Traditional Chinese medicine compound preparation for treating pulmonary fibrosis as well as preparation method and application of traditional Chinese medicine compound preparation

Abstract

The invention provides a traditional Chinese medicine compound preparation for treating pulmonary fibrosis and a preparation method and application thereof. The traditional Chinese medicine compound preparation comprises the following medicinal material compositions: angelica sinensis, astragalus membranaceus, winged euonymus twig, safflower carthamus, ligusticum wallichii and kudzu vine root. The preparation method comprises the following steps: proportioning the medicinal material composition, decocting, filtering, concentrating, drying, crushing, forming and coating. The prescription follows the prescription principle of monarch, minister, assistant and guide, and has the effects of promoting blood circulation to remove blood stasis and clearing and activating the channels and collaterals. The traditional Chinese medicine compound preparation can be used for treating patients with pulmonary fibrosis caused by meridian blockage, qi stagnation and blood stasis.

Description

Technical Field

[0001] The invention belongs to the pharmaceutical field and relates to a traditional Chinese medicine compound preparation for treating pulmonary fibrosis and a preparation method and application thereof. Background Art

[0002] Pulmonary fibrosis is a chronic progressive lung disease with thickened fibrotic alveolar walls leading to impaired gas transfer, restricted ventilation patterns, and, as a result, respiratory failure. Pulmonary fibrosis is a heterogeneous disease with a unique histopathological pattern that includes a large number of chronic respiratory diseases accompanied by the growth of various lung connective tissues, of which interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF) are the most severe and irreversible progressive fibrosis of the lung parenchyma. Due to the continuous advancement of diagnostic methods and the aging population, the mortality and morbidity of pulmonary fibrosis continue to rise, and as of now, there are approximately 10 cases of IPF per 100,000 people and approximately 19.4 cases of ILD per 100,000 people. Disease progression can vary from patient to patient depending on age and sex, lung microbiota, genetic and environmental factors. Overall, the 5-year survival rate of IPF patients is 20% to 40%, while the median survival is 2 to 5 years, and the overall 5-year survival rate of ILD patients is an average of 55% to 75%.

[0003] In general, the development of pulmonary fibrosis is often caused by acute lung inflammation caused by viral and bacterial infections, ionizing radiation, chemotherapy, air irritants and pollutants, which are not promptly addressed, resulting in the deposition of fibrotic tissue in the lungs and respiratory dysfunction. It is worth noting that the cause of IPF is still unclear, and the pathogenic factors or specific associations have not yet been determined, but among the many intrinsic and extrinsic risk factors, viral infections, gastroesophageal reflux disease-related microaspiration, and genetic susceptibility are among them. In 2014, two drugs, pirfenidone and nintedanib, were approved by the FDA for the treatment of pulmonary fibrosis. Despite this, there is still a lack of effective treatments for pulmonary fibrosis, and existing treatments can only delay the progression of the disease, but cannot provide a complete cure. In addition, these drugs have adverse side effects, such as gastric and intestinal bleeding and severe diarrhea. As a last-line treatment, patients need to undergo lung transplantation, which can extend a certain life span. However, this treatment is not feasible for most patients (Savin IA, Zenkova MA, Sen'kova AV. Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches. Int J Mol Sci. 2022 Nov 29; 23(23): 14959. doi: 10.3390 / ijms232314959. PMID: 36499287; PMCID: PMC9735580). Therefore, it is necessary to develop more effective drugs for the treatment of pulmonary fibrosis. Summary of the invention

[0004] The present invention provides a Chinese medicine compound preparation for treating pulmonary fibrosis, and a preparation method and application thereof. The prescription complies with the principle of monarch, minister, assistant and envoy, and has the effects of promoting blood circulation and removing blood stasis, unblocking meridians and activating collaterals. The preparation is used for patients with pulmonary fibrosis caused by meridian blockage, qi stagnation and blood stasis.

[0005] In one aspect, the present invention provides a Chinese medicinal compound preparation for treating pulmonary fibrosis, which comprises the following medicinal material composition: angelica sinensis, astragalus, radix phellodendri, safflower, ligusticum chuanxiong and kudzu root.

[0006] According to one embodiment, the medicinal material composition and content of the Chinese medicine compound preparation include, by weight: 100-300 grams of angelica, 100-300 grams of astragalus, 100-300 grams of ophiopogon, 100-300 grams of safflower, 100-300 grams of ligusticum chuanxiong, and 100-300 grams of kudzu root.

