A pharmaceutical composition for treating rheumatic pain and a preparation method thereof

Abstract

This invention discloses a pharmaceutical composition for treating rheumatic pain and its preparation method. This invention relates to the field of traditional Chinese medicine technology. The composition is made from the following raw materials in parts by weight: 8-16 parts of Clematis chinensis, 6-12 parts of Angelica pubescens, 6-12 parts of Notopterygium incisum, 5-10 parts of Stephania tetrandra, 4-8 parts of Cinnamomum cassia, and 5-10 parts of Paeonia lactiflora. Through the precise combination of Clematis chinensis, Angelica pubescens, Notopterygium incisum, and other wind-dispelling and dampness-removing herbs with Boswellia carterii, Commiphora myrrha, and other blood-activating and stasis-removing herbs, it solves the technical problems commonly found in existing drugs for treating rheumatic pain, such as "slow onset of action via a single pathway, and easy damage to the spleen and stomach or the development of drug resistance with long-term use." It achieves the beneficial effect of multi-target synergistic anti-inflammatory and analgesic effects: Clematis chinensis, Angelica pubescens, Notopterygium incisum, and Stephania tetrandra work together to dispel wind and dampness, unblock meridians, and relieve pain; Cinnamomum cassia warms the meridians and promotes Yang; Paeonia lactiflora and Glycyrrhiza uralensis nourish Yin to relieve pain; Ligusticum chuanxiong and Angelica sinensis nourish and activate blood; Boswellia carterii and Commiphora myrrha remove blood stasis and relieve pain. The entire formula both dispels external pathogens and regulates Qi and blood, addressing both the root cause and the symptoms.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine technology, specifically to a pharmaceutical composition for treating rheumatic pain and its preparation method. Background Technology

[0002] Rheumatic pain is a common clinical condition characterized by pain in the joints, muscles, bones, and soft tissues. It mainly includes rheumatoid arthritis, gouty arthritis, and osteoarthritis.

[0003] Currently, the conventional methods for treating rheumatic pain in clinical practice are mainly divided into two categories: First, there are nonsteroidal anti-inflammatory drugs (NSAIDs), which exert anti-inflammatory and analgesic effects by inhibiting cyclooxygenase activity and reducing prostaglandin synthesis. However, long-term use can easily cause gastrointestinal damage, liver and kidney dysfunction, and adverse cardiovascular events. Secondly, glucocorticoids and immunosuppressants, while able to control disease progression, have serious side effects such as immunosuppression, osteoporosis, and increased risk of infection.

[0004] Traditional Chinese medicine (TCM) has a long history of treating rheumatic pain. Current compound prescriptions often employ toxic herbs such as Aconitum carmichaelii, Aconitum kusnezoffii, and Strychnos nux-vomica to "fight poison with poison." While this approach has some efficacy, it has a narrow therapeutic window, high safety risks, and requires complex processing and decoction techniques, making it inconvenient for patients and resulting in poor patient compliance. Furthermore, many TCM compound prescriptions focus only on dispelling wind and dampness or promoting blood circulation and removing blood stasis, neglecting the underlying cause of "deficiency of vital energy and insufficiency of qi and blood," leading to slow onset of action and frequent relapses. Current extraction processes often employ constant-temperature, constant-concentration reflux extraction, which struggles to ensure the full dissolution of active ingredients with different polarities, resulting in material waste and unstable efficacy.

[0005] Therefore, there is an urgent need to develop a drug composition for treating rheumatic pain that is fast-acting, comprehensive in its effects, highly safe, and easy to manufacture. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a pharmaceutical composition for treating rheumatic pain and a method for preparing the same, thus solving the technical problems mentioned in the background section.

[0007] To achieve the above objectives, the present invention provides the following technical solution: a pharmaceutical composition for treating rheumatic pain, the composition being made from the following raw materials in parts by weight: Clematis chinensis 8-16 parts, Angelica pubescens 6-12 parts, Notopterygium incisum 6-12 parts Stephania tetrandra 5-10 parts, Cinnamomum cassia 4-8 parts, Paeonia lactiflora 5-10 parts Licorice root 3-6 parts, Sichuan lovage rhizome 4-8 parts, Angelica sinensis root 6-12 parts Frankincense 2-5 parts, myrrh 2-5 parts.

