CN112089686A

CN112089686A - Method for producing free drug mucous membrane skin administration preparation

Info

Publication number: CN112089686A
Application number: CN202011087140.9A
Authority: CN
Inventors: 郑鉴忠; 郑婧; 解麦克; 朱丹; 巫才会
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-10-12
Filing date: 2020-10-12
Publication date: 2020-12-18

Abstract

The production of the free drug mucosal skin drug delivery preparation comprises the preparation of free or amorphous drugs, the prevention of the free or amorphous drugs from crystal return, the combination of monarch, minister, assistant and guide and the production of drug preparations. Most of the medicines produced in the prior art are single crystal medicines prepared by chemical synthesis or Chinese herbal medicine separation and extraction, and have the defects of large dosage, low bioavailability, serious side effect and the like. Different medicines are combined for use, but the condition of serious toxic and side effects is difficult to change by simple combination. According to the application, a crystalline bulk drug is prepared into a free or amorphous drug, a monarch, minister, assistant and guide compatibility formula of the traditional Chinese medicine is adopted, different drugs or auxiliary materials are fused with the drugs, included and formed into micelles, suspensions, microemulsions or liposomes, and multiple drugs are mutually restricted and have synergistic effects, so that the toxic and side effects are reduced, and the curative effect is improved. The direct administration of the mucous membrane skin takes effect quickly, and the oral medicine has no gastrointestinal and liver first-pass, thereby avoiding liver damage or gastrointestinal adverse reaction. The western medicine is combined with traditional Chinese medicine, so that the immune balance of the human body is promoted, and the disease resistance is enhanced.

Description

Method for producing free drug mucous membrane skin administration preparation

Technical Field

A method for producing a free drug mucosal skin drug delivery preparation, which belongs to the field of medicine manufacturing.

Background

It is known that oral administration lowers bioavailability due to destruction of gastric acid, intestinal flora and metabolic breakdown of the enzyme system, and even if the drug absorbed by the gastrointestinal tract is broken down by first pass metabolism of the liver, the loss is enormous. In addition, some macromolecular drugs, such as insulin, growth hormone and the like, are hardly absorbed in the gastrointestinal tract, so that the phenomenon of abuse of the injection can be caused in the injection in a wide day.

Mucosa and skin are the most important defense lines for human body to block the invasion of pathogenic microorganisms, and the walls of the gastrointestinal tract, vagina, urethra, respiratory organs (nasal cavity, trachea, bronchus and alveolus), oral cavity, throat, esophagus and other organs are covered by mucosa. The mucosa administration is simple and convenient except oral administration, has small dosage, is economical and practical, overcomes the defects of oral administration and injection, can be particularly directly used at the pathological change part, and has quick absorption and obvious effect. The advantages of mucosal administration for some diseases far exceed oral administration and injection: patches (films), sprays and the like for oral diseases, sublingual tablets; nasal gel, microsphere, liposome, spray, etc. for treating nasal diseases; aerosols, nebulizers, sprays, and the like for respiratory diseases; ophthalmic gels, eye drops, liposomes, microparticles, implants, and the like; gel suppository, hollow suppository, osmotic pump suppository, microcapsule double-layer suppository and enema for treating rectal and perianal diseases; film agent, suppository, tablet, effervescent tablet, gel and intrauterine drug release system for treating vaginal and uterine diseases.

The history of Chinese mucosal skin drug administration method is long. In the precedent of the Han Dynasty's treatise on acute diseases by the treatise on nasal medicines, the juice of leek is smashed and poured into the nose to induce resuscitation and recover the threatened abortion. In Ming dynasty, Ben Cao gang mu, croton oil paper is used for twisting, and the nose is smoked to treat apoplexy, phlegm syncope, qi syncope and poisoning. Modern medical research has been well documented for treating local or systemic diseases for decades, and nitroglycerin sublingual tablets, well known, provide a few minutes of angina pectoris relief, but are of a small, but small, variety of mucosal drug formulations compared to thousands of oral drugs and injections. Mainly has small dosage and high drug concentration for mucosa administration. Many drugs are poorly soluble, and solubility becomes the bottleneck of mucosal drug delivery formulations.

Most of the medicines produced in the prior art are single crystalline medicines prepared by chemical synthesis or Chinese herbal medicine separation and extraction, and the defects of large dose, low bioavailability, serious side effect and the like are quite ineffectual. The method for reducing the side effect of the medicine is various, and western medicines combining different medicines are available, but the effect is difficult to be achieved by simply combining the medicines in order to change the toxic and side effects. The medicines are combined according to the medicine properties to reduce side effects and enhance curative effect, and the traditional Chinese medicine has obvious advantages. The monarch, minister, assistant and guide is the principle of the traditional Chinese medicine, and is stated in the yellow emperor internal classic (plain questions, essential essentials and university treatises): the principal drug is the monarch drug, the assistant drug is the minister drug, and the assistant drug is the guide drug. Two thousand years ago, our ancestors have treated based on the syndrome differentiation, and have been formulated according to the mutual restriction and synergistic action principles of different Chinese herbal medicines. The application can prepare the raw material medicines into free or amorphous medicines, and improve the bioavailability. The monarch, minister, assistant and guide compatibility principle of the traditional Chinese medicine is used for preparing the prescription, different medicines or auxiliary materials are fused with the medicines and are included to form micelle, microemulsion or liposome, the solubility is improved, and a plurality of medicines are mutually restricted and have synergistic effect, so that the curative effect is improved. Free medicine is administrated through mucous membrane and skin, and has no gastrointestinal and liver first-pass effects of oral medicine, gastrointestinal adverse reaction is avoided, liver damage is avoided, and toxic and side effects are greatly reduced. Promoting human body immune balance, enhancing disease resistance, and combining western medicine with traditional Chinese medicine is better.

Disclosure of Invention

The invention breaks through the technical bottleneck of the production of the mucosal skin drug delivery preparation by the following technical scheme.

