CN114796435B

CN114796435B - Oral and nasal pharmaceutical composition with SARS-CoV-2 virus resisting effect and its preparation method

Info

Publication number: CN114796435B
Application number: CN202210512732.3A
Authority: CN
Inventors: 王静蓉; 姜志宏; 余琼希; 丘利芳; 杨子峰; 麦芷桐; 王琳
Original assignee: Macau Univ of Science and Technology
Current assignee: Macau Univ of Science and Technology
Priority date: 2022-05-11
Filing date: 2022-05-11
Publication date: 2023-05-12
Anticipated expiration: 2042-05-11
Also published as: CN114796435A

Abstract

The invention relates to the field of medicines, in particular to an oral-nasal pharmaceutical composition with SARS-CoV-2 prevention and treatment effect and a preparation method thereof. The medicine composition comprises the following active ingredients in parts by weight: 15-30 parts of patchouli oil, 10-20 parts of clove oil, 1-5 parts of tsaoko cardamon oil, 10-20 parts of ginger oil and 10-20 parts of sharpleaf galangal fruit oil.

Description

Oral and nasal pharmaceutical composition with SARS-CoV-2 virus resisting effect and its preparation method

Technical Field

The invention relates to the field of medicines, in particular to an oral-nasal pharmaceutical composition with SARS-CoV-2 prevention and treatment effect and a preparation method thereof.

Background

According to the description of Chinese epidemic history and authentication, aromatic traditional Chinese medicines are the most commonly used traditional Chinese medicines for expelling epidemic diseases due to the effects of avoiding dirt and detoxifying during the period of infectious diseases. Epidemic is epidemic in Han and Wu Di period, and people rely on fumigating aromatic Chinese medicine to inhibit epidemic transmission. A large number of aromatic traditional Chinese medicines and formulas are recorded in the 'preparation of the Qianjin Fangji', including important formulas for avoiding pestilence, such as Taiyi Yi jin san and Realgar pills; also disclosed is a fumigating method using moxa smoke for preventing and treating cataract. Aromatic traditional Chinese medicines are further divided into aromas (56 species in total, such as herba schizonepetae and peppermint, etc.) and rosewood (35 species in total, such as frankincense and sandalwood, etc.); and mentioned that the air sterilization is performed by fumigating rhizoma Atractylodis and folium Artemisiae Argyi etc. in the room. Since 2003, traditional Chinese medicine has exerted a characteristic and advantageous effect in the process of resisting SARS, MERS, EBOV and other viral diseases, and has made an important contribution to the recognition. The traditional Chinese medicine administration in 2009 issued traditional Chinese medicine prevention scheme of influenza A (H1N 1) suggests that aromatic turbidity-eliminating traditional Chinese medicines such as rhizoma atractylodis, folium artemisiae argyi, wrinkled gianthyssop, angelica sinensis, radix angelicae and the like are prepared into sachets or fumigated, and the sachet has the effects of removing the cataract and avoiding the dirt. In the traditional Chinese medicine treatment scheme of the 'novel pneumonia diagnosis and treatment scheme (trial seventh edition) of coronavirus infection' issued by the national health committee in 2020, the clinical treatment period and recovery period of a patient in medical observation period and definite diagnosis are controlled by using Chinese patent medicines or prescriptions containing more aromatic traditional Chinese medicines, and meanwhile, a part of local health committee or Chinese medicine administration also recommends various other modes (external fumigation, moxibustion, sachet wearing and the like) for controlling the novel coronavirus.

At present, no effective anti-novel coronavirus medicine exists, and part of chemical antiviral medicines have certain antiviral effects, but the limitation of the chemical antiviral medicines is also prominent, such as side effects and drug resistance. The traditional Chinese medicine has unique advantages in the aspect of preventing infectious diseases caused by viruses, bacteria and the like, has rich medicinal resources, has long clinical application history, is used for accurately treating dialectical diseases, can act on the diseases at multiple targets, has small drug resistance, is commonly used for aromatic, spicy and heat-clearing medicines to dispel pathogenic factors and remove dampness and heat, and particularly accumulates a great deal of precious experience in the aspect of preventing and treating pestilence (various virulent infectious diseases). In recent years, many research works have explored the certainty and breadth of treatment of respiratory infectious diseases with traditional Chinese medicines. The modern medicine proves that the volatile oil in the traditional Chinese medicine can inhibit the translation of viral proteins or interfere with the fusion process of viral membranes, thereby preventing influenza viruses from entering host cells and having antibacterial and antiviral effects. Furthermore, studies have shown that volatile oils pass through the gaseous form and act to disinfect virus for a short exposure time (5-30 minutes). The traditional Chinese medicine volatile oil has long history and unique advantages in preventing and treating viral diseases, particularly has good curative effect and potential on the current high-dose novel coronavirus, has high safety and wide application range, and is an important resource for preventing and treating novel coronavirus infection.

