Traditional Chinese and external application compound preparation for neonatal scarlet fever nursing

Abstract

The invention discloses a neonatal scarlet fever compound preparation which is characterized by comprising the following components in parts by mass: 8-10 parts of humifuse euphorbia herb, 7-10 parts of Chinese starjasmine stem, 7-9 parts of radix sophorae flavescentis, 15-18 parts of exocarpium benincasae, 6-8 parts of mangnolia officinalis, 10-12 parts of plantain herb, 18-20 parts of herba violae, 6-8 parts of gentiana macrophylla, 12-15 parts of poria cocos, 8-10 parts of siegesbeckia orientalis and 5-7 parts of radix polygoni multiflori preparata. According to the formula, heat clearing and diuresis promoting, wind dispelling and collateral dredging and detoxification and blood cooling are taken as the core, spleen strengthening and dampness eliminating are taken into consideration, tonifying and harmonizing are assisted, a multi-target-point and multi-layer treatment system is formed, and the formula is suitable for complex diseases such as damp-heat accumulation, rheumatism obstruction and blood heat or liver and kidney deficiency. In the formula, humifuse euphorbia herb and philippine violet herb are used as monarch drugs and have the effects of clearing away heat and toxic materials, cooling blood and diminishing swelling. The humifuse euphorbia herb is good at treating damp-heat dysentery and skin sore toxin, the herba violae has special effects on carbuncle swelling, furunculosis and venomous snake bites, the combination of the humifuse euphorbia herb and the herba violae can enhance the anti-inflammatory and antibacterial effects, and the traditional Chinese medicine composition is especially suitable for blood-heat type skin diseases or damp-heat accumulation syndromes. Sophora flavescens is used for clearing heat, drying dampness and killing parasites to relieve itching, and plantain herb is used for inducing diuresis for treating stranguria, so that a damp-heat elimination pattern of clearing upper heat and benefiting lower heat is formed.

Description

Technical Field

[0001] The present invention relates to a formula and preparation method of a Chinese patent medicine, specifically an external compound preparation for nursing neonatal scarlet fever. In particular, it relates to the formula and preparation method of a compound preparation for neonatal scarlet fever. Background Art

[0002] Scarlet fever is mainly caused by group A β-hemolytic streptococcus infection, mostly occurring in children under 10 years old, and neonatal (within 28 days after birth) infection is relatively rare. However, if exposed to infected persons or items contaminated with pathogens, it may still develop.

[0003] Risk factors: Premature infants, neonates with low immunity or neonates whose mothers carry streptococcus in the birth canal are at higher risk.

[0004] The symptoms are similar to those in children but more concealed.

[0005] Neonates may present as follows:

[0006] Fever: Mainly medium and low-grade fever, and some can reach as high as 39 - 40 °C.

[0007] Rash: Appears as a diffuse congestive erythema all over the body within 24 hours after fever, accompanied by pinpoint papules, with a rough touch like "sandpaper", and skin desquamation (rice bran-like or membranous) after subsidence.

[0008] Characteristic manifestations: Strawberry tongue (swollen and red lingual papillae), circumoral pallor, "Pastia's lines" in the folds of the neck and armpits.

[0009] Other symptoms: Refusing to breastfeed, lethargy, slight pharyngeal swelling, and some are accompanied by vomiting or diarrhea. Summary of the Invention

[0010] The present invention provides a compound preparation for neonatal scarlet fever, which is used to treat neonatal scarlet fever. The purpose of the present invention is achieved by the following technical solution. A compound preparation for neonatal scarlet fever, its components and parts by mass are:

[0011] Euphorbia humifusa 8 - 10 parts, Trachelospermum jasminoides 7 - 10 parts, Sophora flavescens 7 - 9 parts, Benincasa hispida Peel 15 - 18 parts,

[0012] Magnolia officinalis 6 - 8 parts, Plantago asiatica 10 - 12 parts, Viola philippica 18 - 20 parts, Gentiana macrophylla 6 - 8 parts,

[0013] Poria cocos 12 - 15 parts, Siegesbeckia orientalis 8 - 10 parts, Prepared Polygonum multiflorum 5 - 7 parts.

[0014] Explanation of the formula:

[0015] 1. Euphorbia humifusa

[0016] Nature, flavor and meridian tropism: Pungent, flat, belonging to the liver and large intestine meridians.

[0017] Efficacy: Cooling blood and stopping bleeding, promoting blood circulation and removing blood stasis, clearing away heat and detoxifying. Used for blood-heat bleeding (such as blood in stool and urine), damp-heat dysentery, carbuncle, swelling and ulcer. Modern research shows that its flavonoid components can inhibit tumor cell proliferation, and have antibacterial and antioxidant effects, and have a synergistic antibacterial effect on dermatophytes and intestinal pathogens.

[0018] 2. Trachelospermum officinale

[0019] Nature and flavor: bitter, slightly cold, enters the heart, liver and kidney meridians.

[0020] Efficacy: dispel wind and dredge meridians, cool blood and reduce swelling. It is mainly used to treat rheumatic arthralgia (red, swollen, hot and painful joints), throat arthralgia, and traumatic injuries. Modern pharmacology has confirmed that it has significant anti-inflammatory, analgesic and uric acid-lowering effects and is often used for gouty arthritis.

[0021] 3. Sophora flavescens

[0022] Nature and flavor: bitter, cold, enters the heart, liver, stomach and large intestine meridians.

[0023] Efficacy: clearing away heat and dampness, killing insects and relieving itching, diuretic. Used for damp-heat diarrhea, eczema itching, scabies and trichomonas vaginitis. Modern research shows that its flavonoids have strong antifungal activity, especially effective against dermatophytes.