The production method of the free drug mucosal skin drug delivery preparation comprises the steps of preparing free or amorphous drugs, preventing the free or amorphous drugs from crystal return, and producing drugs, and is characterized in that: preparing free or amorphous drug, namely mixing and melting the microcrystalline or crystalline drug and the fluxing and shearing agent for 0.2-2 minutes above the free temperature of the drug, and shearing the mixture into free drug mixed solution; the medicine for preventing the free or amorphous state medicine from returning to the crystal is the medicine which is easily dissolved in water or organic solvent, and the auxiliary material is fused with the free or amorphous state medicine, included, formed into micelle, suspension, microemulsion or liposome, and the unstable free or amorphous state medicine is prevented from returning to the stable crystal state medicine.

1. Preparing the free or amorphous drug: 1) mixing and melting water, ethanol and an acid-base salt solution indissolvable microcrystalline or crystalline drug and a fluxing and shearing agent, stopping heating for 0.2-3 minutes when the temperature exceeds the free temperature of the drug, shearing the drug crystals with ordered molecular arrangement into a mixed solution of disordered free drugs, and carrying out crystalline drug → free drug at 80-200 ℃; the fluxing and shearing agent comprises at least two raw materials of water-soluble cellulose or food gum, sugar, surfactant, vitamin, fatty acid, starch, phytosterol and polyalcohol; the mass ratio of the medicine to the fluxing and shearing agent is 1: 0.4-10; 2) the microcrystalline or crystalline drug is dissolved into free or amorphous drug in purified water, aqueous solution or organic solvent at 50-100 ℃.

2. The medicine which is easily dissolved in water or organic solvent, the auxiliary material and the free or amorphous medicine are fused to form micelle, suspension, microemulsion or liposome, and the unstable free or amorphous medicine is prevented from being re-crystallized to form stable crystalline medicine: 1) adding powder medicine or auxiliary materials with the mass being 0.5-10 times of that of the medicine into free medicine mixed liquid at the temperature of 80-195 ℃, uniformly stirring, cooling to 40-70 ℃, coarsely crushing by 20-40 meshes, cooling and hardening crushed particles, and then crushing by a sieve with more than 60 meshes; 2) mixing the free drug mixed solution at 90-150 ℃, the drug aqueous solution at 80-100 ℃, the auxiliary material aqueous solution and the cyclodextrin aqueous solution, stirring or homogenizing, emulsifying, cooling to 55-70 ℃, fusing the free drug for later use, and performing spray drying or freeze drying; 3) dissolving the free or amorphous drug in purified water, aqueous solution or organic solvent at 50-100 ℃, forming micelle, microemulsion or liposome with the mixed solution of the auxiliary material and the free drug, and performing spray drying or freeze drying for later use.

3. The monarch, minister, assistant and guide compatibility is a compatibility method of the traditional Chinese medicine prescription, more than two medicines interact with each other, the toxic and side effect is reduced, the drug resistance is avoided, and the curative effect is synergistically increased.

4. The production of free medicine mucocutaneous administration preparation is a production method of common medicine preparation, and the mucocutaneous administration preparation has various kinds, and can be made into various free or amorphous medicines according to different medicine preparations, and can be made into spray aerosol for respiratory tract administration, external solution for dermatosis administration, lotion, liniment, ointment, cataplasm and patch, eye and nose drops for mucosis administration, gargle, sublingual buccal tablet, nasal suppository, film agent, gynecological suppository, spray, ointment, cream, gel and transdermal patch.

Detailed Description

EXAMPLE A method for producing a free drug inhalant

The inhalant directly administrated by lung and respiratory tract, including aerosol, spray, powder spray, aerosol, etc., has quick action, and has the advantages that the inhalant can not be replaced by other dosage forms, such as tablet, injection, etc. The inhalation preparation is used for preventing and treating diseases of respiratory tract, avoiding gastrointestinal adverse reaction and relieving hepatotoxicity, and has unique characteristics.

The production method of the free medicine inhalant comprises the steps of preparing free or amorphous medicines, preventing the free or amorphous medicines from crystal return, combining monarch, minister, assistant and guide medicines and producing the inhalant, and is characterized in that: preparing free or amorphous drug, namely mixing and melting the microcrystalline or crystalline drug and the fluxing and shearing agent for 0.2-2 minutes above the free temperature of the drug, and shearing the mixture into free drug mixed solution; the medicine and the auxiliary material which are easily dissolved in water or an organic solvent are fused with the free or amorphous medicine to form micro emulsion or liposome, so that the unstable free or amorphous medicine is prevented from returning to the stable crystalline medicine.

1. Preparing the free or amorphous drug: 1) mixing and melting water, ethanol and an acid-base salt solution indissolvable microcrystalline or crystalline drug and a fluxing and shearing agent, stopping heating for 0.2-3 minutes when the temperature exceeds the free temperature of the drug, shearing the drug crystals with ordered molecular arrangement into a mixed solution of disordered free drugs, and carrying out crystalline drug → free drug at 90-190 ℃; the fluxing and shearing agent comprises at least two raw materials of fatty acid, surfactant, vitamin and polyalcohol; the mass ratio of the medicine to the fluxing and shearing agent is 1: 0.4-10; 2) the microcrystalline or crystalline drug is dissolved in purified water, aqueous solution or organic solvent at 50-100 ℃ to be free or amorphous drug.

2. The medicine and the auxiliary materials which are easily dissolved in water or organic solvent are fused with the free or amorphous medicine to form suspension, microemulsion or liposome, so that the unstable free or amorphous medicine is prevented from returning to the stable crystalline medicine: 1) adding powder medicine or auxiliary materials with the mass being 0.5-10 times of that of the medicine into free medicine mixed liquid at the temperature of 80-195 ℃, uniformly stirring, cooling to 40-70 ℃, coarsely crushing by 20-40 meshes, cooling and hardening crushed particles, and then crushing by a sieve with more than 60 meshes; 2) mixing the free drug mixed solution at 90-150 ℃, the drug aqueous solution at 80-100 ℃, the auxiliary material aqueous solution and the cyclodextrin aqueous solution, stirring or homogenizing and emulsifying, cooling to 50-70 ℃, and fusing the free drug for later use; 3) dissolving the drug in a free or amorphous state in purified water, aqueous solution or organic solvent at 50-100 ℃, forming a microemulsion or liposome with the auxiliary material and the free drug mixed solution, and performing spray drying or freeze drying for later use.