The nose is the portal of the lung, and viruses enter through the mouth and nose, infecting the respiratory tract and the lung. The single or compound traditional Chinese medicine volatile oil with the function of resisting novel coronavirus is prepared into personal protection products such as nasal cavity protective agent or mouthwash, and the like, the volatile oil can be automatically volatilized to form a high-concentration gaseous small environment in the nasal cavity, throat and trachea to quickly kill viruses, and meanwhile, the viruses deposited in the nasal cavity are killed through a medicine layer of nasal mucosa and the invasion of the viruses to cells is inhibited, so that an effective anti-line for mouth and nose is formed. The device is particularly suitable for closed places, and achieves the protection of all directions and all time periods.

The invention patent with publication number of CN111184799A provides a traditional Chinese medicine aerosol for resisting coronavirus, which can rapidly kill viruses only by spraying and sucking medicine oil to form a high-concentration gaseous small environment in nasal cavity and trachea, and can not form a medicine layer on the surface of nasal mucosa to block virus invasion. The invention patent with publication number of CN112569331A provides a traditional Chinese medicine composition for preventing new coronaviruses, a preparation method and application thereof, wherein the traditional Chinese medicine composition is prepared into sachets, but the volatility of active ingredients in the traditional Chinese medicine composition is limited, and the traditional Chinese medicine composition is easy to diffuse in air, so that higher effective concentration is difficult to maintain. The invention patent with publication number of CN111280526A provides a mask for preventing pneumonia caused by influenza virus and/or novel coronavirus and a preparation method thereof, wherein a traditional Chinese medicine composition is filled in a traditional Chinese medicine sandwich bag in the mask, but the mask cannot realize omnibearing and full-period protection.

Disclosure of Invention

The first object of the present invention is to provide a pharmaceutical composition for oral and/or nasal administration, comprising, in parts by weight, the following pharmaceutical volatile oils:

15-30 parts of patchouli oil, 10-20 parts of clove oil, 1-5 parts of tsaoko cardamon oil, 10-20 parts of ginger oil and 10-20 parts of sharpleaf galangal fruit oil.

A second object of the present invention is to provide a process for preparing a pharmaceutical composition as described above, comprising:

a) Preparing each of the medicinal volatile oils separately and mixing them together; and

b) Optionally preparing the desired dosage form.

A third object of the present invention is to provide the use of an active ingredient as mentioned above for the preparation of a medicament for the prevention and treatment of SARS-CoV-2.

The beneficial effects of the invention are as follows:

the pharmaceutical composition provided by the invention has a synergistic effect on resisting novel coronaviruses (namely SARS-CoV-2). The nasal cavity protective agent has high safety and good drug effect, the main active ingredient is volatile oil, and the nasal cavity protective agent is particularly suitable for being used as an oral and nasal protective agent, on one hand, the volatile oil is automatically volatilized to form a gaseous small environment in the nasal cavity and the trachea so as to quickly kill viruses, and meanwhile, the volatile oil kills viruses deposited in the nasal cavity through a drug layer of nasal mucosa and inhibits invasion of the volatile oil to cells, so that an effective protective line of the nasal cavity is formed. The device is particularly suitable for closed places, and achieves the protection of all directions and all time periods.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.

Fig. 1 is a finger print of pogostemon cablin [1: beta-patchoulene (3.03%); 2: caryophyllene (1.43%); 3,6: α -guaiacene (7.47%, 2.26%); 4: beta-cnidiene (6.13%); 5: alpha-patchoulene (5.22%); 7,10: alpha-quinoa (9.93%, 3.39%); 8:2, 11-dioxaethylcyclo [4.3.1.1 (3, 10) 0 (6, 9) ] undec-4-ene,3,7,7,10-tetramethyl- (2.26%); 9: carnosine (1.90%); 11: patchouli alcohol (48.81%) ];

fig. 2 is a fingerprint of tsaoko amomum fruit [1: α -pinene (2.30%); 2: beta-pinene (2.51%); 3: alpha-phellandrene (7.56%); 4: p-cymene (1.61%); 5: eucalyptol (44.04%); 6: (Z) - β -ocimene (1.73%); 7:4-Menthen-8-ol (2.50%); 8: (Z) -citral (3.66%); 9: geraniol (1.81%); 10:8-methyl-1-decene (5.54%); 11: (E) -citral (5.42%); 12,13: 4-propylzaldyde (9.42%, 1.52%); 14: nerol (2.14%); 15: nerolidol (1.67%) ];

fig. 3 is a fingerprint of clove [1: eugenol (75.59%); 2: caryophyllene (3.73%); 3: isoeugenol (19.36%) ];

fig. 4 is a fingerprint of turmeric [1: eucalyptol (1.80%); 2: benzene,1- (1, 5-dimethyl-4-hexenyl) -4-methyl- (6.20%); 3: gingerol (10.50%); 4: isostachys alkene (2.15%); 5: beta-sesquiphellandrene (9.49%); 6: aryl curcuminoids (16.87%); 7: curcumone (31.62%); 8: curcuminoids (12.65%) ];