[0007] According to a preferred embodiment, the composition and content of the medicinal materials include: 211 grams of Angelica sinensis, 209 grams of Astragalus membranaceus, 211 grams of Psoralea corylifolia, 106 grams of Carthamus tinctorius, 106 grams of Ligusticum chuanxiong, and 157 grams of Pueraria lobata; with a total weight of 1000 grams.

[0008] According to one embodiment, the Chinese medicine compound preparation further comprises an appropriate amount of auxiliary materials, such as fillers, binders, disintegrants, buffers, preservatives, antioxidants, wetting agents, lubricants, flavoring agents, thickeners, colorants, emulsifiers or stabilizers.

[0009] According to one embodiment, in the Chinese medicine compound preparation, the auxiliary materials include starch and magnesium stearate.

[0010] According to one embodiment, the Chinese medicine compound preparation includes a preparation for decoction, or tablets, pills, granules, capsules or decoctions for oral administration, or other suitable dosage forms.

[0011] According to one embodiment, the dosage form of the Chinese medicine compound preparation is a tablet, such as a sugar-coated tablet.

[0012] On the other hand, the present invention provides a method for preparing a Chinese medicinal compound preparation for treating pulmonary fibrosis.

[0013] According to one embodiment, the Chinese medicine compound preparation is a sugar-coated tablet containing medicinal materials, and the production method includes: batching, decocting, filtering, concentrating, drying, crushing, molding, and coating.

[0014] According to one embodiment, the manufacturing method comprises:

[0015] Mixing ingredients, including weighing the medicinal materials used as the traditional Chinese medicine compound preparation;

[0016] Decoction, comprising decoctioning the medicinal materials with water for three times and combining the decoctions;

[0017] Filtration, comprising filtering the decoction to obtain a filtrate;

[0018] Concentrating, including concentrating the filtrate to form a thick paste;

[0019] Drying, including drying the thick paste under reduced pressure to form a dry paste;

[0020] pulverizing, including pulverizing the dry paste into a fine powder;

[0021] Forming, including forming the fine powder into granules, drying, adding auxiliary materials, mixing and pressing into plain tablets; and

[0022] The coating comprises coating the plain tablet with a sugar coating layer to obtain a sugar-coated tablet.

[0023] According to a specific embodiment, the preparation method includes decocting the medicinal composition with water three times, adding 10 times the amount of water for the first time, decocting for 3 hours, adding 8 times the amount of water for the second time, decocting for 2 hours, and adding 8 times the amount of water for the third time, decocting for 1 hour, and combining the decoctions; filtering, concentrating the filtrate to a thick paste with a relative density of 1.25 to 1.35 (55°C), drying under reduced pressure, crushing into fine powder, making granules, drying, adding an appropriate amount of magnesium stearate, mixing, pressing into 1000 tablets, and coating with sugar to obtain sugar-coated tablets.

[0024] In another aspect, the present invention provides a use of a Chinese medicinal compound preparation for treating pulmonary fibrosis, wherein the use comprises administering a therapeutically effective amount of the Chinese medicinal compound preparation to a patient in need thereof, thereby treating pulmonary fibrosis.

[0025] The Chinese medicine compound preparation can be used for treating patients with pulmonary fibrosis caused by meridian blockage, qi stagnation and blood stasis. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The invention shows the animal experiment modeling and drug administration method involved in the Chinese medicine compound preparation.

[0027] Figure 2 and Figure 3 Displays the dyeing pictures related to the Chinese herbal compound preparation of the present invention. DETAILED DESCRIPTION

[0028] The present invention is now further described by some specific implementations or examples, but is not intended to limit the scope of the claims of the present invention. The subject matter of the present invention and its protection scope should cover changes, substitutions and equivalent contents based on the contents disclosed herein.

[0029] According to one embodiment, the medicinal material composition and content of the Chinese medicine compound preparation include, by weight: 100-300 grams of angelica, 100-300 grams of astragalus, 100-300 grams of ophiopogon, 100-300 grams of safflower, 100-300 grams of ligusticum chuanxiong, and 100-300 grams of kudzu root.

[0030] In one embodiment, the medicinal material composition and the medicinal material content by weight of the Chinese medicine compound preparation are: 211 grams of Angelica sinensis, 209 grams of Astragalus membranaceus, 211 grams of Psoralea corylifolia, 106 grams of Carthamus tinctorius, 106 grams of Ligusticum chuanxiong, and 157 grams of Pueraria root; the total weight is 1000 grams.

