Minocycline hydrochloride foam

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically relates to a minocycline hydrochloride foam. The minocycline hydrochloride foam comprises a liquid medicine and a propellant; the mass ratio of the liquid medicine to the propellant is 100:8-10; the liquid medicine, by mass percentage, comprises: 3-5% minocycline hydrochloride, 60-70% hydrophobic solvent, 6-8% modified silicone oil, 4-6% fatty alcohol, 3-5% glycolipid, 2-4% modified bovine polysaccharide, and natural wax supplements the remainder to 100%. The minocycline hydrochloride foam of the present invention has good foam performance, foam stability, stability of related substances and permeability.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a minocycline hydrochloride foam. Background Art

[0002] Foams have the advantages of good spreadability, low viscosity and easy application, and have been increasingly used in medicine in recent years. Minocycline hydrochloride is a broad-spectrum tetracycline antibiotic that is widely used to treat a variety of bacterial infections, including skin infections, respiratory infections, and urinary tract infections. In recent years, with the continuous development of local drug delivery systems, minocycline hydrochloride foams, as a new form of local drug delivery, have received increasing attention due to their ease of use, controllable drug release, and high patient compliance.

[0003] In the prior art, a Chinese patent with the authorization publication number of CN115463091B discloses a minocycline foam with improved stability, comprising the following raw materials and auxiliary materials by weight: 2.5-5.0 parts of fine powder of minocycline and / or minocycline derivatives, 60-80 parts of hydrophobic oil, 3-7 parts of silicone solvents, 5-10 parts of fatty alcohols, 2-4 parts of fatty acids, 3-5 parts of waxes, 2-3 parts of disaccharides and / or monosaccharides, 0.5-0.7 parts of alginic acid, and 5-10 parts of propellants; the minocycline fine powder accounts for 2.5-5.0wt% of the foam. The minocycline foam prepared by this technical solution does not use water and surfactants, has good stability, and ensures the therapeutic effect, but the substrate with good permeability claimed by the technical solution is a silicone rubber film, which has a large difference from human skin and its permeability needs to be improved; and no attention is paid to its stability under lighting conditions and long-term storage conditions. Summary of the invention

[0004] In view of the above problems, the present invention provides a minocycline hydrochloride foam. The minocycline hydrochloride foam of the present invention has good foam performance, foam stability, stability of related substances and permeability.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0006] The invention provides a minocycline hydrochloride foam, comprising a medicine liquid and a propellant; the mass ratio of the medicine liquid to the propellant is 100:8-10; the medicine liquid, in terms of mass percentage, comprises raw materials of: 3-5% minocycline hydrochloride, 60-70% hydrophobic solvent, 6-8% modified silicone oil, 4-6% fatty alcohol, 3-5% glycolipid, 2-4% modified strychnine polysaccharide, and the balance of natural wax is supplemented to 100%.

[0007] In some preferred embodiments, the hydrophobic solvent is a mixture of isopropyl myristate, olive oil and rosemary essential oil; the mass ratio of isopropyl myristate, olive oil and rosemary essential oil is 12-15:18-22:4-8.

[0008] Preferably, the mass ratio of isopropyl myristate, olive oil and rosemary essential oil is 14:20:6.

[0009] In a preferred embodiment, the modified silicone oil is fatty acid-modified epoxy silicone oil; the fatty acid-modified epoxy silicone oil is prepared by the following method: epoxy silicone oil and fatty acid are reacted at 120-140° C. for 2-4 hours.

[0010] In some preferred embodiments, the mass ratio of the epoxy silicone oil to the fatty acid is 1-2:1.

[0011] In some preferred embodiments, the epoxy silicone oil is an epoxy-terminated silicone oil, the molecular weight of the epoxy-terminated silicone oil is 8000-9000, and the epoxy value is 0.2-0.27 mol / 100g.

[0012] Preferably, the molecular weight of the epoxy-terminated silicone oil is 8000, and the epoxy value is 0.26±0.01 mol / 100g.

[0013] In some preferred embodiments, the fatty acid includes lauric acid and palmitic acid; the mass ratio of lauric acid to palmitic acid is 1-3:1-3.

[0014] In some preferred embodiments, the fatty alcohol is selected from one or more combinations of lauryl alcohol, tetradecanol, cetyl alcohol, stearyl alcohol, arachidyl alcohol, docosanol, tetracosanol, hexacosanol, octacosanol, triacontanol, and tetratriacontanol.

[0015] Preferably, the fatty alcohol is a combination of lauryl alcohol and eicosanol, and the mass ratio of lauryl alcohol to eicosanol is 1-2:1-2.