[0008] In some embodiments, the weight parts of the active pharmaceutical ingredient are: Clematis chinensis 12 parts, Angelica pubescens 9 parts, Notopterygium incisum 9 parts, Fangji 8 parts, Guizhi 6 parts, Baishao 8 parts Licorice 4 parts, Ligusticum chuanxiong 6 parts, Angelica sinensis 9 parts Frankincense 3 parts, myrrh 3 parts.

[0009] In some embodiments, the weight parts of the active pharmaceutical ingredient are: Clematis chinensis 10 parts, Angelica pubescens 10 parts, Notopterygium incisum 8 parts Fangji 6 parts, Guizhi 5 parts, Baishao 10 parts Licorice root 5 parts, Sichuan lovage rhizome 5 parts, Angelica sinensis root 10 parts Frankincense 4 parts, myrrh 4 parts.

[0010] In some embodiments, the weight parts of the active pharmaceutical ingredient are: Clematis chinensis 15 parts, Angelica pubescens 7 parts, Notopterygium incisum 11 parts Fangji 9 parts, Guizhi 7 parts, Baishao 6 parts Licorice root 3 parts, Sichuan lovage rhizome 7 parts, Angelica sinensis root 7 parts Frankincense 2.5 parts, myrrh 2.5 parts.

[0011] In some embodiments, the frankincense and myrrh are both vinegar-processed products, and the white peony root is wine-fried white peony root.

[0012] A method for preparing a pharmaceutical composition for treating rheumatic pain, comprising the following steps: Step A: Weigh each raw material according to the stated weight proportions, dry them, pulverize them into coarse powder, mix them evenly, and obtain mixed coarse powder; Step B: Add 6 to 10 times the total mass of the mixed coarse powder to ethanol with a volume fraction of 60% to 80%, and reflux extract at 60 to 80°C 1 to 3 times, 1 to 2 hours each time. Combine the extracts, filter, and obtain the alcohol extract. Step C: The alcohol extract is concentrated under reduced pressure at 50-70°C to a clear extract with a relative density of 1.10-1.20, and then dried under vacuum or by spray drying to obtain a dried extract; Step D: Crush the dried extract, pass it through an 80-120 mesh sieve, add conventional excipients according to pharmaceutical methods, and prepare a clinically acceptable dosage form.

[0013] In some embodiments, the dosage form is a tablet, capsule, granule, pill, powder, oral liquid, ointment, patch, or spray.

[0014] In some embodiments, the reflux extraction in step B adopts a segmented temperature-variable extraction process: the first extraction stage is performed at 65°C for 1.5 hours, and the second extraction stage is performed at 75°C for 1 hour, with the volume fractions of ethanol in the two extractions being 70% and 60%, respectively.

[0015] In some embodiments, the pharmaceutical composition is used in the preparation of a medicament for treating rheumatic pain caused by rheumatoid arthritis, osteoarthritis, or gouty arthritis.

[0016] In some embodiments, the drug is also used to prepare a topical preparation for relieving rheumatic pain of the cold-dampness obstruction type or the blood stasis obstruction type. The topical preparation comprises the drug composition and a transdermal absorption enhancer, wherein the transdermal absorption enhancer is azone or propylene glycol, and the amount of the enhancer is 0.5% to 2% of the total mass of the drug composition.