fig. 5 is a fingerprint of ginger [1: α -pinene (2.39%); 2: camphene (9.47%); 3: beta-myrcene (1.29%); 4: eucalyptol (13.44%); 5: borneol (2.69%); 6: paraffin alkene (1.22%); 7: (Z) -citral (5.59%); 8: (E) -citral (5.40%); 9: benzene,1- (1, 5-dimethyl-4-hexenyl) -4-methyl- (4.01%); 10: germacrene D (1.52%); 11: gingerol (26.53%); 12: alpha-bacterio-chloro-ene (4.87%); 13: beta-renieratene (4.62%); 14: beta-sesquiphellandrene (8.76%); 15: α -cnidiene (1.98%) ];

fig. 6 is a finger print of rhizoma Atractylodis [1: α -pinene (2.06%); 2: alpha-phellandrene (1.91%); 3:6S-2,3, 8-tetramethyl tricyclo [5.2.2.0 (1, 6) ] undec-2-ene (1.75%); 4: hexamethylbenzene (2.72%); 5: bicyclo [5.3.0] decane, 2-methyl-5- (1-methyl vinyl) -8-methyl- (1.44%); 6: caryophyllene (1.48%); 7,8: γ -cnidiene (2.29%, 4.84%); 9: beta-cedrene (1.14%); 10: alpha-elemene (2.70%); 11: gamma-elemene (6.60%); 12: alpha-gulremacene (1.50%); 13: atractylol (6.22%); 14: beta-eucalyptol (16.15%); 15:3,3 '-diamido-4, 4' -biphenyldiol (20.63%); 16: 4-biphenylcarbaldehyde (14.45%) ];

fig. 7 is a fingerprint of sandalwood [1:4-ethoxyphenyl acetamide (2.65%); 2: carcone (4.11%); 3: 7-propylidene-dicycloheo [4.1.0] heptane (2.26%); 4: cedrol (2.80%); 5: isoglitazone (4.23%); 6: alpha-cedrol (8.70%); 7: cnidiadiene (2.07%); 8: cycloheptyl N.N-dipropylphosphoric acid amide (8.86%); 9: isopropyl myristate (11.51%); 10:2-methyl-3-phenylindole (2.88%); 11: methyl abiet-8-en-18-oate (16.62%); 12: methyl dehydroabietate (10.16%) ];

fig. 8 is a fingerprint of fructus Alpinae Oxyphyllae [1: thyme (13.50%); 2: eucalyptol (8.79%); 3: gamma-terpinene (2.10%); 4: cnidiadiene (2.27%); 5: alpha-copane-8-ol (2.37%); 6: beta-phellandrene (3.60%); 7: yaku blue olene (11.52%); 8: isopropyl isovalerate (7.27%); 9: gamma-cadinene (3.72%); 10: huobadone (8.43%) ];

fig. 9 is a fingerprint of zedoary [1: eucalyptol (4.79%); 2: beta-camphor (1.27%); 3: beta-caryophyllene (3.82%); 4: curcumene (3.50%); 5: beta-phellandrene (1.72%); 6:3-Methyl-4,5, 6a-tetrahydro-1H-pentalen-2-one (38.10%); 7: alpha-caryophyllene (2.70%); 8: eucalyptol (1.66%); 9: aloerene (2.01%); 10: (3E, 7E) -10-Isopropenyl-3, 7-cyclopodecadien-1-one (14.37%) ];

FIG. 10 shows the results of in vitro antiviral activity of Pogostemon cablin, fructus Tsaoko, flos Caryophylli, rhizoma Curcumae Longae, rhizoma Zingiberis recens, rhizoma Atractylodis, lignum Santali albi, fructus Alpinae Oxyphyllae and rhizoma Curcumae.

Detailed Description

Reference now will be made in detail to embodiments of the invention, one or more examples of which are described below. Each example is provided by way of explanation, not limitation, of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment can be used on another embodiment to yield still a further embodiment.

Unless otherwise defined, all terms (including technical and scientific terms) used to describe the invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By way of further guidance, the following definitions are used to better understand the teachings of the present invention. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

The term "and/or," "and/or," as used herein, includes any one of two or more of the listed items in relation to each other, as well as any and all combinations of the listed items in relation to each other, including any two of the listed items in relation to each other, any more of the listed items in relation to each other, or all combinations of the listed items in relation to each other. It should be noted that, when at least three items are connected by a combination of at least two conjunctions selected from "and/or", "or/and", "and/or", it should be understood that, in this application, the technical solutions certainly include technical solutions that all use "logical and" connection, and also certainly include technical solutions that all use "logical or" connection. For example, "a and/or B" includes three parallel schemes A, B and a+b. For another example, the technical schemes of "a, and/or B, and/or C, and/or D" include any one of A, B, C, D (i.e., the technical scheme of "logical or" connection), and also include any and all combinations of A, B, C, D, i.e., any two or three of A, B, C, D, and also include four combinations of A, B, C, D (i.e., the technical scheme of "logical and" connection).

The terms "comprising," "including," and "comprising," as used herein, are synonymous, inclusive or open-ended, and do not exclude additional, unrecited members, elements, or method steps.

The recitation of numerical ranges by endpoints of the present invention includes all numbers and fractions subsumed within that range, as well as the recited endpoint.