[0031] Example 1: Chinese medicinal compound preparation for treating pulmonary fibrosis

[0032]

Ingredients

[0033]

Functions and indications

[0034] [Specifications] Each tablet contains 1.00g of crude drug, and each tablet core weighs 0.3g.

[0035]

Usage and Dosage

[0036] [Prescription] (unit: g) Angelica 211, Astragalus 209, Psoralea corylifolia 211, Carthamus tinctorius 106, Ligusticum chuanxiong 106, Pueraria lobata 157; a total of six ingredients, with a total weight of 1000 grams.

[0037] Example 2: Preparation of a Chinese medicinal compound preparation for treating pulmonary fibrosis

[0038]

Ingredients Process

[0039] 1. According to the "Ingredient Production Instructions", issue a "Material Receipt List" and go to the warehouse to collect the nine medicinal pieces of red peony root that have been cleanly processed and passed the inspection. Check the weight and quality, and review each piece. After verification by a second person, weigh each piece according to the material requisition list and sign or stamp on the material requisition list.

[0040] 2. Ingredients: Blend the six medicinal pieces of Radix Gnaphalii and other herbs prescribed in Example 1, totaling 1000 kg, label them with the product name, quantity, etc., and move them to the intermediate station for use in the extraction process.

[0041]

Extraction and concentration process

[0042] The six medicinal materials of the prescription described in Example 1, such as the Herba Lysimachiae, were put into an extraction tank, and decocted three times with water, 10 times the amount of water was added for the first time, and 8 times the amount of water was added for the second and third times, and the decocting time was 3, 2, and 1 hours, respectively. The decoction was combined, passed through a 100-mesh sieve, and the filtrate was concentrated to a thick paste with a relative density of 1.25±0.05 (55°C).

[0043]

Drying process

[0044] Dry the thick paste until the moisture content is less than 7.5%, take it out and let it cool.

[0045]

Dry paste crushing

[0046] Crush and sieve. The powder should be fine enough to pass through a 60-mesh sieve and be put into a clean container.

[0047]

Granulation and drying process

[0048] 1. Preparation of soft material: Take 1 part of paste powder and add 3% starch into the mixer. After mixing evenly, add appropriate amount of ethanol solution (the concentration of ethanol can be adjusted according to the size of wet particles) to make a soft material with appropriate dry and wet properties and uniformity.

[0049] 2. Granulation: Install a 14-mesh screen on the swing granulator and add soft material for granulation.

[0050] 3. Drying: Turn on the circulating ventilation device to prevent the pellets from melting and burning. The moisture content of the dry pellets should be below 7.0%.

[0051] [Pelletizing and mixing process] (performed in a clean room)

[0052] 1. Granulation: Sieve the dry granules through a 16-mesh sieve.

[0053] 2. Total mixing: Add 0.5% magnesium stearate to the prepared granules, mix thoroughly, put into a clean container, hang a label with the product name, batch number, weight, production date, etc., and transfer to the next process.

[0054]

Tableting process

[0055] Add the granules into the hopper and start the tablet press. After the machine is running normally, adjust the pressure and tablet speed to the specified tablet weight. Check the tablet weight every 30 minutes during the tablet pressing process. The tablet weight difference limit is within ±4.5%. Take 10 tablets each time and make records. Check the appearance of the tablet core at any time. Sieve out the fine powder and residual tablets in the tablet core. Put the qualified tablet core into a clean and dry container, hang a label with the product name, specification, batch number, weight, production date, etc. After passing the inspection according to the intermediate product quality standard, move to the next process.

[0056]

Sugar coating process

[0057] 1. Preparation of sugar coating liquid: weigh 10kg of sugar, add 4kg of purified water, and heat. Stir while heating to make the sugar completely dissolved in the purified water, filter, label, and set aside. (Syrup concentration 70-75%).

[0058] 2. Prepare gelatin slurry: add 180ml purified water to every 50g gelatin, mix well, heat in water for about 40 minutes, and after it is fully dissolved, add it to 2250ml syrup, stir well, hang a label, and set aside.

[0059] 3. Preparation of powder slurry: add 1.8kg syrup to every 1kg talcum powder and stir thoroughly (prepare immediately, the powder slurry concentration is 1:1.8).