[0017] This invention provides a pharmaceutical composition for treating rheumatic pain and its preparation method, which has the following beneficial effects: By precisely combining wind-dispelling and dampness-removing drugs such as Clematis chinensis, Angelica pubescens, and Notopterygium incisum with blood-activating and stasis-removing drugs such as Boswellia carterii and Commiphora myrrha, the technical problems of "slow onset of action through a single pathway, easy damage to the spleen and stomach or the development of drug resistance" that are common in existing drugs for treating rheumatic pain are solved, and the beneficial effects of multi-target synergistic anti-inflammatory and analgesic effects are achieved: Clematis chinensis, Angelica pubescens, Notopterygium incisum and Stephania tetrandra work together to dispel wind and dampness, unblock the meridians and relieve pain; Cinnamomum cassia warms the meridians and promotes yang; Paeonia lactiflora and Glycyrrhiza uralensis are sweet and sour to nourish yin and relieve pain; Ligusticum chuanxiong and Angelica sinensis nourish blood and activate blood circulation; Boswellia carterii and Commiphora myrrha remove blood stasis and relieve pain. The whole formula not only dispels external pathogens but also regulates qi and blood, taking into account both the root cause and the symptoms. Pharmacological experiments showed that the composition could inhibit xylene-induced ear swelling in mice by more than 58%, and increase the pain threshold of the hot plate pain model by more than 71%. The effect was comparable to that of commonly used nonsteroidal anti-inflammatory drugs in clinical practice, and there were no side effects such as gastrointestinal irritation. It truly achieved the clinically beneficial effect of "eliminating pathogens without harming the body's vital energy and relieving pain without damaging the stomach". Attached Figure Description

[0018] Figure 1 This is a schematic flowchart of the preparation method of the present invention. Detailed Implementation

[0019] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] This invention provides a pharmaceutical composition for treating rheumatic pain: the composition is made from the following raw materials in parts by weight: Clematis chinensis 8-16 parts, Angelica pubescens 6-12 parts, Notopterygium incisum 6-12 parts Stephania tetrandra 5-10 parts, Cinnamomum cassia 4-8 parts, Paeonia lactiflora 5-10 parts Licorice root 3-6 parts, Sichuan lovage rhizome 4-8 parts, Angelica sinensis root 6-12 parts Frankincense 2-5 parts, myrrh 2-5 parts.

[0021] By rationally combining the above-mentioned weight proportions, the whole formula has the effects of dispelling wind and dampness, promoting blood circulation and removing blood stasis, and relieving pain by clearing the meridians. The effects of each herb are synergistic rather than simply superimposed, which can be adapted to patients with rheumatic pain of different constitutions and severity of disease. This not only ensures the universality of the therapeutic effect, but also provides room for dosage adjustment for subsequent individualized and precise drug administration.

[0022] In some embodiments, the weight parts of the active pharmaceutical ingredient are: Clematis chinensis 12 parts, Angelica pubescens 9 parts, Notopterygium incisum 9 parts, Fangji 8 parts, Guizhi 6 parts, Baishao 8 parts Licorice 4 parts, Ligusticum chuanxiong 6 parts, Angelica sinensis 9 parts Frankincense 3 parts, myrrh 3 parts.

[0023] The above-mentioned preferred weight ratio was verified by pharmacodynamic experiments. It showed that the inhibition rate of xylene-induced ear swelling in mice reached 58.3%, and the increase rate of pain threshold induced by hot plate reached 71.2%. The effect was comparable to that of ibuprofen and without gastrointestinal irritation. This indicates that the specific ratio achieved the best balance between eliminating pathogens and strengthening the body, and is the optimal dosage combination for anti-inflammatory and analgesic effects.

[0024] In some embodiments, the weight parts of the active pharmaceutical ingredient are: Clematis chinensis 10 parts, Angelica pubescens 10 parts, Notopterygium incisum 8 parts Fangji 6 parts, Guizhi 5 parts, Baishao 10 parts Licorice root 5 parts, Sichuan lovage rhizome 5 parts, Angelica sinensis root 10 parts Frankincense 4 parts, myrrh 4 parts.

[0025] In this formula, the dosage of Angelica sinensis and Paeonia lactiflora is relatively high, which focuses on nourishing blood and soothing the liver, relieving pain and spasms. It is especially suitable for patients with long-term illness and those with blood deficiency or yin deficiency due to wind-cold-dampness, whose clinical manifestations are persistent pain, stiff joints, and worsening at night. It can achieve the treatment goal of "eliminating pathogens without depleting blood".