Concentration values are referred to in this invention, the meaning of which includes fluctuations within a certain range. For example, it may fluctuate within a corresponding accuracy range. For example, 2%, may allow fluctuations within + -0.1%. For values that are larger or do not require finer control, it is also permissible for the meaning to include larger fluctuations. For example, 100mM, fluctuations in the range of.+ -. 1%,.+ -. 2%,.+ -. 5%, etc. can be tolerated. Molecular weight is referred to, allowing its meaning to include fluctuations of + -10%.

In the present invention, the terms "plurality", and the like refer to, unless otherwise specified, 2 or more in number.

In the invention, the technical characteristics described in an open mode comprise a closed technical scheme composed of the listed characteristics and also comprise an open technical scheme comprising the listed characteristics.

In the present invention, "preferred", "better", "preferred" are merely embodiments or examples which are better described, and it should be understood that they do not limit the scope of the present invention. In the present invention, "optional" means optional or not, that is, means any one selected from two parallel schemes of "with" or "without". If multiple "alternatives" occur in a technical solution, if no particular description exists and there is no contradiction or mutual constraint, then each "alternative" is independent.

All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Unless otherwise contradicted by purpose and/or technical solution of the present application, the cited documents related to the present invention are incorporated by reference in their entirety for all purposes. When reference is made to a cited document in the present invention, the definitions of the relevant technical features, terms, nouns, phrases, etc. in the cited document are also incorporated. In the case of the cited documents, examples and preferred modes of the cited relevant technical features are incorporated into the present application by reference, but are not limited to the embodiments that can be implemented. It should be understood that when a reference is made to the description herein, it is intended to control or adapt the present application in light of the description herein.

The invention relates to a pharmaceutical composition for oral and/or nasal use, comprising the following pharmaceutical volatile oils: patchouli oil, clove oil, tsaoko cardamon oil, ginger oil and alpinia oxyphylla oil.

Preferably, the active ingredients comprise the following medicinal volatile oil in parts by weight:

20-25 parts of patchouli oil, 13-17 parts of clove oil, 2-4 parts of tsaoko cardamon oil, 13-17 parts of ginger oil and 13-17 parts of sharpleaf galangal fruit oil.

21-24 parts of patchouli oil, 14-16 parts of clove oil, 2-4 parts of tsaoko cardamon oil, 14-16 parts of ginger oil and 14-16 parts of sharpleaf galangal fruit oil.

In some embodiments, the active ingredient of the pharmaceutical composition further comprises atractylis oil.

10-20 parts of atractylis oil; or 13 to 17 parts by weight.

In some embodiments, the active ingredient of the pharmaceutical composition may or may not contain one or more of the following ingredients or extracts thereof:

herba Ephedrae, semen Armeniacae amarum, coicis semen, rhizoma Atractylodis, herba Artemisiae Annuae, rhizoma Polygoni Cuspidati, herba Verbenae, rhizoma Phragmitis, semen Lepidii, exocarpium Citri Grandis, pericarpium Citri Tangerinae, poria, radix Platycodi, cortex Magnolia officinalis, ginseng radix, radix astragali, atractylodis rhizoma, radix Saposhnikoviae, flos Lonicerae, rhizoma Osmundae, herba Eupatorii, pericarpium Citri Tangerinae, rhizoma Phragmitis, radix Isatidis, caulis Perillae, radix et rhizoma Rhei, curcuma rhizome, lignum Santali albi, and Curcumae rhizoma.

The active ingredient may be present in an amount effective to exert its antiviral effect. In some embodiments, the pharmaceutical composition comprises about 0.01 wt.% to about 99.9 wt.%, about 0.1 wt.%, about 0.5 wt.%, about 1 wt.%, about 2 wt.%, about 5 wt.%, about 10 wt.%, about 20 wt.%, about 30 wt.%, about 40 wt.%, about 50 wt.%, about 60 wt.%, about 70 wt.%, about 80 wt.%, about 90 wt.% of the active ingredient, based on the total weight of the composition.

By "oral and/or nasal pharmaceutical composition" is meant a composition suitable for oral and/or nasal delivery, including oral and/or intranasal delivery. The particular form of the oral and/or nasal composition is not limited. In some embodiments, the oral and/or nasal composition is in the form of a solution, suspension, dispersion, emulsion, or gel. In some embodiments, the composition is in the form of an oily liquid. In some embodiments, the composition is anhydrous or free of water (as used herein, "free of water" means that the composition is formulated in the absence of water, but there may be trace amounts). In some embodiments, the composition comprises a semi-solid phase that is free of water. In some embodiments, the composition is a hydrophilic gel or latex agent (i.e., an emulsion incorporated into a gel matrix). In some embodiments, the composition is a hydrophobic gel, such as an oleogel or organogel. In some embodiments, the composition includes a three-dimensional viscoelastic gel having a small molecular weight organogelator (e.g., <900 Da) and/or a polymeric gelator. In some embodiments, the composition is spreadable.

In one embodiment, the medicament of the invention is a simple mixture.

In some embodiments, the pharmaceutical composition is any one of an aerosol, a gel, a paste, a mouthwash, a nasal wash, and a cataplasm.

The aerosol is a preparation prepared by packaging a medicine and a proper propellant in a pressure-resistant container with a special valve system, and when the aerosol is used, the content is quantitatively or non-quantitatively sprayed by the pressure of the propellant, the medicine is mostly atomized aerosol, and the mist drops are generally smaller than 50 mu m.