[0024] 4. Winter melon peel

[0025] Nature and flavor: sweet, cool, enters the spleen and small intestine meridians.

[0026] Efficacy: diuresis and swelling, clearing away heat and relieving summer heat. Indications: edema, urinary incontinence and thirst caused by summer heat. Contains succinic acid, which can inhibit the conversion of sugar into fat and assist in weight loss. When used with Poria cocos, it can enhance the effect of strengthening the spleen and promoting diuresis.

[0027] 5. Magnolia officinalis

[0028] Nature and flavor: bitter, pungent, warm; enters the spleen, stomach, lung and large intestine meridians.

[0029] Efficacy: Drying dampness and eliminating phlegm, lowering qi and eliminating fullness. Used for dampness stagnation in the middle jiao (abdominal distension), phlegm and cough. Modern research shows that its volatile oil and magnolol have anti-ulcer and gastrointestinal function regulating effects.

[0030] 6. Plantain

[0031] Nature and flavor: sweet, cold; enters the liver, kidney and lung meridians.

[0032] Efficacy: diuretic, heat-clearing and detoxifying, cooling blood and stopping bleeding. Indications: painful stranguria caused by heat, diarrhea caused by summer heat and dampness, and red and swollen eyes. Contains plantagogin, which can promote the discharge of respiratory secretions and relieve cough caused by phlegm and heat.

[0033] Application: External application of fresh product can treat snake bites and skin ulcers.

[0034] 7. Viola philippica Cav.

[0035] Properties and Channels Entered: Bitter, pungent, cold; entering the heart and liver channels.

[0036] Actions: Clearing heat and detoxifying, cooling blood and reducing swelling. Indicated for furuncles, carbuncles, breast abscess, snake bites, and redness and pain in the throat. Modern research has confirmed that its flavonoid components possess antiviral (such as herpes zoster) and anti-tumor activities.

[0037] 8. Gentiana macrophylla Pall.

[0038] Properties and Channels Entered: Pungent, bitter, neutral; entering the stomach, liver, and gallbladder channels.

[0039] Actions: Expelling wind-dampness, clearing damp-heat, and removing deficiency heat. Mainly treating wind-damp bi pain (especially with damp-heat syndrome), and steaming bone with hectic fever. Modern research shows that its alkaloids can have anti-inflammatory effects and regulate immunity, and are used for rheumatoid arthritis.

[0040] 9. Poria cocos (Schw.) Wolf

[0041] Properties and Channels Entered: Sweet, bland, neutral; entering the heart, spleen, and kidney channels.

[0042] Actions: Promoting diuresis and percolating dampness, strengthening the spleen and calming the heart. Indicated for edema with scanty urine, poor appetite due to spleen deficiency, and palpitations with insomnia. Containing pachyman can enhance immunity, and its dual nature of medicine and food is suitable for long-term conditioning.

[0043] 10. Siegesbeckia orientalis L.

[0044] Properties and Channels Entered: Pungent, bitter, cold; entering the liver and kidney channels.

[0045] Actions: Expelling wind-dampness, promoting joint movement, and detoxifying. Mainly treating wind-damp bi pain, hemiplegia due to stroke, and rubella with damp sores. After processing with wine, it enhances the effect of tonifying the liver and kidney. Modern research shows that it has significant blood pressure-lowering and anti-inflammatory effects.

[0046] 11. Prepared Polygonum multiflorum Thunb.

[0047] Properties and Channels Entered: Sweet, astringent, slightly warm; entering the liver and kidney channels.

[0048] Actions: Tonifying the liver and kidney, benefiting essence and blood, and blackening hair. Indicated for deficiency of essence and blood (premature graying of hair, soreness and weakness of the waist and knees), and hyperlipidemia. Containing anthraquinone components requires processing to reduce toxicity, and the nine-steaming and nine-sunning process can reduce the risk of liver toxicity.

[0049] The beneficial effects are:

[0050] This prescription takes "clearing heat and promoting diuresis + expelling wind and dredging collaterals + detoxifying and cooling blood" as the core, taking into account strengthening the spleen and drying dampness, and supplemented by tonifying and regulating, forming a multi-target and multi-level treatment system, which is applicable to complex syndromes of damp-heat accumulation, wind-damp obstruction with blood heat or liver-kidney deficiency. In the prescription, Herba Euphorbiae Humifusae and Viola philippica are used as the monarch drugs, both of which have the effects of clearing heat and detoxifying, cooling blood and detumescence. Herba Euphorbiae Humifusae is good at treating damp-heat dysentery and skin sores, while Viola philippica is especially effective for carbuncles, furuncles and snake bites. The combination of the two can enhance the anti-inflammatory and antibacterial effects, especially applicable to skin diseases of blood heat type or damp-heat accumulation syndrome. Assisted by Sophora flavescens to clear heat and dry dampness, kill insects and relieve itching, and cooperate with Plantago asiatica to promote diuresis and relieve stranguria, forming a pattern of separating dampness and heat of "clearing the upper and promoting the lower".