3. The monarch, minister, assistant and guide compatibility is a compatibility method of the traditional Chinese medicine prescription, more than two medicines interact with each other, the toxic and side effect is reduced, the drug resistance is avoided, and the curative effect of the medicines is synergistically increased.

4. The inhalant is produced by a production method of a common inhalant, has various inhalant types, selects different raw materials, processing equipment and production methods according to different inhalants, and produces inhalants for respiratory tract administration by using various free or amorphous medicines in monarch, minister, assistant and guide compatibility, including aerosol, spray, powder spray, aerosol and the like. Take inhalant of monarch drug sialic acid and heparin sodium as an example.

Method for producing free medicine virus-removing inhalant

1. The formula of the inhalant (all medical grade medicine raw materials purchased in the market) is as follows: sialic acid, heparin sodium, polyinosinic acid, hesperidin, copper gluconate, L-arginine, galactose, phytosterol, vitamin E, modified soybean lecithin powder, glycerol, glycyrrhizic acid, edible essence, normal saline and purified water.

2. The prescription notes are that 1) monarch drugs: sialic acid, the scientific name of which is N-acetylneuraminic acid, is a natural carbohydrate compound widely existing in animals, commercial sialic acid is a new food raw material, and the consumption is less than or equal to 500 mg/day; the virus spikes are combined with sialic acid on the surface of animal cells to invade the cells; sialic acid in the preparation can be easily combined with virus spike to capture virus, so that coronavirus, influenza virus, etc. can not invade human body cells; secondly, heparin sodium is a natural anticoagulant substance in an animal body, and the commercial heparin sodium is used for preventing and treating thrombosis or embolic diseases and is injected with 15000-20000 units (160 mg of 120-; the heparin sodium can be tightly combined with spike proteins on the surfaces of various viruses such as new coronavirus, cold virus and the like, so that the viruses are prevented from infecting a human body. 2) Ministerial drugs: poly-inosinic acid is an artificially synthesized nucleotide dimer and high-efficiency interferon inducer, inhibits the replication of infected viruses, and can strengthen the cell activity and improve the immune function of organisms; secondly, the hesperidin can be combined with S protein of the coronavirus spike to effectively prevent the coronavirus from invading the human body; the hesperidin has definite functions of biological activities such as oxidation resistance, antibiosis, antiphlogosis, antivirus and the like, is used for treating respiratory tract infection, has no side effect, and can not generate drug resistance; ③ the copper gluconate is a health-care product, and the oral administration is 0.5 to 1.5mg per day, and the intravenous drip is 1 to 2mg each time; research data show that copper gluconate can inhibit the activity of the PLpro protein of the novel coronavirus; the carrageenin is a food gelling agent, a suspending agent, an emulsifying agent, a stabilizing agent and the like, also has the activities of anticoagulation, blood fat reduction, immunoregulation, gastric ulcer resistance, rheumatoid arthritis resistance and the like, and particularly can inhibit coronavirus and rhinovirus from entering body cells; a few viruses leaking out of the net are removed by the cooperation of poly-sarcosine, hesperidin, copper gluconate and carrageenan. 3) The adjuvant plant sterol and the vitamin E have synergistic antioxidant and antiviral effects, and the phospholipid is an amphoteric surfactant and has emulsifying property and antiviral function; 4) the L-arginine aqueous solution is a hesperidin solvent, can also form sialic acid glycoprotein with galactose and sialic acid, and enhances the virus capturing capacity, and the galactose is a fluxing shearing agent of phytosterol, and is fused with the phytosterol, phospholipid, glycerol and monarch, minister, assistant and guide medicaments, and is included to form micelle, suspension, microemulsion or liposome, so that the function of mucous membrane of respiratory system is maintained. The monarch, minister, assistant and guide medicines can synergistically eliminate viruses, resist bacteria and diminish inflammation and promote human body immune balance.

3. Production process of inhalation powder spray for clearing virus

1) Preparation of free or amorphous drug

a. Dissolving 50g of sialic acid in 700ml of physiological saline at 70-80 ℃, and adjusting the pH value to about 7 by using 10% L-arginine aqueous solution to prepare free sialic acid solution.

b. 50g of heparin sodium is taken and dissolved in 2300ml of physiological saline with the temperature of about 45 ℃ to obtain a free heparin sodium solution.

c. 5g of polyinosinic acid is put into 500ml of normal saline and stirred for 30min at about 45 ℃ to obtain a free polyinosinic acid solution.

d. 1500ml of 8% arginine solution prepared by purified water, ultrasonic deoxidation at 40-50 ℃, addition of 100g of hesperidin (content of 85%), complete dissolution, adjustment of pH value to 7.5-8.1, filtration by a 0.22 mu m filter membrane (filter) and preparation of free or amorphous hesperidin solution.

e. Mixing vitamin E50g, phytosterol 50g and galactose 200g, stirring and heating. Melting completely at about 175 ℃, stopping heating when the temperature rises to about 180-185 ℃ for 15 seconds, and keeping the temperature at 130-150 ℃ to obtain the free phytosterol mixed solution.

f. Adding modified soybean phospholipid powder 150g into purified water 3000ml and glycerol 150g, stirring and heating, and completely dispersing and dissolving at about 80 deg.C to obtain phospholipid glycerol water solution.

g. Adding 80% glycyrrhizic acid 25g into 200ml purified water, stirring, heating, completely dissolving at 90 deg.C, and filtering with 0.22 μm filter membrane (filter) to obtain glycyrrhizic acid solution.

h. 4g of copper gluconate was dissolved in 120ml of purified water at 80 ℃ to prepare a free copper gluconate solution.

i. 100g of carrageenan is put into 1400ml of purified water, stirred and heated to about 85 ℃, and after complete dissolution, the carrageenan is filtered by a 0.5 mu m filter membrane to prepare a carrageenan solution.