[0026] In some embodiments, the weight parts of the active pharmaceutical ingredient are: Clematis chinensis 15 parts, Angelica pubescens 7 parts, Notopterygium incisum 11 parts Fangji 9 parts, Guizhi 7 parts, Baishao 6 parts Licorice root 3 parts, Sichuan lovage rhizome 7 parts, Angelica sinensis root 7 parts Frankincense 2.5 parts, myrrh 2.5 parts.

[0027] In this formula, the dosage of Clematis chinensis, Notopterygium incisum, and Stephania tetrandra is relatively high, which enhances the effects of dispelling wind and dampness, clearing the meridians and relieving pain. At the same time, the dosage of frankincense and myrrh is low to avoid excessive warming and drying. It is suitable for patients with excess rheumatism, heaviness and swelling of limbs, and aggravation by cold. It takes effect quickly and is not likely to cause drug dependence.

[0028] In some embodiments, frankincense and myrrh are both processed with vinegar, and white peony is stir-fried with wine.

[0029] Vinegar processing can guide the medicine into the liver meridian and enhance its effects of removing blood stasis and relieving pain, while reducing the irritation of frankincense and myrrh to the gastrointestinal tract; wine-fried white peony can mitigate its cold nature and enhance its effects of promoting blood circulation and unblocking collaterals. After processing, the overall bioavailability of the formula is increased by more than 15%, and there is no risk of gastric mucosal damage with long-term use.

[0030] like Figure 1 As shown, a method for preparing a pharmaceutical composition for treating rheumatic pain, comprising the following steps: Step A: Weigh each raw material according to the weight proportions, dry them, pulverize them into coarse powder, mix them evenly, and obtain mixed coarse powder; Step B: Add 6 to 10 times the total mass of the mixed coarse powder to ethanol with a volume fraction of 60% to 80%, and reflux extract at 60 to 80°C 1 to 3 times, 1 to 2 hours each time. Combine the extracts, filter, and obtain the ethanol extract. Step C: Concentrate the alcohol extract under reduced pressure at 50-70°C to a clear extract with a relative density of 1.10-1.20, and then vacuum dry or spray dry to obtain a dried extract; Step D: Crush the dried extract, pass it through an 80-120 mesh sieve, add conventional excipients according to pharmaceutical methods, and prepare a clinically acceptable dosage form.

[0031] The above preparation method, through alcohol extraction, low-temperature vacuum concentration and drying, retains the fat-soluble active ingredients (such as osthol and ligustilide) in each medicinal ingredient to the maximum extent, while avoiding the destruction of heat-sensitive components by high temperature. The yield of the resulting extract is stable between 18% and 22%, and the transfer rate of active ingredients exceeds 85%. Moreover, the process is simple, reproducible and suitable for large-scale industrial production.

[0032] In some embodiments, the dosage form is a tablet, capsule, granule, pill, powder, oral liquid, ointment, patch, or spray.

[0033] It covers a variety of dosage forms, including oral and topical, which can meet the needs of systemic drug administration (tablets, granules, etc.) and can also be used topically (plasters, sprays) to concentrate the drug at the lesion site, reduce systemic exposure and thus reduce the risk of adverse reactions, providing flexible drug administration options for patients with different compliance and different stages of disease.

[0034] In some embodiments, the reflux extraction in step B adopts a segmented temperature-variable extraction process: the first extraction stage is performed at 65°C for 1.5 hours, and the second extraction stage is performed at 75°C for 1 hour, with the volume fractions of ethanol in the two extractions being 70% and 60%, respectively.

[0035] The segmented temperature-varying extraction process utilizes the selective solubility differences of various components by solvents of different polarities and the effect of temperature on diffusion rate. This allows highly alcohol-soluble components to be fully dissolved under high temperature and high alcohol conditions, while moderately polar components are prevented from excessive degradation under low temperature and low alcohol conditions. The total extraction rate is more than 22% higher than that of constant temperature and constant alcohol extraction, and the content of indicator components (osthol and paeoniflorin) in the obtained extract is more balanced, significantly improving the quality consistency between batches.

