to 20% (w / w); (ii) The amount of CA extract is about 0.1% to 40% (w / w); and / or (iii) The amount of moisturizing polymeric biomaterial is from about 0.1% to 90% (w / w); optionally from about 0.1% to about 70% (w / w).

4. The topical formulation according to any one of claims 1 to 3, wherein the moisturizing polymeric biomaterial comprises collagen, keratin, hyaluronic acid or a salt thereof, or a combination thereof, wherein the salt of hyaluronic acid is optionally sodium hyaluronate.

5. The topical formulation of claim 4, wherein the moisturizing polymeric biomaterial comprises collagen derived from fish, pig, or bovine.

6. The topical preparation according to any one of claims 1 to 5, wherein the topical preparation is in the form of a cream, gel, ointment or sheet dressing.

7. The topical formulation of claim 6, wherein the topical formulation is a cream formulation, and wherein the topical formulation comprises a pharmaceutically effective excipient comprising an oil base, an emulsifier, and water.

8. The topical formulation according to claim 7, wherein the oil base comprises fatty acid esters, aliphatic higher alcohols, paraffin oil, lanolin oil, silicone oil, medium-chain oil and / or silicone polymers.

9. The topical formulation of claim 8, wherein the oil base comprises petrolatum, dimethicone, or a combination thereof.

10. The topical formulation according to any one of claims 7 to 9, wherein the emulsifier comprises anionic surfactant, cationic surfactant, amphoteric surfactant and / or nonionic surfactant.

11. The topical formulation of claim 10, wherein the emulsifier comprises a polysorbate compound, a dehydrated sorbitol compound, or a combination thereof.

12. The topical formulation according to any one of claims 7 to 11, wherein the pharmaceutically effective excipient further comprises one or more of the following: (a) Skin conditioning agents; (b) Emollients; (c) Stiffening agents; (d) Moisturizers; and (e) Preservatives.

13. The topical formulation according to any one of claims 7 to 12, wherein the topical formulation comprises about 0.1 to 10% by weight of PA extract, about 0.1 to 24% by weight of CA extract, and / or about 0.1 to 20% by weight of collagen.

14. The topical formulation of claim 13, wherein the topical formulation comprises a pharmaceutically effective excipient comprising white petrolatum and water.

15. The topical formulation of claim 6, wherein the topical formulation is a gel formulation, and wherein the pharmaceutically effective excipient comprises a gelling agent and water.

16. The topical formulation of claim 15, wherein the gelling agent comprises a cellulose derivative, carbomer, or a combination thereof.

17. The topical formulation of claim 16, wherein the gelling agent comprises carboxymethyl cellulose.

18. The topical formulation according to any one of claims 15 to 17, wherein the pharmaceutically effective excipient further comprises an emollient and / or a preservative.

19. The topical formulation of claim 6, wherein the topical formulation is an ointment, and wherein the pharmaceutically effective excipient comprises an ointment base.

20. The topical formulation of claim 19, wherein the ointment base comprises polyethylene glycol, an oil base, or a combination thereof.

21. The topical formulation of claim 20, wherein the ointment base comprises petrolatum, dimethicone, or a combination thereof.

22. The topical formulation according to any one of claims 19 to 21, wherein the pharmaceutically effective excipient further comprises a preservative.

23. The topical formulation according to any one of claims 19 to 22, wherein the topical formulation comprises, by weight, about 0.1 to 20% of PA extract; about 0.1 to 40% of CA extract; and / or about 0.1 to 70% of collagen.

24. The topical formulation of claim 23, wherein the pharmaceutically acceptable excipient comprises white petrolatum.

25. The topical formulation of claim 6, wherein the topical formulation is a sheet dressing, and wherein the pharmaceutically effective excipient comprises the dressing.

26. The topical preparation of claim 25, wherein the dressing is a bandage, membrane, synthetic or bio-hydrogel, hydrocolloid, film, foam, gauze, dermal patch, tape, skin substitute, paste, powder, or fiber.

27. The topical formulation according to claim 25 or 26, wherein the pharmaceutically effective excipient further comprises an antioxidant, a growth factor, and / or an extracellular matrix protein.

28. The topical formulation according to any one of claims 25 to 26, wherein the topical formulation comprises about 2 to 4% by weight of PA extract, about 8 to 15% by weight of CA extract, and / or about 80 to 90% by weight of collagen.

29. A method for promoting wound healing in a subject, the method comprising placing a topical preparation according to any one of claims 1 to 28 on the wound site of a subject in need.

30. The method of claim 29, wherein the topical preparation is applied to the wound site at least once daily.

31. The method of claim 29 or 30, wherein the subject is a human patient with an acute or chronic wound.

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