2) Preventing the free or amorphous drug from returning to the crystal, preparing the monarch, minister, assistant and guide drugs and producing the original drug.

Mixing and stirring a free copper gluconate solution, a free sialic acid solution, a glycyrrhizin solution and a carrageenan solution, heating to about 95 ℃, spraying or sprinkling a free phytosterol mixed solution at about 140 ℃, stirring, homogenizing and emulsifying for 20-30 min, naturally cooling to about 85 ℃, adding a phosphatide glycerol aqueous solution at about 80 ℃, stirring, homogenizing and emulsifying. Adding a free or amorphous hesperidin solution, a free heparin sodium solution, a free polyinosinic acid solution and 10ml of liquid apple essence respectively at about 50 ℃, stirring, homogenizing, adjusting the pH value to 6.9-7.2, homogenizing, filtering by using a filter membrane (filter) with the diameter of 0.22 mu m, and then fixing the volume to 10L to prepare the original liquid medicine (stock solution for short) of the free medicine inhalant for removing viruses.

3) Production of powder spray for removing virus

In the production of the powder inhalation, magnesium stearate particles with the particle size of 6-20 mu m are added to play a flow aiding role in the micro powder medicine.

a. Powder inhalation for preventing and treating upper respiratory diseases. 3, mixing 10L of the original inhalant solution for removing the virus of the free medicine and 1L of mannitol solution (230 g of mannitol is dissolved in purified water completely at about 60 ℃, the volume is determined to be 1L), stirring and homogenizing, adjusting the pH value to 6.9-7.2, filtering by using a filter membrane (filter) with the diameter of 0.22 mu m, spray drying, mixing 1440g of obtained powder and 60g of particle magnesium stearate, stirring uniformly, sterilizing, and packaging in a multi-dose dry powder inhalation device, such as a capsule, a vesicle and the like, adopting a special dry powder inhalation device, actively inhaling by a patient, wherein the particles of the atomized medicine are 4-15 mu m, mainly deposited in an upper respiratory tract (nasal cavity, oral cavity, throat and trachea), and are administrated for 200-300 mg for 1-2 times a day. Can be used for preventing and treating upper respiratory diseases such as rhinitis, pharyngolaryngitis, tonsillitis, tracheitis, asthma, and oral ulcer. It can also be used for preventing influenza, common cold, and new coronavirus.

b. Powder inhalation for preventing and treating lung diseases. 3, 10L of the original solution of the inhalant for removing the virus from the produced free drug is spray-dried and micronized (0.5-6 μm) by using a jet mill, and 1240g of powder aerosol is obtained. Mannitol is micronized (5-10 μm). 1240g of the micropowder medicament, 200g of the micropowder mannitol and 60g of the particle magnesium stearate are mixed, evenly stirred, sterilized and packaged in a multi-dose dry powder inhalation device, such as a capsule, a vesicle and the like, and the atomized medicament is inhaled into the lung by adopting a special dry powder inhalation device, wherein 200mg of the atomized medicament is administrated each time. Can be used for adjuvant treatment of pulmonary diseases such as pulmonary tuberculosis, pulmonary carcinoma, neocoronary pneumonia, and pulmonary fibrosis.

The main medicine content of each gram of the powder inhalation is as follows: sialic acid 33mg, heparin sodium 33mg, polyinosinic acid 3.3mg, hesperidin 57mg, and copper gluconate 2.7 mg. The medicinal particles with the particle size of 2-5 mu m in the powder inhalation can deposit in the lung to treat lung diseases, new coronary pneumonia, pulmonary fibrosis and the like, and the particles of mannitol and magnesium stearate with the particle size of more than 5 mu m deposit in the upper respiratory tract and have no negative effect on the lung.

4. Process for producing virus-removing inhalant aerosol or spray

1) Preparation of free or amorphous drug

a. 80g of sialic acid is dissolved in 900ml of physiological saline with the temperature of 70-85 ℃, and the pH value is adjusted to about 7 by using 10% L-arginine aqueous solution to prepare free sialic acid solution.

b. 80g of heparin sodium is taken and dissolved in 2400ml of physiological saline with the temperature of about 50 ℃ to obtain a free heparin sodium solution.

c. 10g of poly-inosinic acid is put into 400ml of normal saline and stirred for 30min at about 50 ℃ to obtain free poly-inosinic acid solution.

h. 10g of copper gluconate was dissolved in 120ml of purified water at 80 ℃ to prepare a free copper gluconate solution.

i. 100g of carrageenan is put into 1500ml of purified water, stirred and heated to about 85 ℃, and after complete dissolution, the carrageenan is filtered by a 0.5 mu m filter membrane to prepare a carrageenan solution.

j. Adding 10g of salicylic acid into 100ml of 10% arginine solution, stirring and heating to about 85 ℃, and completely dissolving to prepare a free salicylic acid solution.

Mixing and stirring a free copper gluconate solution, a free sialic acid solution, a glycyrrhizic acid solution and a carrageenan solution, heating to about 95 ℃, spraying or sprinkling a free phytosterol mixed solution at about 140 ℃, stirring, homogenizing and emulsifying for 20-30 min, naturally cooling to about 85 ℃, adding a phosphatide glycerol aqueous solution at about 80 ℃, stirring and homogenizing. Respectively adding a free or amorphous hesperidin solution, a free heparin sodium solution, a free polyinosinic acid solution, a salicylic acid solution and 10ml of liquid apple essence at about 50 ℃, stirring, homogenizing, adjusting the pH value to 6.9-7.2, homogenizing, filtering by using a filter membrane (filter) with the diameter of 0.22 mu m, and fixing the volume to 10L to prepare the original medicine aerosol or spray (stock solution for short) of the free medicine for removing the virus.

Main drug content per ml aerosol or spray: sialic acid 8mg, heparin sodium 8mg, polyinosinic acid 1mg, hesperidin 8.5mg, and copper gluconate 1 mg.