[0060] 4. Preparation of colored syrup: Dissolve the pigment used in each pot in 50ml of purified water, add 450ml of syrup, stir well, hang labels and set aside.

[0061] 5. Coating: 0.3-0.4 kg of sucrose per 1 kg of tablet core, 0.4-0.5 kg of talcum powder per 1 kg of tablet core, 0.01 g of tartrate per 1 kg of tablet core, 1 g of gelatin per 1 kg of tablet core, and 1.2 g of Sichuan wax powder per 1 kg of tablet core.

[0062] Example 3: Modeling and testing of a Chinese medicine compound preparation for treating pulmonary fibrosis

[0063] Animal experiments

[0064] Pulmonary fibrosis: 1U, 6 rats (3 control rats, 3 treated rats);

[0065] Pulmonary fibrosis: 2U, 6 rats (3 control rats, 3 treated rats);

[0066] Skin 1U, 100ul, 10 animals (5 control animals, 5 treated animals);

[0067] Skin 1U, 150ul, 6 animals (3 control animals, 3 treated animals);

[0068] Sham: 2.

[0069] Modeling and drug administration regimen:

[0070] C57BL / 6J mice, 6-8 weeks old.

[0071] 1. The normal control group of mice was injected with PBS or saline subcutaneously.

[0072] 2. Mouse skin fibrosis model: Prepare a 1 mg / mL solution and subcutaneously inject bleomycin 100 μL (100 μg / mouse) and 150 μL (150 μg / mouse) at the same location on the back skin, five times a week for two weeks.

[0073] 3. Mouse skin fibrosis model + drug administration group.

[0074] 4. The normal control group of mice was injected with PBS or saline.

[0075] 5. Mouse idiopathic pulmonary fibrosis model: a single intratracheal injection of bleomycin (1 U / kg).

[0076] 6. Mouse idiopathic pulmonary fibrosis model: a single intratracheal injection of bleomycin (2U / kg).

[0077] Dosage:

[0078] The Chinese medicine compound preparation described in Example 1 was used, and the drug was administered once a day by gavage for three consecutive weeks starting from the first administration of bleomycin, at 0.025, 0.05, and 0.1 tablets per mouse per time. According to the equivalent dose ratio (0.0026) calculated based on the body surface area of ​​a human (70 kg) and a mouse (20 g), the dosage was 0.05 tablets per mouse.

[0079] Staining protocol:

[0080] 1. Take the skin of the mouse at the injection site, soak it in formalin solution, and embed it in paraffin:

[0081] 1) HE staining, Masson staining, and measurement of dermal thickness.

[0082] 2) Immunohistochemistry: TGF-b, macrophages (CD68+), neutrophils (Ly6G+), B cells (CD20+), and T cells (CD3+), Col I, Col III, and Col V.

[0083] 3) Fluorescent staining: Picrosirius staining.

[0084] 4) Fluorescence double labeling: CD11b+CX3CR1+ macrophages.

[0085] 2. Take the left and right lungs of the mouse, soak them in formalin solution, and embed them in paraffin:

[0086] 1) HE staining and Masson staining.

[0087] 2) Immunohistochemistry: TGF-b, CD31, α-SMA, caspase-3, endothelin-1, VEGF, macrophages (CD68+), neutrophils (Ly6G+), B cells (CD20+), and T cells (CD3+), Col I, Col III, and Col V 3).

[0088] 3) Fluorescent staining: Picrosirius staining.

[0089] 4) Fluorescence double labeling: CD11b+CX3CR1+ macrophages.

[0090] result:

[0091] Figure 1 Bleomycin treatment increased the number and tissue infiltration of CD11b+CX3CR1+ macrophages, and it was found that treatment with fusu tablets could reduce the infiltration of CD11b+CX3CR1+ macrophages. Figure 2 and Figure 3 All are lung tissues: 20× (observed under a 20x microscope) results. Figure 2The first row is HE staining. The control group had intact lung tissue structure, with no obvious inflammatory cells or fibrotic lesions. The model group mice had obvious destruction of lung tissue structure, widened alveolar spaces, and significantly thickened alveolar walls, with inflammatory infiltration. After treatment with Fusu tablets, the lung tissue structure improved. The second row is Sirius red staining, which is mainly used for quantitative analysis of collagen content. After staining, collagen fibers appear red and muscle fibers appear yellow. From the staining results, we can see that compared with the sham operation group, after bleomycin modeling, the collagen fibers (red) in the mouse skin and lung tissue increased, indicating an increase in the degree of fibrosis. After treatment with Fusu tablets, the degree of fibrosis was significantly improved. Figure 3 The first line is the staining of collagen ColⅤ. Compared with the control group, the model group mice clearly showed obvious ColⅤ deposition in the lung tissue; after treatment with fusu tablets, the collagen deposition in the lung tissue was effectively improved. The second line is CD68 staining, CD68 is a macrophage marker. Compared with the control group, the number of CD68-positive cells in the model group increased, indicating inflammatory infiltration; after treatment with fusu tablets, the inflammatory response of lung tissue was effectively improved. In summary, it shows that the Chinese medicine components of this compound have a good effect on pulmonary fibrosis.