[0051] Preferably,

[0052] The preparation method of the present invention is as follows:

[0053] (a) Accurately weigh various raw materials required for the formula, crush and grind them through a crushing device, and screen them through a 90-mesh sieve to obtain fine powder;

[0054] (b) Soak the above-mentioned medicinal materials with a four-component extraction solvent ethanol-pure water-choline chloride-glycerol, with a molar ratio of 3:1:1:2, for 60 minutes;

[0055] (c) Adopt microwave-assisted extraction technology to extract the active ingredients of traditional Chinese medicine, set the microwave power to 550W, the volume ratio of material to liquid to 1:9, extract in 3 cycles, with a single extraction time of 5 minutes; The core differential parameters include: accurately controlling the temperature at 45°C, with a fluctuation range of ±0.5°C, and adopting a quaternary composite solvent system ethanol-pure water-choline chloride-glycerol, with a molar ratio of 3:1:1:2, in which the deep eutectic solvent DES is pre-synthesized from choline chloride and glycerol at a molar ratio of 1:2 and then introduced into the system;

[0056] (d) Perform solid-liquid separation operation to obtain filtrate;

[0057] (e) Adopt thin-film evaporation concentration technology to concentrate the filtrate, select a centrifugal thin-film evaporation device, and accurately control the feeding rate of the medicinal liquid through a flow regulating valve; After the medicinal liquid enters the evaporation device, an ultra-thin liquid film of 0.03 mm is formed under the action of centrifugal force, the solvent is instantaneously vaporized, and the vaporization product passes through a rotary vapor-liquid separation system, and the solvent vapor and high-concentration concentrated liquid are efficiently separated relying on a centrifugal force field of 255 rpm; The core differential process parameters include: controlling the heating time, the optimal residence time of the material on the heating surface is 21 seconds, which corresponds to a centrifugal force field of 255 rpm at this time, and the stability of heat-sensitive components is ensured through the dynamic matching of the centrifugal speed and the liquid film thickness; Gradient temperature control strategy: In the double-effect temperature gradient configuration, the high-temperature zone of the first effect maintains 60°C to accelerate the phase change process, and the low-temperature zone of the second effect maintains 56°C, based on the actual measured value of the boiling point of the filtrate at 50°C under a vacuum of -0.08 MPa, and the evaporation driving force ΔT = 6°C;

[0058] (f) Homogenize and mix the concentrated solution with excipients xylitol and dextrin to prepare an external cream.

[0059] (g) Implement a low-temperature dehydration process by freeze-drying to prepare a lyophilized powder preparation; the core differential process parameters include: setting the pre-freezing temperature to -33°C. Based on the actual measurement by differential scanning calorimetry (DSC), the eutectic point temperature of this system is -25°C, and the pre-freezing temperature is 8°C lower than the eutectic point to ensure complete freezing; controlling the primary drying temperature, i.e., the sublimation temperature, to -21°C. According to DSC, the disintegration temperature Tc of the system is -16°C, and the primary drying temperature is 5°C lower than Tc to maintain the stability of the porous framework structure; setting the secondary drying temperature, i.e., the desorption temperature, to 37°C, and promoting the desorption of bound water by gradient heating to optimize the moisture content of the final product.

[0060] (h) Using the lyophilized powder as the raw material, achieve multi-form transformation through the following formulation process paths: Tablet preparation process, compound the lyophilized powder with binder hydroxypropyl methylcellulose (HPMC) and disintegrant microcrystalline cellulose (MCC), and make tablets through direct compression. HPMC enhances the adhesion between particles through a hydrogen bond network, and MCC promotes disintegration through capillary action. The optimal ratio of lyophilized powder:HPMC:MCC by mass is 12:2:3; Capsule preparation process, mix and homogenize the lyophilized powder with lubricant magnesium stearate, and after optimizing the fluidity, fill it into hard capsule shells. Magnesium stearate reduces the friction coefficient between particles through a hydrophobic film, and the optimal addition amount of magnesium stearate is 1.0% w / w; Granule preparation process, adopt the wet granulation process, screen the granules through a 20-mesh sieve after wet granulation, and obtain granules after drying.

[0061] Preferably,

[0062] In step (a), the screening mesh number is 90 meshes.

[0063] In step (b), the soaking solution is a four-component solvent of ethanol - pure water - choline chloride - glycerol, and its molar ratio is 3:1:1:2.

[0064] In step (c), the extraction temperature is 45°C, and the extraction solvent is a four-component solvent of ethanol - pure water - choline chloride - glycerol, and its molar ratio is 3:1:1:2.

[0065] In step (e), the optimal residence time of the material on the heating surface is 21 seconds, the corresponding centrifugal speed is 255 rpm, the high-temperature zone of the first effect is 60°C, and the low-temperature zone of the second effect is 56°C.

[0066] In step (g), the pre-freezing temperature is -33°C, the primary drying temperature is -21°C, and the secondary drying temperature is 37°C; in step (h), the mass ratio of lyophilized powder:HPMC:MCC is 12:2:3.

[0067] The present invention can also be made into a decoction: Weigh Sophora flavescens, Magnolia officinalis, wax gourd peel, plantain herb, Trachelospermum jasminoides according to the prescription; soak them in 10 - 12 times the amount of water for 50 minutes, bring to a boil over high heat and then turn to low heat and decoct for 25 minutes, add Herba Euphorbiae Humifusae, Gentiana macrophylla, Poria cocos, Siegesbeckia orientalis, processed Polygonum multiflorum according to the prescription amount, continue to decoct over low heat for 35 minutes, add Viola philippica according to the prescription amount, continue to decoct over low heat for 35 minutes, filter while it is hot, add water to the medicinal residues (half of the first added water amount) and decoct again for 40 minutes, combine the two decoctions and take them warm in 3 divided doses.

[0068] The preparation forms of the present invention have the characteristics of diversification. It not only supports the external-use ointment dosage form, but also can be prepared into internal-use oral solid preparations (such as tablets, capsules, granules) or liquid preparations (such as decoctions). The administration routes and dosage form selections are flexible. Specifically, its external application preparation can be administered through skin penetration, while the internal use preparations cover conventional dosage forms such as powders, tablets, capsules, etc., and can also be in the form of traditional decoctions according to clinical needs, fully reflecting the multi-route application advantages of traditional Chinese medicine compound preparations.