The gel refers to a thick liquid or semisolid preparation prepared from the medicine and auxiliary materials capable of forming gel. Preferably it is an aqueous gel, the matrix used for which is for example acrylic, chitosan derivatives, alginic acid, modified cellulose, carbomers. Carbomers are further selected from carbomer 934, carbomer 940, carbomer 941, and the like. The gel agent often contains a pH regulator, preferably triethanolamine, naOH, etc.

The ointment is preferably an ointment, cream or patch.

The cataplasma is a novel external preparation, and is an external preparation which is prepared by dissolving or mixing a medicine in a water-soluble polymer material matrix, spreading on a backing material, and applying on skin.

The pharmaceutical composition further comprises at least one of (i) to (v):

(i) Lipophilic or partially lipophilic vehicles;

(ii) A surfactant;

(iii) Carbomers and/or triethanolamine;

(iv) A pharmaceutically active component selected from the group consisting of: vitamins, analgesics, anti-inflammatory agents, antipruritics, antipyretics and anesthetics; and

(v) Water (preferably distilled water).

In some embodiments, the lipophilic or partially lipophilic vehicle is selected from the group consisting of: eucalyptus oil, castor oil, hydrogenated castor oil, soybean oil, sesame oil, peanut oil, glycerin, paraffin, lanolin, fatty acid esters, medium chain triglycerides, fatty acid glycerides, polyethylene glycol, and phospholipids.

The surfactant is selected from anionic, cationic, amphoteric and nonionic surfactants including, but not limited to: one or more of almond oil PEG-6-ester, lecithin, fatty acid ester of polyhydric alcohol, fatty acid ester of sorbitan, fatty acid ester of polyoxyethylene, fatty acid ester of sucrose, fatty acid ester of polyglycerol, oleoyl polyoxylglyceride, oleoyl polyethylene glycol glyceride, sorbitol, glycerol, polyethylene glycol and polyethylene glycol glycerol fatty acid ester.

The surfactant, if present, may be present in an amount effective to exert surfactant properties. In some embodiments, the composition comprises from about 1 wt% to about 20 wt%, from about 1 wt% to about 10 wt%, from about 1 wt% to about 5 wt%, about 4 wt%, or about 2 wt% surfactant, based on the total weight of the composition. In some embodiments, the composition comprises from 1 wt% to 20 wt%, from 1 wt% to 10 wt%, from 1 wt% to 5 wt%, 4 wt%, or 2 wt% surfactant, based on the total weight of the composition.

Various vitamins may be included in the topical compositions of the present invention. For example, vitamin A and its derivatives, anti-bad thrombus, vitamin B, biotin, pantothenic acid, vitamin D and mixtures thereof can be used. Vitamin E, tocopheryl acetate and derivatives can also be used.

A safe and effective amount of an anti-inflammatory agent may be added to the compositions of the present invention, preferably in an amount of from about 0.1% to about 10%, more preferably from about 0.5% to about 5% of the composition. The exact anti-inflammatory dose used in the compositions of the present invention will depend on the particular anti-inflammatory agent used, as such agents vary greatly in potency.

Anti-inflammatory agents include but are not limited to corticosteroids, for example, hydrocortisone, hydroxytriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, dexamethasone dipropionate, clobetasol valerate, methylprednisolone, dexamethasone, desoxysebacone acetate, dexamethasone, beclomethasone, diflorasone diacetate, diflurolone valerate, fludrolone, clodrolone, fludrocortisone, flumidostanol, fluosinolone acetonide, fluocinolone acetonide, flubutazone, fludrolone, fluprednisodine (fluprednylide) acetate, fludropinone, ha Xibian pine, hydrocortisone acetate, hydrocortisone butyrate may be used Methylprednisone, triamcinolone, cortisone, fluetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, meflosone, amprenol, betamethasone and the remaining esters thereof, prednisone acetate, clocortisone, clestinone, diclofenac, difluprednate, flucloprednisone, flumidone, fipronil, fluprednisone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortisone, methylprednisolone, palatethasone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures thereof.

Useful anesthetic or antipruritic agents are selected from the group consisting of lidocaine, lidocaine hydrochloride, ding Paika-cause hydrochloride, chloroprocaine hydrochloride, diphenhydramine hydrochloride, etidocaine hydrochloride, mepivacaine hydrochloride, tetracaine hydrochloride, dyclonine hydrochloride, hexacaine hydrochloride, benzocaine, benzyl alcohol, picric acid, butyl ester of p-aminobenzoate, camphor, camphoric meta-cresol, delbocaine hydrochloride, isoquinicaine hydrochloride, diphenhydramine hydrochloride, juniper tar, methanol, phenol, sodium phenolate, timocaine hydrochloride, resorcinol, and mixtures thereof.

The composition may also include components known to be beneficial in achieving/improving the use experience, such as:

fragrance: e.g., benzaldehyde (e.g., cherry, almond); citral; hyperthyroidism relieving; decanal (orange, lemon); c-8 aldehyde, C-9 aldehyde and C-12 aldehyde (citrus fruit); tolualdehyde (cherry, almond); 2, 6-dimethyloctanal (green fruit); 2-dodecenal (citrus, orange). Mixtures of these fragrances may also be used.