3) Aerosol production

Sterilizing the stock solution of the aerosol or the spraying agent, filling the stock solution into a pressure-resistant bottle, inserting a valve into the pressure-resistant bottle, sealing the valve, and filling the HFA-134a propellant to obtain the aerosol for removing the virus from the free drug. Spraying for 1 time a day under 2-4 times (0.2-0.4 ml). The main medicine content is as follows: 1.6-3.2 mg of sialic acid, 1.6-3.2 mg of heparin sodium, 0.2-0.4 mg of polyinosinic acid, 1.7-3.4 mg of hesperidin and 0.2-0.4 mg of copper gluconate.

4) Spray production process

Sterilizing the stock solution of the aerosol or the spraying agent, and quantitatively filling into a spray bottle (10 ml/bottle) to obtain the free medicine virus-removing spraying agent. Spraying 2-3 times (0.2-0.5 ml) each time 1-2 times a day. The content of main medicines each time is as follows: 1.6-4.0 mg of sialic acid, 1.6-4.0 mg of heparin sodium, 0.2-0.5 mg of polyinosinic acid, 1.7-4.2 mg of hesperidin and 0.2-0.5 mg of copper gluconate.

The free drug virus-removing inhalant can form fog particles with the particle size of 1-5 mu m through a spraying device, an aerial fog device and an atomizing device, 60 percent of the free drug virus-removing inhalant can reach the lung and be deposited in alveolus, and the free drug virus-removing inhalant with the particle size of more than 6 mu m is mainly deposited in the nasal cavity and the upper respiratory tract. The medicine fog particles enter respiratory mucosa, can capture and eliminate virus, and prevent and treat early virus infection. The medicine is especially suitable for people who have positive detection but do not have symptoms, people who have been contacted with an infected person or have the same vehicle, the same machine and the same room to prevent respiratory system viral diseases, such as diseases caused by influenza virus, Ebola virus, coronavirus, novel coronavirus, rhinovirus and the like.

The same principle or method is used with Ridesivir, ribavirin, oseltamivir, interferon-alpha, lopinavir/ritonavir, chloroquine, Abriduo, darunavir, amantadine, rimantadine, enfuvirdine, Malavirus, acyclovir, ganciclovir, valacyclovir, famciclovir, foscarnet, lamivudine, zidovudine, emtricitabine, tenofovir, adefovir, saquinavir, ritonavir, indinavir, neviravir, amprenavir, polyinosine, tillomycin, lentinan, green tea catechin, Astragalus polysaccharides, glycyrrhizin, ferulic acid, quercetin, rutin, epigallocatechin, baicalin, scutellarin, piceidin, nicotinamide, polydatin, polygonum cuspidatum, and other, 1-2 of the medicines such as the rhaponticin, the alkannin, the cyclosporine A and the like are monarch medicines, and other medicines and auxiliary materials are ministerial medicines and adjuvant medicines to produce various inhalants for removing free medicines or inhibiting viruses. For example, inhalants for removing new coronavirus with free drugs (aerosol, spray, powder spray, etc.), inhalants for removing influenza virus with free drugs, inhalants for removing cold virus with free drugs, inhalants for removing ebola virus with free drugs, inhalants for removing massa virus with free drugs, inhalants for removing SARS virus with free drugs, etc.

1-2 antituberculosis drugs such as isoniazid, rifampicin, pyrazinamide, sodium p-aminosalicylate, ethambutol, rifapentine, streptomycin, prothioconazole, isoniazid rifampicin or sodium p-aminosalicylate can also be used as monarch drugs for producing inhalants for treating pulmonary tuberculosis.

EXAMPLE two Process for the production of free rotigotine gel

Rotigotine is a dopamine agonist and is used for treating Parkinson's disease and restless legs syndrome, but the gastrointestinal and liver first pass effects are very obvious, the bioavailability is extremely low (< 1% -5%), and the rotigotine is not suitable for oral administration. Only rotigotine transdermal patches are available in the market at present, and the defects are many. The problem of extremely low bioavailability of rotigotine can be overcome by nasal administration of free rotigotine gel.

The production method of the free rotigotine gel comprises the steps of preparing the free rotigotine, preventing the free rotigotine from crystal reversion, combining monarch, minister, assistant and guide medicines and producing the free rotigotine gel, and is characterized in that: preparing free rotigotine, wherein the free rotigotine comprises microcrystalline or crystalline rotigotine and a fluxing and shearing agent which are mixed and melted, exceed the free temperature of the rotigotine for 0.2-2 minutes and are sheared into free rotigotine mixed liquor; the medicine and the auxiliary materials which are easily dissolved in water or an organic solvent are fused with the free rotigotine to form a microemulsion or liposome so as to prevent the unstable free rotigotine from returning to the stable crystalline rotigotine.

1. Preparation of free rotigotine: 1) mixing and melting rotigotine and a fluxing and shearing agent, stopping heating after the temperature exceeds the free temperature of rotigotine for 0.2-3 minutes, shearing rotigotine crystals with ordered molecular arrangement into a free rotigotine mixed solution with disordered molecules, and crystallizing rotigotine → free rotigotine at 90-190 ℃; the fluxing and shearing agent comprises at least two raw materials of phytosterol, surfactant, vitamin and sugar; the mass ratio of the rotigotine to the fluxing shearing agent is 1: 2-8; 2) the microcrystalline or crystalline drug is dissolved into free or amorphous drug in purified water, a dissolution assisting water solution or an organic solvent at 50-100 ℃.

2. The medicine and the auxiliary materials which are easily dissolved in water or organic solvent are fused with the free or amorphous medicine to form suspension, microemulsion or liposome, so that the unstable free or amorphous medicine is prevented from returning to the stable crystalline medicine: 1) adding powder medicine or auxiliary materials with the mass being 0.5-10 times of that of the medicine into free medicine mixed liquid at the temperature of 90-190 ℃, uniformly stirring, cooling to 40-70 ℃, coarsely crushing by 20-40 meshes, cooling and hardening crushed particles, and then crushing by a sieve with more than 60 meshes; 2) mixing the free drug mixed solution at 95-150 ℃, the drug aqueous solution at 80-100 ℃, the auxiliary material aqueous solution and the cyclodextrin aqueous solution, stirring or homogenizing, cooling to 55-70 ℃, fusing the free drug for later use, and performing spray drying or freeze drying; 3) dissolving the free or amorphous drug in purified water, aqueous solution or organic solvent at 50-100 ℃, forming micelle, microemulsion or liposome with the auxiliary material and the free drug mixed solution, and performing spray drying or freeze drying for later use.