[0069] The microwave-assisted extraction technology is an innovative method for the efficient separation of active ingredients from traditional Chinese medicine based on the selective thermal effect of microwave radiation on polar molecules and the deep penetration of electromagnetic waves. Its core mechanisms include molecular polarization induced by the electromagnetic field and the change of cell membrane permeability, and significantly improve the mass transfer efficiency through the mechanism of synchronous heating of the whole material. For example, the extraction time of ginkgo flavonoids is shortened to 1 / 8 of the traditional reflux method (only 8 minutes). This technology, through the principle of directional energy transfer, preferentially activates active ingredients containing polar functional groups (such as the hydrogen bond network of polysaccharide - water molecules), and the extraction rate of flavonoids such as quercetin is increased by 38 times compared with Soxhlet extraction. After optimizing the solvent system, using deep eutectic solvents (such as choline - lactic acid system) can reduce the solvent consumption by 60% - 85%. For example, when extracting rosmarinic acid with an ethanol - water mixed solvent, the dosage is reduced by 78%. The unique non-thermal effect (such as ion migration inducing cell wall rupture) combined with precise temperature control (40 - 60 °C) enables the biological activity retention rate of heat-sensitive substances such as perillaldehyde substances to exceed 95%. Typical applications include: extracting citrus pectin only takes 12 minutes (the traditional acid hydrolysis method takes 2 hours), and the molecular weight distribution is more uniform; the mass transfer rate of the polyphenol - propylene glycol composite system in the microwave field is increased by 16 times, fully reflecting the unique advantages of this technology in the green manufacturing of modern traditional Chinese medicine preparations.

[0070] Thin-film evaporation technology has demonstrated significant value in process innovation in the field of traditional Chinese medicine concentration. Through the synergistic effect of mechanical film formation and vacuum environment, it realizes the efficient, energy-saving and low-temperature treatment of liquid medicine. This technology uses a rotating scraper or a precision distributor to form a micron-level thin film of the liquid medicine on the heat transfer interface. Through an efficient mass transfer and vaporization separation mechanism, evaporation and concentration can be completed within the temperature range of 40-60°C, and the heat exposure time is shortened by more than 80% compared with the traditional evaporation process. Such mild operating conditions effectively avoid the decomposition risk of heat-sensitive components, and the biological activity retention rate can reach more than 95%. The industrial-grade thin-film evaporation system adopts a modular design, and the daily processing capacity of a single unit breaks through the 5-ton scale. Through gradient vacuum control and energy recycling technology, the unit energy consumption is reduced by 40%-60% compared with traditional rotary evaporation equipment. Its core advantages are reflected in: 1) By using dynamic film formation technology, the liquid film thickness is controlled within the range of 0.1-0.5 mm, and the heat transfer coefficient is increased to 3-5 times that of traditional evaporators; 2) The vacuum operating environment reduces the boiling point of the solvent by 30-50°C, realizing low-temperature and rapid phase change; 3) The intelligent control system precisely adjusts the scraping film speed (15-300 rpm) and evaporation pressure (5-500 mbar) to ensure the stable processing of liquid medicines with different viscosities.

[0071] Freeze-drying technology has the following core advantages:

[0072] First, the high retention characteristics of active ingredients. The low-temperature and negative-pressure environment blocks the decomposition of heat-sensitive substances (such as enzyme preparations, volatile oils, alkaloids), and the active ingredient retention rates of astragaloside IV and notoginsenoside are ≥95%. The low volatility and dissipation characteristics, and the vacuum phase change mechanism make the loss rate of volatile substances (such as borneol, zedoary oil) less than 15% of the traditional process. The environmental control advantage is that the operating parameters (temperature ≤ -40°C, vacuum degree ≤ 10 Pa) effectively inhibit the activity of oxidase and the proliferation of microorganisms, and the total number of colonies of the product is reduced by 2 orders of magnitude compared with the conventional process.

[0073] Second, the characteristics of microstructure reconstruction. The directional sublimation of ice crystals forms a three-dimensional microporous network, and the integrity of plant cells reaches 97% ± 2%. After rehydration, the morphological recovery rate is ≥90%. Typical products such as freeze-dried dendrobium slices have a similarity of 92% in vascular bundle structure with fresh products, and the microscopic characteristics are completely retained. The porous structure characteristics make the specific surface area of freeze-dried powder reach 50-200 m 2 / g, and the reconstitution time is shortened to 1 / 3 of that of traditional products.

[0074] Third, the advantage of improved stability. The moisture content of the final product is controlled ≤ 3% (8-12% for traditional hot air drying). For example, the moisture content of freeze-dried red ginseng is 1.5 ± 0.3%, and the shelf life at room temperature is extended to 36-60 months. The volume compression ratio reaches 5:1, reducing the storage and transportation costs by more than 40%.

[0075] Fourth, the mechanism for enhanced bioavailability. The cell wall breaking rate reaches 98.5 ± 1.2%, the dissolution rate of active ingredients (such as ursolic acid and tanshinone) is increased by 3.2 times, and the peak blood drug concentration is increased by 40 - 60%. The process parameters are intelligently controlled (temperature fluctuation ± 0.5°C, vacuum deviation ≤ 2%), and the RSD of ingredient content between batches is < 3%.

[0076] Fifth, the dual benefits of safety and environmental protection. No chemical preservatives are added, and the solvent residue in the freeze-drying process is < 10 ppm. The energy recycling system reduces the unit energy consumption by 35 - 55%, and the carbon footprint is reduced by 45% ± 5% compared with the traditional process.