[0092] The present invention is described herein by some specific embodiments and is also described by some examples for the purpose of description. For those skilled in the art, the present invention may adopt some other embodiments, and the details described herein may be replaced, modified or combined without departing from the gist of the present invention, and these contents should all belong to the scope of the present invention.

Claims

1. A Chinese medicinal compound preparation for treating pulmonary fibrosis, characterized in that: The medicinal materials of the traditional Chinese medicine compound preparation are: angelica sinensis, astragalus, radix phellodendri, safflower, ligusticum chuanxiong and kudzu root.

2. The Chinese herbal compound preparation according to claim 1, wherein the composition and content of the medicinal materials of the Chinese herbal compound preparation are calculated by weight as follows: 100-300 grams of angelica sinensis, 100-300 grams of astragalus, 100-300 grams of ghost arrow feather, 100-300 grams of safflower, 100-300 grams of chuanxiong, and 100-300 grams of kudzu root.

3. The Chinese medicine compound preparation according to claim 1, wherein the composition and content of the medicinal materials are: 211 grams of Angelica sinensis, 209 grams of Astragalus membranaceus, 211 grams of Psoralea corylifolia, 106 grams of Carthamus tinctorius, 106 grams of Ligusticum chuanxiong, and 157 grams of Pueraria lobata; total weight 1000 grams.

4. The Chinese medicinal compound preparation according to any one of claims 1 to 3, further comprising an appropriate amount of auxiliary materials.

5. The Chinese medicinal compound preparation according to any one of claims 1 to 3, wherein the Chinese medicinal compound preparation is a preparation for decoction, or a tablet, pill, granule, capsule or decoction for oral administration. The Chinese medicinal compound preparation according to claim 5 , wherein the tablet is a sugar-coated tablet.

7. A method for preparing a Chinese medicinal compound preparation for treating pulmonary fibrosis according to any one of claims 1 to 6, wherein the Chinese medicinal compound preparation is a sugar-coated tablet containing medicinal materials, and the preparation method comprises: Batching, decoction, filtering, concentration, drying, crushing, shaping, and coating.

8. The method according to claim 7, comprising: Mixing ingredients, including weighing the medicinal materials used as the traditional Chinese medicine compound preparation; Decoction, comprising decoctioning the medicinal materials with water for three times and combining the decoctions; Filtration, comprising filtering the decoction to obtain a filtrate; Concentrating, comprising concentrating the filtrate to form a thick paste; Drying, including drying the thick paste under reduced pressure to form a dry paste; pulverizing, including pulverizing the dry paste into a fine powder; Forming, including forming the fine powder into granules, drying, adding auxiliary materials, mixing and pressing into plain tablets; and The coating comprises coating the plain tablet with a sugar coating layer to obtain a sugar-coated tablet.

9. The method according to claim 8, comprising: The medicinal material is decocted with water for three times, 10 times the amount of water is added for the first time, and the decocting time is 3 hours, 8 times the amount of water is added for the second time, and the decocting time is 2 hours, and 8 times the amount of water is added for the third time, and the decocting time is 1 hour, and the decoctions are combined; filtering; concentrating the filtrate to a thick paste with a relative density of 1.25 to 1.35 (55° C.); drying under reduced pressure; crushing into fine powder; making into granules, drying, adding an appropriate amount of magnesium stearate, mixing, and pressing into tablets; coating with sugar to obtain sugar-coated tablets.

10. Use of the Chinese medicinal compound preparation for treating pulmonary fibrosis according to any one of claims 1 to 6, comprising administering a therapeutically effective amount of the Chinese medicinal compound preparation to a patient in need, thereby treating pulmonary fibrosis.

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