Preservatives, antioxidants, pigments.

Moisturizer/moisturizer: the compositions of the present invention may also contain one or more humectants/moisturizers. Various humectants/moisturizers can be used in amounts of from about 1% to about 10%, more preferably from about 2% to about 8%, and most preferably from about 3% to about 5%. These include urea; guanidine; glycolic acid and glycolate salts (e.g., ammonium and quaternary alkylammonium); lactic acid and lactate salts (such as ammonium and quaternary alkyl ammonium); polyhydroxy alcohols such as sorbitol, glycerin, hexanetriol, propylene glycol, hexylene glycol, and the like; polyethylene glycol; sugar and starch; sugar and starch derivatives (e.g., alkoxylated glucose); d-panthenol; hyaluronic acid; lactoyl monoethanolamine; acetamide monoethanolamine; and mixtures thereof.

The present invention also provides a method of preparing a pharmaceutical composition as described above, comprising:

b) Optionally preparing the desired dosage form.

In some embodiments, the method of preparing each pharmaceutical volatile oil is selected from distillation, solvent extraction, ultrasonic assisted extraction, microwave extraction, or supercritical fluid extraction.

The invention also relates to the application of the pharmaceutical composition (or active ingredient) in preparing medicines for preventing and treating SARS-CoV-2.

The pharmaceutical composition may be administered in any suitable amount. In some embodiments, about 0.1ml to about 1ml, such as about 0.1ml to about 0.3ml, about 0.15ml to about 0.25ml, or about 0.175ml to about 0.225ml, is administered per nostril to the mouth, one or both nostrils. In some embodiments, 0.1ml to 1ml, such as 0.1ml to 0.3ml, 0.15ml to 0.25ml, or 0.175ml to 0.225ml, is administered per nostril, intraoral, one or both nostrils. In some embodiments, about 0.1ml, about 0.15ml, about 0.2ml, about 0.25ml, or about 0.3ml is administered per nostril to the mouth, one or both nostrils. In some embodiments, 0.1ml, 0.15ml, 0.2ml, 0.25ml, or 0.3ml is administered per nostril to the mouth, one or both nostrils. In some embodiments, about 0.2ml or less is administered per nostril to the mouth, one or both nostrils. In some embodiments, 0.2ml or less is administered per nostril to the mouth, one or both nostrils.

In some embodiments, the amount of the composition administered to the mouth, one or both nostrils, per nostril comprises from about 0.001g to about 0.3g of the agent, such as from about 0.005g to about 0.2g of the agent or from about 0.01g to about 0.1g of the agent. In some embodiments, the amount of the composition administered to the mouth, one or both nostrils, per nostril comprises from 0.001g to 0.3g of the agent, such as from 0.005g to 0.2g of the agent or from 0.01g to 0.1g of the agent. In some embodiments, the amount of the composition administered to the mouth, one or both nostrils, per nostril comprises about 0.001g, about 0.004g, about 0.005g, about 0.01g, about 0.02g, about 0.03g, about 0.04g, about 0.05g, about 0.09g, or about 0.1g of the agent. In some embodiments, the amount of the composition administered to the mouth, one or both nostrils, per nostril comprises 0.001g, 0.004g, 0.005g, 0.01g, 0.02g, 0.03g, 0.04g, 0.05g, 0.09g, or 0.1g of the agent.

In some embodiments, the composition is administered once daily to the mouth, one or both nostrils, each nostril. In some embodiments, the composition is administered into the mouth, one or both nostrils, twice daily per nostril. In some embodiments, the composition is administered three, four, five, or six times per nostril, intraoral, or both nostrils.

Embodiments of the present invention will be described in detail below with reference to examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples, in which specific conditions are not noted, are preferably referred to in the guidelines given in the present invention, and may be according to the experimental manuals or conventional conditions in the art, and may be referred to other experimental methods known in the art, or according to the conditions suggested by the manufacturer.

In the specific examples described below, the measurement parameters relating to the raw material components, unless otherwise specified, may have fine deviations within the accuracy of weighing. Temperature and time parameters are involved, allowing acceptable deviations from instrument testing accuracy or operational accuracy.

Examples

1. Preparing the traditional Chinese medicine volatile oil:

reference to the method (method a) prescribed in general rule 2204 of the Chinese pharmacopoeia (2015 edition, four sections). Weighing appropriate amount of coarse powder (or fragments) of each medicinal material, placing into 1000mL round bottom flask, adding appropriate amount of distilled water (8 times of feed-liquid ratio), connecting volatile oil extractor with reflux condenser, adding water from upper end of condenser to fill scale part of volatile oil tester, and overflowing into flask, heating slowly to boil while keeping micro-boiling for about 6 hours, stopping heating until oil amount in tester is not increased, collecting distillate, standing and cooling for a moment, transferring into centrifuge tube, centrifuging for 10 min (10000 r/min), collecting volatile oil layer, reading oil amount and obtaining volatile oil of each sample. As a result, the oil yields of patchouli, tsaoko cardamom, clove, turmeric, ginger, atractylodes, sandalwood, alpinia oxyphylla and zedoary were 0.42%, 1.80%, 10.67%, 1.50%, 0.06%, 0.62%, 1.30%, 0.29% and 0.21%, respectively.