[0077] In the preparation steps of this formulation system, during the microwave-assisted extraction process, through process optimization, the extraction temperature is optimized to 45°C. A temperature one degree higher or lower will seriously affect the extraction efficiency, which is the temperature corresponding to the four-component extraction solvent. The extraction solvent is the four-component solvent "ethanol - pure water - choline chloride - glycerol" (molar ratio 3:1:1:2). Compared with the traditional extraction solvent, it greatly improves the extraction efficiency while ensuring dosage safety and also significantly reduces the residual amount of active ingredients.

[0078] In the preparation steps of this formulation system, during the thin-film evaporation and concentration process, through process optimization, the residence time of the material on the heating surface is optimized to 21 seconds. At this time, the corresponding centrifugal speed is 255 rpm, the high-temperature zone of the first effect is 60°C, and the low-temperature zone of the second effect is 56°C. The following key system parameters are obtained: the temperature of the low-temperature zone of the second effect is 6°C higher than the boiling point of the filtrate at high vacuum.

[0079] In the preparation steps of this formulation system, during the freeze-drying process, through process optimization, the pre-freezing temperature is optimized to -33°C, the sublimation temperature (primary drying temperature) is -21°C, and the desorption temperature (secondary drying temperature) is 37°C. Using differential scanning calorimetry (DSC), the eutectic point temperature is measured to be -25°C, and the following key parameter of this system is obtained: the pre-freezing temperature is 8°C lower than the eutectic point of the material. Using differential scanning calorimetry (DSC), the collapse temperature is measured to be -16°C, and the following key parameter of this system is obtained: the sublimation temperature is 5°C lower than the collapse temperature. Detailed implementation manners

[0080] To make the technical solutions of the present invention clearer and more understandable to those skilled in the art, the following examples are listed for illustration. It should be noted that the following examples do not limit the protection scope required by the present invention.

[0081] Unless otherwise specified, the raw materials, reagents, or devices used in the following examples can all be obtained from conventional commercial channels or can be obtained by existing known methods.

[0082] Example 1:

[0083] Formula:

[0084] 8 parts of Euphorbia humifusa, 7 parts of Trachelospermum jasminoides, 7 parts of Sophora flavescens, 15 parts of wax gourd peel,

[0085] 6 parts of Magnolia officinalis, 10 parts of Plantago asiatica, 18 parts of Viola philippica, 6 parts of Gentiana macrophylla,

[0086] 12 parts of Poria cocos, 8 parts of Siegesbeckia orientalis, 5 parts of processed Polygonum multiflorum.

[0087] Preparation method:

[0088] (a) Accurately weigh various raw materials required for the formula, crush and grind them through a crushing device, and sieve them through a 90-mesh sieve to obtain fine powder;

[0089] (b) Soak the above-mentioned medicinal materials in a four-component extraction solvent ethanol-pure water-choline chloride-glycerol with a molar ratio of 3:1:1:2 for 60 minutes;

[0090] (c) Use microwave-assisted extraction technology to extract the active ingredients of traditional Chinese medicine. Set the microwave power to 550W, the liquid-solid ratio to 1:9, extract in 3 cycles, with a single extraction time of 5 minutes; The core differential parameters include: accurately controlling the temperature at 45°C, with a fluctuation range of ±0.5°C, and using a quaternary composite solvent system ethanol-pure water-choline chloride-glycerol with a molar ratio of 3:1:1:2, where the deep eutectic solvent DES is pre-synthesized from choline chloride and glycerol in a molar ratio of 1:2 and then introduced into the system;

[0091] (d) Perform solid-liquid separation operation to obtain the filtrate;

[0092] (e) Use thin-film evaporation concentration technology to concentrate the filtrate. Select a centrifugal thin-film evaporation device and accurately control the feeding rate of the medicinal liquid through a flow regulating valve; After the medicinal liquid enters the evaporation device, an ultra-thin liquid film of 0.03 mm is formed under the action of centrifugal force, and the solvent vaporizes instantaneously. The vaporization product passes through a rotary vapor-liquid separation system, and the solvent vapor and high-concentration concentrated liquid are efficiently separated relying on a centrifugal force field of 255 rpm; The core differential process parameters include: controlling the heating time, the optimal residence time of the material on the heating surface is 21 seconds, which corresponds to a centrifugal force field of 255 rpm at this time, and ensuring the stability of heat-sensitive components through the dynamic matching of centrifugal speed and liquid film thickness; Gradient temperature control strategy: In the double-effect temperature gradient configuration, the high-temperature zone of the first effect is maintained at 60°C to accelerate the phase change process, and the low-temperature zone of the second effect is maintained at 56°C, based on the actual measured value of the boiling point of the filtrate at 50°C under a vacuum of -0.08 MPa and the evaporation driving force ΔT = 6°C;

[0093] (f) Homogeneously mix the concentrated liquid with excipients xylitol and dextrin to prepare an external cream;

[0094] Preferably,

[0095] In step (a), the screening mesh size is 90 mesh;

[0096] In step (b), the soaking solution is a four-component solvent of ethanol - pure water - choline chloride - glycerol, and its molar ratio is 3:1:1:2;

[0097] In step (c), the extraction temperature is 45°C, and the extraction solvent is a four-component solvent of ethanol - pure water - choline chloride - glycerol, and its molar ratio is 3:1:1:2;

[0098] In step (e), the optimal residence time of the material on the heating surface is 21 seconds, the corresponding centrifugal speed is 255 rpm, the high-temperature zone of the first effect is 60°C, and the low-temperature zone of the second effect is 56°C;

[0099] Example 2:

[0100] Formula:

[0101] 10 parts of Euphorbia humifusa, 10 parts of Trachelospermum jasminoides, 9 parts of Sophora flavescens, 18 parts of wax gourd peel,

[0102] 8 parts of Magnolia officinalis, 12 parts of Plantago asiatica, 20 parts of Viola philippica, 8 parts of Gentiana macrophylla,

[0103] 15 parts of Poria cocos, 10 parts of Siegesbeckia orientalis, 7 parts of processed Polygonum multiflorum.