[0036] In some embodiments, the pharmaceutical composition is used in the preparation of a medicament for treating rheumatic pain caused by rheumatoid arthritis, gouty arthritis, or other similar conditions.

[0037] The pharmaceutical composition of this invention was validated in an adjuvant-induced arthritis rat model. After 21 days of continuous administration, joint swelling decreased by 61%, the arthritis index decreased by 64%, and synovial hyperplasia and inflammatory cell infiltration were significantly reduced. At the same time, in vitro xanthine oxidase inhibition experiments showed that it also had a certain inhibitory effect on uric acid production. This indicates that the composition has multiple pharmacological activities such as anti-inflammatory, immunomodulatory and uric acid-lowering effects, and can be used to treat rheumatic pain caused by a variety of etiologies, thus expanding the scope of clinical indications.

[0038] In some embodiments, the drug is also used to prepare a topical preparation for relieving rheumatic pain of the cold-dampness obstruction type or the blood stasis obstruction type. The topical preparation comprises a drug composition and a transdermal absorption enhancer, wherein the transdermal absorption enhancer is azone or propylene glycol, and the amount of the enhancer is 0.5% to 2% of the total mass of the drug composition.

[0039] By adding azone or propylene glycol as transdermal absorption enhancers, the cumulative transdermal absorption of the active ingredient over 24 hours is increased by 2.5 to 2.8 times. Furthermore, the topical formulation does not require the first-pass effect of the liver and acts directly on local meridians and acupoints. It is especially suitable for patients with cold-dampness obstruction (worsened by cold and relieved by warmth) or blood stasis obstruction (stabbing pain worsens at night). It can achieve the effect of local warming sensation within 10 minutes, while avoiding the gastrointestinal discomfort that oral formulations may cause, significantly improving the safety of long-term medication and patient compliance.

[0040] It is worth noting that all standard parts used in this invention can be purchased from the market, and irregularly shaped parts can be customized according to the description and drawings. The specific connection methods of each part all adopt conventional methods such as bolts, rivets, and welding that are mature in the prior art. The models of electrical structure equipment involved can be selected according to the user's needs, as long as they meet the requirements of this application. In addition, the circuit connection adopts conventional connection methods in the prior art. The supporting electrical structures such as the control, current detection, position feedback, predictive voltage synchronization, and parameter adjustment of the electrical equipment are all existing technologies, such as PLC controllers and module structures, so they will not be described in detail here.

[0041] A specific embodiment of this application is described below with reference to the accompanying drawings: Example 1: Preparation of oral tablets and evaluation of their anti-inflammatory and analgesic efficacy 1. Raw material ratio Weigh the following raw materials in the indicated weight proportions: Clematis chinensis 12 parts, Angelica pubescens 9 parts, Notopterygium incisum 9 parts, Stephania tetrandra 8 parts, Cinnamomum cassia 6 parts, Paeonia lactiflora 8 parts, Glycyrrhiza uralensis 4 parts, Ligusticum chuanxiong 6 parts, Angelica sinensis 9 parts, Boswellia carterii 3 parts, and Commiphora myrrha 3 parts. Among these, Boswellia carterii and Commiphora myrrha are processed with vinegar, and Paeonia lactiflora is stir-fried with wine.

[0042] 2. Preparation method The first step is raw material pretreatment: Impurities are removed from each of the above-mentioned raw materials, and they are dried in a 45℃ oven for 12 hours until the moisture content is reduced to below 8%. The dried materials are then pulverized into coarse powder, passed through a 20-mesh sieve, and then mixed in a three-dimensional mixer for 30 minutes to obtain a mixed coarse powder.

[0043] The second step is ethanol reflux extraction: Add 8 times the total mass of the mixed coarse powder (70% ethanol by volume), heat to 70°C, and reflux twice. The first extraction time is 1.5 hours, and the second extraction time is 1 hour. After each extraction, filter while hot through a 200-mesh filter cloth, and combine the two filtrates to obtain the ethanol extract.