4. The production of free rotigotine gel is a production method of common gel, and various free or amorphous medicines with monarch, minister, assistant and guide compatibility are used for producing the rotigotine gel for nasal administration.

Method for producing free rotigotine gel

1. The free rotigotine gel formula (all medical grade medicine raw materials purchased in the market) is as follows: rotigotine, sialic acid, galactose, phytosterol, vitamin E, taurine, modified soybean lecithin powder, glycerol, poloxamer 407, poloxamer 188, edible essence, -polylysine and purified water.

2. The prescription notes are that 1) monarch drugs: rotigotine, 6mg of drug is released every 24 hours by each patch of rotigotine transdermal patches currently on the market; 2) ministerial drugs: firstly, the sialic acid derivative monosialotetrahexosylganglioside sodium injection is used for treating Parkinson's disease, the first dose is 500-1000 mg, the injection is instilled into the vein, and 200mg is taken every day from day 2. Subcutaneous, intramuscular, or intravenous drip. It is generally used for 18 weeks; ② taurine can increase the synthesis and release of striatal dopamine; 3) adjuvant plant sterol and vitamin E are synergistically antioxidant, phospholipid is an amphoteric surfactant and has emulsifying property, and galactose, the plant sterol and the vitamin E are fluxing and shearing agents of rotigotine; 4) the poloxamer 407 and the poloxamer 188 form gel, the edible essence improves the smell, and the polylysine is a food additive, a natural preservative and a broad-spectrum bacteriostatic agent.

The free rotigotine is fused with the phytosterol, phospholipid, glycerol and monarch, minister, assistant and guide medicaments to form micelles, suspension, microemulsion or liposome, and then forms gel with poloxamer. The monarch, minister, assistant and guide medicines have synergistic effect and promote the metabolic balance of dopamine in human body.

3. Production process of free rotigotine gel

1) Preparation of free or amorphous drug

a. Dissolving 10g of sialic acid in 100ml of purified water at 70-85 ℃, and adjusting the pH value to about 6 to prepare a free sialic acid solution.

b. Dissolving 10g of taurine in 100ml of purified water with the temperature of 70-85 ℃ to obtain a free taurine solution.

c. Dissolving 15g of poloxamer 188 in 120ml of purified water at 70-85 ℃, and completely dissolving to obtain poloxamer 188 solution.

d. And dissolving 200g of poloxamer 407 in purified water at 3-4 ℃ to obtain a poloxamer 407 solution.

e. Taking 200ml of purified water and 10g of glycerol, adding 10g of modified soybean lecithin powder, stirring and heating, and completely dispersing and dissolving at about 80 ℃ to obtain a phospholipid glycerol aqueous solution.

f. Mixing vitamin E10g, phytosterol 10g, galactose 20g and rotigotine 10g, stirring and heating. And (3) completely melting at about 170 ℃, stopping heating after the temperature rises to about 180 ℃ for 15 seconds, and keeping the temperature at 120-140 ℃ to obtain the free rotigotine mixed solution.

g. 1g of polylysine was dissolved in 10ml of purified water to prepare a polylysine solution.

Mixing and stirring a free taurine acid solution, a free saliva acid solution, a phosphatide glycerol aqueous solution and a poloxamer 188 solution, heating to about 90 ℃, spraying or sprinkling a free rotigotine mixed solution at about 130 ℃, stirring, homogenizing and emulsifying for 20-30 min, naturally cooling to about 40 ℃, cooling to about 10 ℃, adding 1ml of liquid osmanthus essence and a polylysine solution, stirring and homogenizing, adding a poloxamer 407 solution, stirring, homogenizing, adjusting the pH value to about 6, fixing the volume to 1000ml, stirring and uniformly mixing, putting into a refrigerator at 4 ℃ for refrigerating for 24 hours, and completely swelling to obtain the free rotigotine thermo-sensitive gel solution.

3) Production of free rotigotine gel

The completely swollen gel solution was sterilized and filled in a fixed amount (10 ml/package). The gelling temperature is 32-34 ℃. The main medicine content is as follows: rotigotine 1mg/ml, sialic acid 1mg/ml, taurine 1mg/ml, gel is emulsion state at normal temperature, and is converted into gel at nasal cavity temperature, which is favorable for adhesion of preparation in nasal cavity, and has high bioavailability and good brain targeting property.

Replacing poloxamer 407 with other matrix to produce common gel, or adjusting matrix variety or proportion to produce rotigotine cream, ointment. Also can produce the free rotigotine sustained-release transdermal patch.

The same principle or method, the following drugs for treating neurodegenerative disease-related disorders (parkinson's disease, senile dementia, etc.): dangshen oligosaccharide, leonurine, piperine, coumarins, memantine hydrochloride, carbonphthalides, haematococcus pluvialis, ligusticum wallichii essential oil, zedoary turmeric essential oil, tsaoko amomum fruit essential oil, cedar essential oil, cardamom amomum fruit essential oil, fructus drynariae total flavonoids, ginsenoside, dimethyl phloroglucinol, Lanzhou lily polysaccharide, African tetrandrine, pentacyclic triterpenes, rose polysaccharide, phloroglucinol derivatives, tetradentate monoquinoline derivatives, diterpenes, arctigenin ethers, pramipexole, rasagiline, isoquinoline derivatives, trametinib, flavonoid glycoside dimer, trihexyphenidyl hydrochloride, butylphthalide-telmisartan combination, torasemide and baclofen combination, ferulic acid, rhein, metallofullerene, chicoric acid, fingolin, dihydrocoumarin, icariin, huperzine A, losartan, amantadine-A, gardenoamide A, 1-2 of levodopa, carbidopa, meglumine and other medicines are monarch medicines, and other medicines and auxiliary materials are ministerial medicines, so that various free medicine gels (temperature-sensitive gels or common gels), emulsifiable paste, cream, ointment, transdermal patches and the like are produced.