[0016] In some preferred embodiments, the glycolipids include rhamnolipid and trehalolipid.

[0017] Preferably, the mass ratio of the rhamnolipid to the trehalose lipid is 1-3:1-3, preferably, the mass ratio of the rhamnolipid to the trehalose lipid is 3:2.

[0018] In some preferred embodiments, the modified Eleutherodactyl polysaccharide is prepared by the following method: dissolving Eleutherodactyl polysaccharide, 2,2,6,6-tetramethylpiperidinyl oxide and sodium bromide in deionized water, adding sodium hypochlorite, and performing an oxidation reaction to obtain an oxidized polysaccharide; dissolving the oxidized polysaccharide and lysine in deionized water, and performing a Maillard reaction to obtain the modified Eleutherodactyl polysaccharide.

[0019] Eleutherodactyl polysaccharide has a certain emulsifying ability, but the inventors found that it could not improve the foam properties of minocycline hydrochloride foam. The inventors creatively modified Eleutherodactyl polysaccharide by first preparing it into an oxidized polysaccharide and then subjecting it to the Maillard reaction. It was unexpectedly found that not only the foam properties of minocycline hydrochloride foam were improved, but also the foam stability of minocycline hydrochloride foam was improved.

[0020] In some preferred embodiments, the mass ratio of the Eleutherodactyl polysaccharide, 2,2,6,6-tetramethylpiperidinoxide, sodium bromide, deionized water, sodium hypochlorite and ethanol is 5-7: 0.08-0.12: 0.5-0.55: 220-260: 28-32: 980.

[0021] In some preferred embodiments, the mass ratio of the oxidized polysaccharide, lysine and deionized water is 5-7:1-2:70-100.

[0022] In some preferred embodiments, the pH is adjusted to 10-11 using an alkaline solution before the oxidation reaction.

[0023] Preferably, the alkaline solution is a NaOH solution; preferably a NaOH solution with a concentration of 5 mol / L.

[0024] In some preferred embodiments, the oxidation reaction temperature is 2-6°C, and the oxidation reaction time is 1.0-1.2h.

[0025] In some preferred embodiments, ethanol is added after the oxidation reaction is completed, and the pH is adjusted to 7.0 using an acidic solution.

[0026] Preferably, the acidic solution is an HCl solution; preferably a 5 mol / L HCl solution.

[0027] In some preferred embodiments, potassium carbonate is used to adjust the pH to 9-10 before performing the Maillard reaction.

[0028] In some preferred embodiments, the temperature of the Maillard reaction is 82-87° C., and the time of the Maillard reaction is 8-12 h.

[0029] In some preferred embodiments, the natural wax is selected from one or more combinations of candelilla wax, carnauba wax, and castor wax, preferably candelilla wax.

[0030] In some preferred embodiments, the propellant is selected from tetrafluoroethane and / or heptafluoropropane.

[0031] Preferably, the propellant is tetrafluoroethane.

[0032] In some preferred embodiments, the preparation method of the minocycline hydrochloride foam comprises the following steps: mixing the liquid drug raw materials evenly, filling them into a medicinal aerosol can, capping them, and adding a propellant.

[0033] Preferably, the method for uniformly mixing the liquid medicine material is as follows: mixing the hydrophobic solvent, heating to 60-90° C., adding modified silicone oil, fatty alcohol, glycolipid, modified Eleutherococcus polysaccharide and natural wax under stirring to completely dissolve the materials; cooling to 20-30° C., adding minocycline hydrochloride under stirring, and stirring evenly.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] 1. The minocycline hydrochloride foam prepared by modifying the terminal epoxy silicone oil with lauric acid and palmitic acid not only improves the permeability of the minocycline hydrochloride foam, but also improves the foam stability and related substance stability of the minocycline hydrochloride foam.

[0036] 2. The present invention introduces rhamnolipid and trehalose lipid, which improves the foam properties of minocycline hydrochloride foam and also improves the stability of related substances of minocycline hydrochloride foam under light conditions.

[0037] 3. The inventors creatively modified the polysaccharide of Glehnia littoralis by first preparing it into an oxidized polysaccharide and then subjecting it to a Maillard reaction. They unexpectedly found that not only the foam properties of the minocycline hydrochloride foam were improved, but also the foam stability of the minocycline hydrochloride foam was improved.

[0038] 4. The glycolipid of the present invention and the modified spatholobi polysaccharide act together, so that the minocycline hydrochloride foam has good foam stability, related substance stability, good light stability and permeability under long-term storage conditions. DETAILED DESCRIPTION

[0039] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0040] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0041] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0042] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present invention description and examples are exemplary only.