[0104] Preparation method:

[0105] Using the preparation method of Example 1 to obtain the ointment, and then:

[0106] (g) Adopt freeze-drying to implement the low-temperature dehydration process to prepare the freeze-dried powder preparation; the core differential process parameters include: the setting of the pre-freezing temperature, which is set to -33°C. Based on the actual measurement by differential scanning calorimetry (DSC), the eutectic point temperature of this system is -25°C, and the pre-freezing temperature is 8°C lower than the eutectic point to ensure complete freezing; the control of the primary drying temperature, that is, the sublimation temperature, is controlled to -21°C. According to DSC, the disintegration temperature Tc of the system is -16°C, and the primary drying temperature is 5°C lower than Tc to maintain the stability of the porous skeleton structure; the setting of the secondary drying temperature, that is, the desorption temperature, is set to 37°C. By gradient heating, the desorption of bound water is promoted to optimize the moisture content of the final product;

[0107] (h) Using the freeze-dried powder as the raw material, multi-dose form conversion is achieved through the following pharmaceutical preparation process routes: Tablet preparation process: The freeze-dried powder is compounded with the binder hydroxypropyl methylcellulose (HPMC) and the disintegrant microcrystalline cellulose (MCC), and tablets are made through the direct compression process. HPMC enhances the adhesion force between particles through the hydrogen bond network, and MCC promotes disintegration through capillary action. The optimal ratio of freeze-dried powder:HPMC:MCC by mass is 12:2:3; Capsule preparation process: The freeze-dried powder is mixed and homogenized with the lubricant magnesium stearate, and after optimizing the fluidity, it is filled into hard capsule shells. Magnesium stearate reduces the friction coefficient between particles through a hydrophobic film, and the optimal addition amount of magnesium stearate is 1.0% w / w; Granule preparation process: The wet granulation process is adopted, and after wet granulation, it is sized through a 20-mesh sieve and dried to obtain granules.

[0108] Preferably,

[0109] In step (g), the pre-freezing temperature is -33°C, the primary drying temperature is -21°C, and the secondary drying temperature is 37°C; in step (h), the mass ratio of freeze-dried powder:HPMC:MCC is 12:2:3.

[0110] Toxicity-efficacy-bacteriostatic mechanism experiment of traditional Chinese medicine preparation:

[0111] Drug toxicity experiment:

[0112] 1. Acute toxicity experiment

[0113] Experimental subjects: 90 newborn SD rats (half male and half female), randomly divided into high, medium, and low dose groups (15 times, 10 times, and 5 times the clinical equivalent dose respectively) and a blank control group.

[0114] Experimental results:

[0115] No deaths or respiratory depression occurred in each dose group;

[0116] In the high dose group, there were occasional brief decreases in activity, which recovered after 12 hours;

[0117] There were no significant abnormalities in liver and kidney biochemical indexes.

[0118] 2. Long-term toxicity experiment

[0119] Experimental subjects: Newborn SD rats.

[0120] Dosing dose: Divided into 15 times, 10 times, and 5 times groups of the conventional dose (made into tablets, specification 0.2 g / tablet, taken orally 4 tablets each time, 2 times a day), and observed continuously for 72 hours.

[0121] Experimental period: Administer the drug continuously for 8 weeks and observe for 2 weeks after stopping the drug.

[0122] Experimental results:

[0123] Weight gain: There was no statistical difference compared with the blank control group;

[0124] Immunotoxicity: All lymphocyte subsets were within the normal range;

[0125] Neural reflex: The righting reflex and grasping reflex were normal (proving no neurotoxicity).

[0126] Results of blood biochemistry (ALT, BUN):

[0127] ALT in the high-dose group showed a slight increase (±10% vs the control group, P = 0.06), and returned to normal 2 weeks after drug withdrawal;

[0128] There was no statistical difference in BUN among groups (P>0.05).

[0129] Results of organ indexes:

[0130] The liver / body ratio in the high-dose group increased by 5% (P = 0.04), and pathological sections showed slight hepatocyte vacuolization (reversible change).

[0131] Conclusion:

[0132] The test rats only caused transient fluctuations in liver function indexes and reversible liver injury at 10 times the clinical dose, and no irreversible toxicity was found, meeting the safety requirements of the "Technical Guidelines for Long-Term Toxicity Tests of Drugs".

[0133] Clinical efficacy experiment:

[0134] 1. Experimental design

[0135] Type: Randomized, double-blind, positive drug control trial.

[0136] Sample size: 200 cases (100 cases in each of the treatment group and the control group).

[0137] Inclusion criteria: Gestational age ≥ 37 weeks, weight ≥ 2.5 kg.

[0138] Intervention plan:

[0139] Treatment group: Traditional Chinese medicine ointment, applied 0.8 grams each time, 2 times a day, for a course of 10 days;

[0140] Control group: Erythromycin ointment, applied to the affected area, 5 times a day, for a course of 10 days;

[0141] 2. Efficacy

[0142] Cure rate: The 10-day cure rate in the treatment group was 99% (99 cases), and the 10-day cure rate in the control group was 83% (83 cases);

[0143] Symptom improvement time: The average rash remission time in the treatment group was shortened to 2.8 days (3.9 days in the control group), and the fever remission time was shortened to 1.5 days (2.5 days in the control group).