[0044] The third step, concentration and drying: The alcohol extract was transferred to a vacuum concentration tank and concentrated at 60°C and a vacuum of -0.08 MPa to a clear extract with a relative density of 1.15 (measured at 60°C). The clear extract was spread evenly in a vacuum drying tray and dried under vacuum at 55°C and -0.09 MPa for 24 hours to obtain a dried extract. The yield was calculated to be 18.7% (based on the total weight of the raw materials).

[0045] Step 4, Formulation: The dried extract is pulverized using a high-efficiency pulverizer and passed through a 100-mesh sieve to obtain extract powder. Microcrystalline cellulose (25% by weight of extract powder), crospovidone (8%), and magnesium stearate (1%) are added to the extract powder and mixed in a mixer for 20 minutes. Tablets are then formed using a shallow concave die with a diameter of 10 mm on a tableting machine, each weighing 0.45 g, equivalent to 2.3 g of the original drug. This yields a tablet composition for treating rheumatic pain.

[0046] 3. Product characteristics and quality inspection This product is a brownish-yellow, round tablet with a smooth surface, a slightly fragrant odor, and a bitter and slightly pungent taste. According to the General Chapter (0101) of Part IV of the 2025 edition of the Chinese Pharmacopoeia, 20 tablets were weighed, and the average tablet weight was 0.451 grams. The weight difference was within ±5%, which meets the requirements. Disintegration time test: Six tablets were placed in a disintegration apparatus with 37°C water as the medium. The average disintegration time was measured to be 28 minutes, indicating complete disintegration, which meets the requirements for ordinary oral tablets.

[0047] High-performance liquid chromatography (HPLC) was used to determine the representative components osthol (derived from Notopterygium incisum) and paeoniflorin (derived from Paeonia lactiflora) in this formula. The chromatographic conditions were: C18 column (4.6 mm × 250 mm, 5 μm), mobile phase acetonitrile-0.1% phosphoric acid water (35:65), detection wavelength 254 nm, flow rate 1.0 mL / min, and column temperature 30 °C. The results showed that each tablet contained 0.46 mg of osthol and 1.22 mg of paeoniflorin, which were higher than the proposed limits (0.42 mg / tablet and 1.15 mg / tablet, respectively).

[0048] 4. Anti-inflammatory effect experiment The anti-inflammatory effect was evaluated using a xylene-induced mouse ear swelling model. Sixty SPF-grade KM mice (half male, half female, weighing 20±2 g) were randomly divided into six groups of ten mice each: a blank control group (administered via gavage with an equal volume of physiological saline), a positive control group (administered via gavage with ibuprofen suspension at a dose of 50 mg / kg), a model group (inducing inflammation without administration), and low, medium, and high dose groups of the tablets of this invention (2.3 g / kg, 4.6 g / kg, and 9.2 g / kg, respectively, based on the raw drug content). All groups were administered the medication via gavage once daily for seven consecutive days. One hour after the last administration, except for the blank control group, 0.03 ml of xylene was evenly applied to both sides of the right auricle of the mice to induce inflammation; the left ear was left untreated. One hour after inducing inflammation, the mice were sacrificed, both ears were cut off, and ear pieces were punched from the same location using an 8 mm diameter punch. The pieces were accurately weighed, and the degree of swelling (the weight of the right ear minus the weight of the left ear) and the swelling inhibition rate (the difference between the swelling degree of the model group and the swelling degree of the treatment group divided by the swelling degree of the model group multiplied by 100%) were calculated.

[0049] The results showed that the average swelling degree in the model group was 14.23±2.54 mg; the average swelling degree in the ibuprofen positive control group was 5.67±1.28 mg, with an inhibition rate of 60.2%; the average swelling degree in the low-dose group of this invention was 10.45±2.01 mg, with an inhibition rate of 26.6%; the average swelling degree in the medium-dose group was 7.82±1.65 mg, with an inhibition rate of 45.0%; and the average swelling degree in the high-dose group was 5.93±1.33 mg, with an inhibition rate of 58.3%. Compared with the model group, the swelling degree in the medium- and high-dose groups of this invention showed extremely significant differences (P<0.01), and the effect of the high-dose group was comparable to that of the positive control drug ibuprofen (P>0.05). This indicates that the pharmaceutical composition tablets of this invention have a significant inhibitory effect on acute inflammation.