EXAMPLE III cream production method for mucosal skin administration of free drug

There are many kinds of creams, and niacinamide acne-removing cream is taken as an example.

1. The free nicotinamide acne-removing cream formula (all medical-grade medicine raw materials purchased in the market) is as follows: nicotinamide, salicylic acid, phytosterol, vitamin E, ursolic acid, modified soybean lecithin powder, glycerol, L-arginine, SG-40, monoglyceride and diglyceride, edible essence and purified water.

2. The prescription notes that 1) the whitening skin-care and acne-removing efficacy of the monarch drug nicotinamide is clear; 2) ministerial drugs: salicylic acid is used for treating skin-related diseases such as dandruff, comedo, blackhead, acne, blemish and the like, and is a broad-spectrum bacteriostatic agent; ② ursolic acid can remove color spots and freckles, and also has the functions of sterilization and anti-inflammation; 3) adjuvant plant sterol and vitamin E are synergistically antioxidant, phospholipid is an amphoteric surfactant and has emulsifying property, and SG-40, monoglyceride and vitamin E are fluxing and shearing agents of the plant sterol; 4) the water solution of the medicine L-arginine is cosolvent of salicylic acid and pH regulator, SG-40 and monoglyceride are emulsifier and surfactant, and the edible essence improves the smell.

3. Production process of free nicotinamide acne-removing cream

1) Preparation of free or amorphous drug

a. 40g of nicotinamide was dissolved in 130ml of purified water at 80 ℃ to give a solution of free nicotinamide.

b. Dissolving 12g of arginine in 100ml of purified water, adding 8g of salicylic acid, heating to 70-85 ℃, and completely dissolving the salicylic acid to prepare a free salicylic acid solution.

c. 15g of ursolic acid was dissolved in 80ml of purified water at 50 ℃ to obtain an aqueous ursolic acid solution.

d. Mixing purified water 200ml and glycerol 100G, adding modified soybean phospholipid powder 30G, stirring and heating, adding 100gSG-40 at 80 deg.C, and completely dissolving phospholipid and S-G40 to obtain phospholipid, SG-40, and glycerol aqueous solution.

e. Mixing vitamin E5 g, phytosterol 20g, monoglyceride 50gSG-40 g, and monoglyceride 40g, stirring, and heating. Melting completely at about 170 ℃, stopping heating when the temperature rises to about 185 ℃ for 15 seconds, and keeping the temperature at 120-140 ℃ to obtain the free phytosterol mixed solution.

Mixing and stirring a free nicotinamide solution, a free salicylic acid solution and a phospholipid SG-40 glycerol aqueous solution, heating to about 90 ℃, spraying or sprinkling a free phytosterol mixed solution at about 130 ℃, stirring, emulsifying and homogenizing for 20-30 min, naturally cooling to 50 ℃, adding 5ml of liquid osmanthus essence (or other essences) and an ursolic acid aqueous solution, stirring and homogenizing, adjusting the pH value to about 6.5 by using an arginine aqueous solution, fixing the volume to 1000ml, stirring and homogenizing, and cooling to obtain the free nicotinamide cream technical product.

3) Production of free nicotinamide cream

Sterilizing raw free nicotinamide cream, and quantitatively filling (15 g/bottle). The main medicine content is as follows: 40mg/ml of nicotinamide, 8mg/ml of salicylic acid and 15mg/ml of ursolic acid.

Free nicotinamide, salicylic acid, ursolic acid, phytosterol, phospholipid, glycerin, SG-40 and monoglyceride are fused to form a suspension, a microemulsion or a liposome cream, and the monarch, minister, assistant and guide medicaments have a synergistic effect, promote smooth sebum excretion, balance human skin metabolism, effectively remove acnes, have small irritation and repair acne marks on the skin.

By the same principle or method, instead of SG-40, Vaseline as matrix, etc. is used to reduce water consumption, and free nicotinamide cream or ointment is produced. Can be used for preparing cream, ointment or cream for treating dermatoses such as vitiligo, psoriasis, acne, dermatitis, eczema, allergy, psoriasis, urticaria, allergic dermatitis, seborrheic dermatitis, pruritus, lupus erythematosus, neurodermatitis, and pustule of palms and soles, and mosquito bite, insect bite, bee bite, and ant bite.

Applying the principles and methods of the above-described embodiments, antineoplastic agents such as alkylating antineoplastic agents, e.g., cyclophosphamide, thiotepa, semustine, mechlorethamine hydrochloride, busulfan, chlorambucil, carmustine, altretamine, lomustine, melphalan, nitrakastine, ifosfamide, and dibromomannitol; antimetabolite antineoplastic agents such as cytarabine, fluorouracil, methotrexate, hydroxyurea, tegafur, methylisoindigo and mercaptopurine; antibiotic antineoplastic agents such as actinomycin D, mitomycin, doxorubicin hydrochloride, pingyangmycin hydrochloride, epirubicin hydrochloride, pirarubicin hydrochloride and daunorubicin hydrochloride; antineoplastic agents of natural origin such as homoharringtonine, vincristine sulfate, hydroxycamptothecin, etoposide, vindesine sulfate, vinblastine sulfate, vinorelbine bitartrate, paclitaxel, vinblastine, transfer factor, vinorelbine, docetaxel, zedoary turmeric oil, panaxan, colchicine, 9-aminocamptothecin, 7-ethylcamptothecin, epipodophyllotoxin, scorpion venom, turmeric, ligustrazine, matrine, pachyman, achyranthes bidentata polysaccharides, salvia miltiorrhiza, zedoary, podophyllum, ganoderan, icariin, tanshinone, rhein, allicin, ginsenoside, sophora flavescens, bear gall, elemene, saikoside and tea polyphenols; hormonal antineoplastics such as aminoglutethimide, tamoxifen, flutamide, gonadorelin, leuprorelin, letrozole and estramustine; hormonal antineoplastics such as aminoglutethimide, tamoxifen, flutamide, gonadorelin, leuprorelin, letrozole and estramustine; bioengineering recombinant antitumor drugs such as rituximab, tumor necrosis factor, interferon, interleukin and Gardner antitumor vaccine; antineoplastic active ingredients such as vincristine, colchicines, paclitaxel, camptothecin, hydroxycamptothecin, etoposide, interferon alpha, interferon gamma and cisplatin; the anticancer new medicine carboplatin, 5-fluorouracil (5-FU), docetaxel, hydroxyurea, methotrexate, bleomycin, capecitabine, cetuximab, nivalepotriol, ewolimumab, nimotuzumab, tyrosine kinase inhibitor, etc. 1-2 of the medicines are monarch medicines, other medicines and auxiliary materials are ministerial and adjuvant medicines to produce various free medicine anti-cancer inhalants (aerosol, atomizing agent, spraying agent, powder spraying agent and the like), anti-cancer gels (temperature-sensitive gels, common gels and the like), anti-cancer creams, anti-cancer ointments and the like. Such as aerosol, spray and powder for treating lung cancer, oral and oropharyngeal cancer, nasal cancer, tongue cancer, etc., and cream, ointment, gel (common gel and temperature-sensitive gel) for treating oral cancer, nasal cancer, tongue cancer, etc., or cervical cancer, rectal cancer, skin cancer, etc.