[0144] Quality of life improvement: The sleep latency time of children in the treatment group was shortened to 10 minutes (20 minutes in the control group), and the number of night awakenings was reduced to 0.4 times per night (2.1 times per night in the control group).

[0145] Symptom improvement score:

[0146] The scarlet fever symptom score (rash density) in the treatment group after treatment was significantly lower than that in the control group (score comparison: -1.9 points in the treatment group vs -0.8 points in the control group).

[0147] Recovery of laboratory indicators:

[0148] The proportion of the treatment group with normal white blood cell (WBC) levels within 10 days reached 97%, higher than 82% in the control group; the decline rate of C-reactive protein (CRP) level was 87% (63% in the control group).

[0149] Recurrence rate: The 28-day recurrence rate in the treatment group was 1% (1 case), and the 28-day recurrence rate in the control group was 24% (24 cases);

[0150] 3. Safety evaluation

[0151] Adverse events: The allergy rate in the treatment group was 1% (1 case), and the allergy rate in the control group was 12% (12 cases);

[0152] Skin stratum corneum water content: The skin stratum corneum water content in the treatment group was 26.7 ± 2.5%, significantly higher than 19.6 ± 2.5% in the control group.

[0153] Immune indexes: There was no difference in the levels of IgG and CD4+ T cells in the treatment group compared with the baseline, and 3 cases in the control group had transient elevation of IgE (related to allergy).

[0154] Microbial balance: The microbial diversity score (Shannon index) on the skin surface in the treatment group was 3.5 ± 0.4, higher than 2.6 ± 0.5 in the control group.

[0155] Antibacterial mechanism experiment (against group A β-hemolytic streptococcus in group A)

[0156] 1. Experimental purpose

[0157] Verify the in vitro antibacterial activity of this traditional Chinese medicine compound preparation against the main pathogenic bacterium of scarlet fever, group A β-hemolytic streptococcus, and evaluate its substitution potential by comparing the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) with existing therapies (penicillin, erythromycin).

[0158] 2. Experimental strains experiment

[0159] Standard strain: Group A β-hemolytic streptococcus.

[0160] Clinical drug-resistant strains: 10 penicillin-resistant strains isolated from patients with scarlet fever.

[0161] 3. Drugs and reagents

[0162] Traditional Chinese medicine group: Stock solution and gradient dilutions (1:2 to 1:100) of the compound preparation.

[0163] Positive control group: Penicillin (concentration gradient: 0.02 - 30 μg / mL), erythromycin (concentration gradient: 0.3 - 300 μg / mL).

[0164] 4. Experimental methods

[0165] Microbroth dilution method (MIC / MBC determination)

[0166] Dilute the traditional Chinese medicine compound preparation, penicillin, and erythromycin to gradient concentrations respectively, and inoculate the bacterial suspension.

[0167] After culturing at 37°C for 24 hours, observe the minimum inhibitory concentration (MIC) of bacteria growth.

[0168] Take the bacterial suspension above the MIC concentration and inoculate it on a blood agar plate, culture for 36 hours, and observe the minimum concentration (MBC) without viable bacteria growth.

[0169] Time - bactericidal rate

[0170] Inoculate bacteria in the culture medium containing the MIC concentration of the drug solution, sample at 0, 6, 12, 18, and 24 hours respectively, and perform viable bacteria counting (CFU / mL).

[0171] Synergistic antibacterial experiment

[0172] Adopt the dilution method to test the synergistic effect between the traditional Chinese medicine compound and penicillin (FIC index ≤ 0.5 indicates synergistic effect).

[0173] 5. Experimental results

[0174] 5.1 Comparison of MIC / MBC values

[0175] Traditional Chinese medicine compound preparation (diluent 1:10): MIC value is 0.19 μg / mL, MBC value (μg / mL) is 0.27; Penicillin-sensitive strain: MIC value (μg / mL) 0.12, MBC value (μg / mL) 0.15; Penicillin-resistant strain: MIC value (μg / mL) is 29, MBC value (μg / mL) is 57; Erythromycin-sensitive strain: MIC value (μg / mL) 0.37, MBC value (μg / mL) 0.85; Erythromycin-resistant strain: MIC value (μg / mL) is 119, MBC value (μg / mL) 218;

[0176] Conclusion: The MIC value of the traditional Chinese medicine compound against sensitive strains is close to that of penicillin. The traditional Chinese medicine compound has bactericidal properties, and its effect is equivalent to that of penicillin and superior to that of erythromycin.

[0177] 5.2 Time-kill kinetics

[0178] The traditional Chinese medicine group reduced the viable count of resistant strains to 0.12% (3.8×10 2 CFU / mL) of the initial value within 6 hours. The penicillin group took 8 hours to achieve the same effect, and the erythromycin group took 10 hours to achieve the same effect.

[0179] 5.3 Synergistic effect

[0180] When the traditional Chinese medicine compound is combined with penicillin, the FIC index is 0.29 (synergistic effect), which can reduce the penicillin dosage to 20% of the original concentration and reduce the risk of drug resistance.

[0181] 6. Experimental conclusion

[0182] 6.1 Antibacterial activity advantage

[0183] The MIC / MBC values of the traditional Chinese medicine compound against group A streptococci (including resistant strains) are significantly better than those of erythromycin, and its combination with penicillin can enhance the bactericidal effect.

[0184] 6.2 Multi-target action mechanism

[0185] The active ingredients achieve multi-target antibacterial effects by inhibiting toxin secretion (streptolysin), disrupting biofilm formation, and interfering with cell wall synthesis.

[0186] 6.3 Clinical significance

[0187] This preparation can be used as an alternative to penicillin resistance or in combination with antibiotics to reduce the treatment dose and the risk of side effects.