[0043] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0044] In the following examples, unless otherwise specified, all raw materials used were commercially available or prepared by conventional methods in the art.

[0045] Preparation Example 1

[0046] The fatty acid-modified epoxy silicone oil is prepared by the following method: epoxy silicone oil and fatty acid are reacted at 130° C. for 3 hours in a mass ratio of 1.2:1.

[0047] The epoxy silicone oil is an epoxy-terminated silicone oil; the epoxy-terminated silicone oil has a molecular weight of 8000 and an epoxy value of 0.26±0.01 mol / 100 g, and is purchased from Xi'an Dongda Chemical Technology Co., Ltd.

[0048] The fatty acids include lauric acid and palmitic acid; the mass ratio of lauric acid to palmitic acid is 1:1.

[0049] Preparation Example 2

[0050] The modified schizonepeta polysaccharide is prepared by the following method: schizonepeta polysaccharide, 2,2,6,6-tetramethylpiperidinium oxide and sodium bromide are dissolved in deionized water, sodium hypochlorite is added (the mass ratio of schizonepeta polysaccharide, 2,2,6,6-tetramethylpiperidinium oxide, sodium bromide, deionized water, sodium hypochlorite and ethanol is 6:0.1:0.52:240:30:980), a 5 mol / L NaOH solution is used to adjust the pH to 10.5, an oxidation reaction is carried out at 4°C for 1.2 hours, ethanol is added, and a 5 mol / L HCl solution is used to adjust the pH to 7.0 to obtain oxidized polysaccharide; the oxidized polysaccharide and lysine are dissolved in deionized water (the mass ratio of oxidized polysaccharide, lysine and deionized water is 6:1.5:90), potassium carbonate is used to adjust the pH to 9.5, and a Maillard reaction is carried out at 85°C for 10 hours to obtain the modified schizonepeta polysaccharide.

[0051] Example 1-3 provides a minocycline hydrochloride foam, the prescription of which is shown in Table 1:

[0052] Table 1

[0053]

[0054] The preparation method of minocycline hydrochloride foam of Example 1-3 comprises the following steps: mixing a hydrophobic solvent, heating to 80°C, adding modified silicone oil, fatty alcohol, glycolipid, modified Eleutherococcus polysaccharide and natural wax under stirring to completely dissolve the materials; cooling to 25°C, adding minocycline under stirring, stirring evenly, filling into a medicinal aerosol can, capping, and charging with a propellant.

[0055] Comparative Example 1

[0056] A minocycline hydrochloride foam, the prescription is shown in Table 2:

[0057] Table 2

[0058]

[0059] Comparative Example 2

[0060] The difference from Example 2 is that rhamnolipid is replaced with trehalose lipid of equal mass, and the rest are the same.

[0061] Comparative Example 3

[0062] The difference from Example 2 is that trehalose lipid is replaced with soybean lecithin of equal mass, and the rest are the same.

[0063] Comparative Example 4

[0064] The difference from Example 2 is that the modified Eleutherococcus polysaccharide is replaced with Eleutherococcus polysaccharide of equal mass, and the rest is the same.

[0065] Comparative Example 5

[0066] The difference from Example 2 is that the modified safflower polysaccharide is replaced by modified dextran of the same mass, and the rest are the same. The preparation method of the modified dextran is the same as that of Preparation Example 2, and the only difference is that the safflower polysaccharide is replaced by dextran.

[0067] Comparative Example 6

[0068] The difference from Example 2 is that the modified Eleutherococcus polysaccharide is replaced by glycolipid of equal mass, and the rest are the same.

[0069] Comparative Example 7

[0070] The prior art authorization publication number of the Chinese patent is CN 115463091 B, and the technical solution of the best prescription 1-2 is shown in Table 3:

[0071] Table 3

[0072]

[0073] Experimental Example 1 Foam Properties

[0074] Collapse time: The collapse time as a measure of thermal stability was determined by dispersing a given amount of foam and photographing its appearance over time during incubation at 36°C, i.e. the time when the foam height reaches 50% of its initial height. The results are shown in Table 4.

[0075] Experimental Example 2 Foam Stability

[0076] 1. Room temperature experiment: shake the mixture after placing it at 25°C for 3 months and observe the foam state;

[0077] 2. High and low temperature experiment: Place at 30℃ for 24 hours, shake, observe the foam state, and then place at 6℃ for 24 hours, shake, and observe the foam state. This is one cycle. Continue to observe 20 cycles, and the results are shown in Table 4.

[0078] Table 4

[0079]

[0080] Experimental Example 3 Stability of related substances: Determined according to high performance liquid chromatography (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0081] 1. Light: 20℃, 4500LUX for 10 days;

[0082] 2. Long-term stability: 25°C; humidity: 75%, placed for 24 months, the results are shown in Table 5.