The above description is only a partial embodiment of the production of the free drug mucocutaneous administration preparation. The mucosal skin drug delivery preparation has various types and different production methods. Within the scope of the principle of the present invention, there are also several kinds of free drug mucocutaneous drug delivery preparation production methods, and these methods should be regarded as the protection scope of the present invention.

Claims

1. The production method of the free drug mucosal skin drug delivery preparation comprises the steps of preparing free or amorphous drugs, preventing the free or amorphous drugs from crystal return, combining monarch, minister, assistant and guide medicines and producing the drug preparation, and is characterized in that: preparing free or amorphous drug, namely mixing and melting the microcrystalline or crystalline drug and the fluxing and shearing agent for 0.2-2 minutes above the free temperature of the drug, and shearing the mixture into free drug mixed solution; the medicine for preventing the free or amorphous state medicine from returning to the crystal is the medicine which is easily dissolved in water or organic solvent, and the auxiliary material is fused with the free or amorphous state medicine, included, formed into micelle, suspension, microemulsion or liposome, and the unstable free or amorphous state medicine is prevented from returning to the stable crystal state medicine.

2. The production method of the free drug mucocutaneous administration preparation according to claim 1 is characterized in that the free or amorphous drug is prepared: 1) mixing and melting water, ethanol and an acid-base salt solution indissolvable microcrystalline or crystalline drug and a fluxing and shearing agent, stopping heating for 0.2-3 minutes when the temperature exceeds the free temperature of the drug, shearing the drug crystals with ordered molecular arrangement into a mixed solution of disordered free drugs, and carrying out crystalline drug → free drug at 80-200 ℃; the fluxing and shearing agent comprises at least two raw materials of water-soluble cellulose or food gum, sugar, surfactant, vitamin, fatty acid, starch, phytosterol and polyalcohol; the mass ratio of the medicine to the fluxing and shearing agent is 1: 0.4-10; 2) the microcrystalline or crystalline drug is dissolved into free or amorphous drug in purified water, aqueous solution or organic solvent at 50-100 ℃.

3. The method for producing the free drug mucocutaneous administration preparation according to claim 1, characterized in that the free or amorphous drug recrystallization prevention agent is a drug which is easily soluble in water or organic solvents, and an excipient is fused with the free or amorphous drug to form micelles, suspensions, microemulsions or liposomes, and the unstable free or amorphous drug is prevented from being recrystallized into a stable crystalline drug: 1) adding powder medicine or auxiliary materials with the mass being 0.5-10 times of that of the medicine into free medicine mixed liquid at the temperature of 80-195 ℃, uniformly stirring, cooling to 40-70 ℃, coarsely crushing by 20-40 meshes, cooling and hardening crushed particles, and then crushing by a sieve with more than 60 meshes; 2) mixing the free drug mixed solution at 90-150 ℃, the drug aqueous solution at 80-100 ℃, the auxiliary material aqueous solution and the cyclodextrin aqueous solution, stirring or homogenizing, emulsifying, cooling to 55-70 ℃, fusing the free drug for later use, and performing spray drying or freeze drying; 3) dissolving the free or amorphous drug in purified water, aqueous solution or organic solvent at 50-100 ℃, forming micelle, microemulsion or liposome with the mixed solution of the auxiliary material and the free drug, and performing spray drying or freeze drying for later use.

4. The production method of the free drug mucocutaneous drug delivery preparation according to claim 1, characterized in that the monarch, minister, assistant and guide compatibility is a compatibility method of a traditional Chinese medicine prescription, more than two drugs interact with each other, the toxic and side effect is reduced, and the curative effect is synergistically enhanced.

5. The production method of the free drug mucosal skin drug delivery preparation according to claim 1, which is characterized in that the production method of the free drug mucosal skin drug delivery preparation is a common preparation production method, different raw materials, processing equipment and production methods are selected according to different mucosal skin drug delivery preparations, and a plurality of free or amorphous drugs with monarch, minister, assistant and guide compatibility are used for producing the mucosal skin drug delivery preparation, including patches, sprays and sublingual tablets for oral diseases; nasal gel, microsphere, liposome, and spray for treating nasal diseases; ear drops, ear washes, sprays, ointments, creams, gels, earplugs, ear pills; aerosols, nebulisers, sprays of diseases of the respiratory system; ophthalmic gels, eye drops, liposomes, microparticles, implants; gel suppository, hollow suppository, osmotic pump suppository, microcapsule double-layer suppository and enema for treating rectal and perianal diseases; film, suppository, tablet, effervescent tablet, gel and intrauterine drug delivery system for treating vaginal and uterine diseases, spray, ointment, cream, gel and transdermal patch for treating dermatoses or skin care products.