2. Establishing a traditional Chinese medicine volatile oil fingerprint spectrum:

detection was performed using an Agilent GC-MS 7890A-5975C (1) capillary chromatography column: DB-1MS,30m,0.25mm i.d, 0.25 μm film thickness; (2) sample inlet temperature: 250 ℃; (3) interface temperature: 280 ℃; (4) carrier gas flow rate: 1.0mL/min; (5) split ratio: 100:1; (6) heating program: starting at 100 ℃, raising the temperature to 300 ℃ at a rate of 8 ℃ per minute, and maintaining for 5 minutes; (7) mass spectrometry ion source temperature: 230 ℃; (8) quadrupole temperature: 150 ℃. The data processing is completed by a GC-MS analysis software system, each chromatographic peak is matched with a standard spectrum by searching an NIST08 mass spectrum library, and the relative percentage content of each chromatographic peak is calculated according to the normalization of the peak area. The result shows that the finger print of each Chinese medicinal volatile oil is shown in figures 1-9.

3. Anti-novel coronavirus cell assay:

the experiment was conducted by the Guangzhou respiratory health institute, and all experimental procedures were completed in the BSL-3 laboratory.

Materials: test drugs (the above-mentioned volatile)Hair oil); SARS-CoV-2 clinical isolate (GeneBank accession number MT 123290.1) at a titer of 10 ^-7 TCID ₅₀ Per mL, using a viral titer of 100TCID ₅₀ Holes; vero E6 african green monkey kidney cell line, purchased from the american ATCC biological standard resource center, was cultured in RPMI 1640 medium with 2% fetal bovine serum.

Cytotoxicity test: inoculating 2×10 on 96-well cell culture plate ⁵ The cells/well were cultured for 16-20h until the cells grew into a monolayer, and the medium was discarded. The test drugs were serially diluted 4-fold with complete medium and added to the cells at 100 μl per well to obtain the drug-added group. At the same time, a cell control group and a positive control group are arranged, and each group is provided with 4 compound holes. After 72h of cell culture, cell viability was determined by MTT method, whereby the median toxic concentration (CC ₅₀ )。

In vitro antiviral activity assay: inoculating 5×10 on 96-well cell culture plate ⁴ The cells/well were cultured for 16-20h until the cells grew into a monolayer, and the medium was discarded. Continuously diluting the tested medicine with a complete culture medium for 4 times, sequentially sucking 50 mu L to 96-well plates, and adding 50 mu L of virus liquid into each well plate; meanwhile, a cell control group, a model group and a positive control group are arranged, and each group is provided with 4 compound holes. After cell culture for 24h, cell morphology Changes (CPE) were observed and recorded under an inverted microscope. The cytopathy is "-", the pathological changes are "+", the pathological changes are 25% -50%, 50 to 75 percent of lesions are "++", lesions 75% -100% is "++++". Based on the observations, the half-Inhibitory Concentration (IC) of the drug was calculated by Reed-Muench method ₅₀ ). Finally, the antiviral activity is expressed as a Selection Index (SI), calculated as CC ₅₀ And IC ₅₀ Ratio of (i) si=cc ₅₀ /IC ₅₀ . The results show that the 9 traditional Chinese medicine volatile oils have anti-new coronavirus activity (SI>1) IC of patchouli, tsaoko cardamon, clove, turmeric, ginger, rhizoma atractylodis, sandalwood, sharpleaf galangal fruit and zedoary ₅₀ (SI value) is divided into 31.88. Mu.g/mL (1.96), 9.33. Mu.g/mL (1.95), 77.35. Mu.g/mL (1.95), 43.57. Mu.g/mL (3.22), 29.10. Mu.g/mL (1.99), 18.82. Mu.g/mL (1.86), 20.30. Mu.g/mL (1.94), 17.10. Mu.g/mL (1.95) and 15.10. Mu.g/mL (1.16) (see FIG. 10).

4. Preparation of compound traditional Chinese medicine volatile oil and anti-novel coronavirus activity thereof

Example 1: comprises 23 parts of patchouli oil and 15 parts of clove oil by volume.

Example 2: comprises 3 parts of tsaoko oil and 15 parts of clove oil by volume.

Example 3: comprises 23 parts of patchouli oil, 15 parts of clove oil and 15 parts of ginger oil by volume.

Example 4: comprises 23 parts of patchouli oil, 15 parts of clove oil and 15 parts of sharpleaf galangal fruit oil by volume.

Example 5: comprises 23 parts of patchouli oil and 15 parts of sharpleaf galangal fruit oil by volume.

Example 6: comprises 23 parts of patchouli oil, 15 parts of ginger oil and 15 parts of sharpleaf galangal fruit oil by volume.

Example 7: comprises 23 parts of patchouli oil, 3 parts of tsaoko cardamon oil, 15 parts of ginger oil and 15 parts of sharpleaf galangal fruit oil by volume.