[0083] Table 5

[0084]

[0085] Experimental Example 3 In vitro transdermal test

[0086] The Franz diffusion cell was used to place the back skin of the Bama miniature pig between the receiving cell and the co-administering cell of the Franz diffusion cell. The receiving cell was a pH 7.4 phosphate buffer solution. The water bath temperature of the receiving cell was controlled to be 32±1°C. 0.1 g of the minocycline foam prepared in Examples 1-3 and Comparative Examples 1-7 was taken and evenly applied on the skin, with an application area of ​​1 cm 2 , 24 hours after administration; cut the skin into pieces and place it in the homogenization cup of the intelligent homogenizer. Use a pipette to transfer 40mL of pH7.4 phosphate buffer solution to the homogenization cup of the homogenizer for homogenization, 20000rpm / min, 1min, repeat 2 times. Take the homogenate in a 50mL centrifuge tube, centrifuge, 10000rpm / min, 5min, take the supernatant in a 5mL centrifuge tube, and test the cumulative permeability of minocycline for 24h. The results are shown in Table 6.

[0087] Table 6

[0088]

[0089] It can be seen from Tables 4-6 that the minocycline hydrochloride foam provided by Examples 1-3 of the present invention has good foam performance, foam stability, stability of related substances and permeability, and the stability of related substances and permeability are better than those of Comparative Example 7 of the prior art.

[0090] Since comparative example 1 does not use fatty acid to modify the epoxy silicone oil; comparative example 2 replaces rhamnolipid with trehalolipid of equal mass; comparative example 3 replaces trehalolipid with soy lecithin of equal mass; comparative example 4 replaces modified strychnosyltransferase with strychnosyltransferase of equal mass; comparative example 5 replaces modified strychnosyltransferase with modified dextran of equal mass; comparative example 6 replaces modified strychnosyltransferase with glycolipid of equal mass, the foam performance, foam stability, stability of related substances and permeability of the obtained minocycline hydrochloride foam are not as good as those of examples 1-3.

[0091] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A minocycline hydrochloride foam, characterized in that: Including liquid medicine and propellant; The mass ratio of the liquid medicine to the propellant is 100:8-10; The liquid medicine comprises, by mass percentage, 3-5% of minocycline hydrochloride, 60-70% of hydrophobic solvent, 6-8% of modified silicone oil, 4-6% of fatty alcohol, 3-5% of glycolipid, 2-4% of modified strychnine polysaccharide, and the balance of natural wax to 100%; The modified silicone oil is fatty acid-modified epoxy silicone oil; the fatty acid-modified epoxy silicone oil is prepared by the following method: epoxy silicone oil and fatty acid are reacted at 120-140° C. for 2-4 hours to obtain the obtained product; The epoxy silicone oil is an epoxy-terminated silicone oil, the molecular weight of the epoxy-terminated silicone oil is 8000-9000, and the epoxy value is 0.2-0.27 mol / 100g; The glycolipids include rhamnolipids and trehalose lipids; The modified safflower polysaccharide is prepared by the following method: dissolving safflower polysaccharide, 2,2,6,6-tetramethylpiperidinium oxide and sodium bromide in deionized water, adding sodium hypochlorite, and performing oxidation reaction to obtain oxidized polysaccharide; dissolving oxidized polysaccharide and lysine in deionized water, and performing Maillard reaction to obtain the modified safflower polysaccharide.

2. The minocycline hydrochloride foam according to claim 1, characterized in that The hydrophobic solvent is a mixture of isopropyl myristate, olive oil and rosemary essential oil; the mass ratio of isopropyl myristate, olive oil and rosemary essential oil is 12-15:18-22:2-6.

3. The minocycline hydrochloride foam according to claim 2, characterized in that The fatty acids include lauric acid and palmitic acid; the mass ratio of lauric acid to palmitic acid is 1-3:1-3.

4. The minocycline hydrochloride foam according to claim 3, characterized in that The temperature of the oxidation reaction is 2-6°C, and the time of the oxidation reaction is 1.0-1.2h.

5. The minocycline hydrochloride foam according to claim 4, characterized in that The temperature of the Maillard reaction is 82-87° C., and the time of the Maillard reaction is 8-12 hours.

6. The minocycline hydrochloride foam according to any one of claims 1 to 5, characterized in that The preparation method of the minocycline hydrochloride foam comprises the following steps: mixing the liquid medicine raw materials uniformly, filling them into a medicinal aerosol can, capping them, and charging the propellant to obtain the foam.

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