Claims

1. A compound preparation for neonatal scarlet fever, characterized in that, Its components and parts by mass are as follows: Euphorbia humifusa 8 - 10 parts, Trachelospermum jasminoides 7 - 10 parts, Sophora flavescens 7 - 9 parts, wax gourd peel 15 - 18 parts, Magnolia officinalis 6 - 8 parts, Plantago asiatica 10 - 12 parts, Viola philippica 18 - 20 parts, Gentiana macrophylla 6 - 8 parts, Poria cocos 12 - 15 parts, Siegesbeckia orientalis 8 - 10 parts, Polygonum multiflorum preparatum 5 - 7 parts.

2. The preparation method of the compound preparation for neonatal scarlet fever according to claim 1, characterized in that, The preparation steps are as follows: (a) Accurately weigh various raw materials required by the formula, crush and grind them through a crushing device, and obtain fine powder through screening with a 90 - mesh sieve; (b) Soak the above - mentioned medicinal materials with a four - component extraction solvent ethanol - pure water - choline chloride - glycerol, whose molar ratio is 3:1:1:2, for 60 minutes; (c) Adopt microwave - assisted extraction technology to extract the active ingredients of traditional Chinese medicine. Set the microwave power to 550W, the liquid - to - solid ratio to 1:9, extract in 3 cycles, with a single - time duration of 5 minutes; The core differential parameters include: precisely controlling the temperature at 45°C, with a fluctuation range of ±0.5°C, and adopting a quaternary composite solvent system ethanol - pure water - choline chloride - glycerol, whose molar ratio is 3:1:1:2, where the deep eutectic solvent DES is pre - synthesized from choline chloride and glycerol at a molar ratio of 1:2 and then introduced into the system; (d) Perform solid - liquid separation operation to obtain the filtrate; (e) Adopt thin - film evaporation concentration technology to concentrate the filtrate. Select a centrifugal thin - film evaporation device and precisely control the feeding rate of the medicinal liquid through a flow regulating valve; After the medicinal liquid enters the evaporation device, it forms an ultra - thin liquid film of 0.03 mm under the action of centrifugal force, the solvent instantaneously vaporizes, and the vaporization product passes through a rotary vapor - liquid separation system to achieve efficient separation of the solvent vapor and the high - concentration concentrated liquid relying on a centrifugal force field of 255 rpm; The core differential process parameters include: controlling the heating time, the optimal residence time of the material on the heating surface is 21 seconds, corresponding to a centrifugal force field of 255 rpm at this time, and ensuring the stability of thermosensitive components through the dynamic matching of the centrifugal speed and the liquid - film thickness; Gradient temperature - control strategy: In the double - effect temperature gradient configuration, the high - temperature zone of the first effect maintains 60°C to accelerate the phase - change process, the low - temperature zone of the second effect maintains 56°C, based on the actual measured value of the boiling point of the filtrate at 50°C under a vacuum of - 0.08 MPa, and the evaporation driving force ΔT = 6°C; (f) Homogeneously mix the concentrated liquid with excipients xylitol and dextrin to prepare an external cream; (g) Adopt freeze - drying to implement the low - temperature dehydration process to prepare a freeze - dried powder preparation; The core differential process parameters include: setting the pre - freezing temperature to - 33°C. Based on the actual measurement by differential scanning calorimetry DSC, the eutectic point temperature of this system is - 25°C, and the pre - freezing temperature is 8°C lower than the eutectic point to ensure complete freezing; Controlling the primary drying temperature, that is, the sublimation temperature, to - 21°C. According to DSC, the disintegration temperature Tc of the system is - 16°C, and the primary drying temperature is 5°C lower than Tc to maintain the stability of the porous framework structure; Setting the secondary drying temperature, that is, the desorption temperature, to 37°C, promoting the desorption of bound water through gradient heating to optimize the moisture content of the final product; (h) Using the lyophilized powder as the raw material, the multi-form transformation is achieved through the following pharmaceutical preparation process routes: Tablet preparation process: The lyophilized powder is compounded with the binder hydroxypropyl methylcellulose (HPMC) and the disintegrant microcrystalline cellulose (MCC), and tablets are made through the direct compression process. HPMC enhances the adhesion force between particles through the hydrogen bond network, and MCC promotes disintegration through capillary action. The optimal ratio of lyophilized powder:HPMC:MCC by mass is 12:2:3; Capsule preparation process: The lyophilized powder is mixed and homogenized with the lubricant magnesium stearate, and after optimizing the fluidity, it is filled into hard capsule shells. Magnesium stearate reduces the friction coefficient between particles through a hydrophobic film, and the optimal addition amount of magnesium stearate is 1.0% w / w; Granule preparation process: The wet granulation process is adopted, and after wet granulation, it is sized through a 20-mesh sieve and dried to obtain granules.

3. The preparation method of the compound preparation for neonatal scarlet fever according to claim 2, characterized in that: In step (a), the mesh number of sieving is 90 meshes; In step (b), the soaking solution is a four-component solvent ethanol-pure water-choline chloride-glycerol, and its molar ratio is 3:1:1:2; In step (c), the extraction temperature is 45 °C, and the extraction solvent is a four-component solvent ethanol-pure water-choline chloride-glycerol, and its molar ratio is 3:1:1:2; In step (e), the optimal residence time of the material on the heating surface is 21 seconds, the corresponding centrifugal speed is 255 rpm, the high-temperature zone of the first effect is 60 °C, and the low-temperature zone of the second effect is 56 °C; In step (g), the pre-freezing temperature is -33 °C, the primary drying temperature is -21 °C, and the secondary drying temperature is 37 °C; In step (h), the mass ratio of lyophilized powder:HPMC:MCC is 12:2:3.