Example 8: comprises 23 parts of patchouli oil, 15 parts of clove oil, 15 parts of ginger oil and 15 parts of sharpleaf galangal fruit oil by volume.

Example 9: comprises 23 parts of patchouli oil, 15 parts of clove oil, 3 parts of tsaoko cardamon oil, 15 parts of ginger oil and 15 parts of sharpleaf galangal fruit oil.

Example 10: comprises 23 parts of patchouli oil, 15 parts of clove oil, 3 parts of tsaoko cardamon oil, 15 parts of ginger oil, 15 parts of sharpleaf galangal fruit oil and 15 parts of rhizoma atractylodis oil by volume.

TABLE 1 anti-New coronavirus Activity (IC) of examples 1-10 ₅₀ )

The results show that the ICs of examples 9 and 10 ₅₀ Is lower than single volatile oil (fructus Tsaoko) with highest activity, which means that the two compound traditional Chinese medicine volatile oils exert synergistic effect and have better anti-new coronavirus activity.

5. Preparation of gel

Volatile oil of single or compound traditional Chinese medicine: 1-50 parts by weight of carbomer-940: 8-40 parts by weight of tween-80: 8-20 parts by weight of glycerol: 160-400 parts by weight of triethanolamine: 32-56 parts by weight of purified water: 500-800 parts by weight. Swelling carbomer-940 in 40 times of purified water for 12 hr to obtain semisolid gel (I), adding Tween-80 and glycerol into the gel (I), stirring to obtain soft extract (II), adding triethanolamine into the soft extract (II), adding single or compound Chinese medicinal volatile oil, stirring to obtain soft extract (III), adding purified water slowly, and stirring.

6. Preparation of ointments

Volatile oil of single or compound traditional Chinese medicine: 1-50 parts by weight of liquid paraffin: 250-350 parts by weight of lanolin: 650-750 parts by weight. Heating liquid paraffin and lanolin in 60deg.C water bath, stirring until the liquid is uniform and transparent, adding single or compound Chinese medicinal volatile oil, and stirring.

7. Preparation of mouthwash

Volatile oil of single or compound traditional Chinese medicine: 1-50 parts by weight of glycerol: 5-100 parts by weight of polysorbate: 0.5-50 weight parts, and 800-950 weight parts of purified water. Adding volatile oil of single or compound Chinese medicinal materials and polysorbate into glycerol under stirring, stirring thoroughly, and adding purified water.

The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. The scope of the invention is therefore intended to be covered by the appended claims, and the description and drawings may be interpreted in accordance with the contents of the claims.

Claims

1. The oral and/or nasal pharmaceutical composition comprises the following active ingredients in parts by weight:

15-30 parts of patchouli oil, 10-20 parts of clove oil, 1-5 parts of tsaoko cardamon oil, 10-20 parts of ginger oil and 10-20 parts of sharpleaf galangal fruit oil;

the pharmaceutical composition is used for resisting SARS-CoV-2 virus.

2. The pharmaceutical composition according to claim 1, wherein the active ingredients comprise the following pharmaceutical essential oils in parts by weight:

3. The pharmaceutical composition according to claim 1 or 2, wherein the active ingredient further comprises 10-20 parts of atractylis oil.

4. The pharmaceutical composition according to claim 3, wherein the atractylis oil is 13-17 parts.

5. The pharmaceutical composition of any one of claims 1, 2, 4, which is any one of aerosol, gel, paste, nasal wash, and cataplasm.

6. The pharmaceutical composition according to any one of claims 1, 2, 4, further comprising at least one of (i) - (iv):

(i) Lipophilic or partially lipophilic vehicles;

(ii) A surfactant;

(iii) Carbomers and/or triethanolamine; and

(iv) And (3) water.

7. The pharmaceutical composition of claim 6, wherein the lipophilic or partially lipophilic vehicle is selected from the group consisting of: eucalyptus oil, castor oil, hydrogenated castor oil, soybean oil, sesame oil, peanut oil, glycerin, paraffin, lanolin, fatty acid esters, medium chain triglycerides, fatty acid glycerides, polyethylene glycol, and phospholipids.

8. The pharmaceutical composition of claim 6, wherein the surfactant is selected from the group consisting of: one or more of almond oil PEG-6-ester, lecithin, fatty acid ester of sorbitan, fatty acid ester of polyoxyethylene sorbitan, fatty acid ester of sucrose, fatty acid ester of polyglycerol, oleoyl polyoxylglyceride, oleoyl polyethylene glycol glyceride, sorbitol, glycerol, polyethylene glycol, and polyethylene glycol glycerol fatty acid ester.

9. A method of preparing the pharmaceutical composition of any one of claims 1-8, comprising:

preparing each of the medicinal volatile oils separately and mixing them together.

10. The method of claim 9, further comprising: preparing the required dosage form.

11. The method according to claim 9 or 10, wherein the method for preparing the volatile oil of each drug is selected from distillation, solvent extraction, ultrasonic-assisted extraction, microwave extraction or supercritical fluid extraction.

12. Use of a pharmaceutical composition according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of SARS-CoV-2 virus.