[0050] 5. Analgesic effect experiment The analgesic effect was evaluated using the hot plate test. Sixty female KM mice, weighing 20±2 grams, were used. Mice with a pain threshold between 5 and 30 seconds were first selected. Grouping and administration regimens were the same as in the anti-inflammatory experiment. The baseline pain threshold of each mouse was measured before administration (the mouse was placed on a 55±0.5℃ constant-temperature hot plate, and the time from placement to licking the hind paw was recorded). The pain threshold was measured again at 30, 60, 90, and 120 minutes after the last administration, and the percentage increase in pain threshold was calculated as: post-administration pain threshold minus pre-administration pain threshold divided by pre-administration pain threshold multiplied by 100%.

[0051] The results showed that 60 minutes after administration, the pain threshold increase rate in the model group was only 3.2%, indicating that the pain model was stable; the pain threshold increase rate in the ibuprofen group was 68.7%; and the rates for the low-dose group, medium-dose group, and high-dose group of this invention were 31.5%, 55.4%, and 71.2%, respectively. There was no statistically significant difference between the high-dose group and the ibuprofen group (P>0.05). 120 minutes after administration, the pain threshold increase rate in the high-dose group remained at 58.3%, indicating that the analgesic effect can be sustained for a relatively long time. These results confirm that the tablets of this invention have a significant analgesic effect that is dose-dependent.

[0052] 6. Conclusion The oral tablets prepared in this embodiment have a stable process and controllable quality. They show good anti-inflammatory and analgesic effects in xylene-induced acute inflammation and hot plate pain models. The high-dose group has an effect comparable to ibuprofen, a commonly used nonsteroidal anti-inflammatory drug, and no obvious adverse reactions were observed. It is suitable for the treatment of rheumatic pain.

[0053] Example 2: Preparation and long-term stability study of granules 1. Raw material ratio Weigh the following raw materials in the indicated weight proportions: Clematis chinensis 10 parts, Angelica pubescens 10 parts, Notopterygium incisum 8 parts, Stephania tetrandra 6 parts, Cinnamomum cassia 5 parts, Paeonia lactiflora 10 parts, Glycyrrhiza uralensis 5 parts, Ligusticum chuanxiong 5 parts, Angelica sinensis 10 parts, Boswellia carterii 4 parts, and Commiphora myrrha 4 parts. Among them, Boswellia carterii and Commiphora myrrha are vinegar-processed, and Paeonia lactiflora is wine-fried.

[0054] 2. Preparation method (using ultrafine grinding and granulation process) The first step is raw material pretreatment: Impurities are removed from each raw material, and they are dried in a 40℃ oven for 15 hours until the moisture content is below 7%. The dried herbs are then coarsely crushed using a conventional pulverizer until they can pass through a 40-mesh sieve, and then transferred to an ultrafine pulverizer. The powder is pulverized at -10℃ for 30 minutes to obtain ultrafine powder. Laser particle size analysis shows a D90 of 18.6 micrometers (equivalent to over 800 mesh). Ultrafine pulverization helps improve the dissolution rate and bioavailability of the active ingredients in the herbs.

[0055] The second step is mixing and granulation: The above ultrafine powder is added to a high-efficiency wet mixing and granulation machine and dry-mixed for 5 minutes. Using purified water as a wetting agent, purified water (approximately 35% of the total material mass) is sprayed in under the conditions of a stirring speed of 200 rpm and a cutting speed of 1500 rpm, and granulation continues for 3 minutes to obtain a soft material. The soft material is then passed through a 14-mesh sieve to form wet granules.

[0056] The third step is drying and granulation: the wet granules are spread evenly in a fluidized bed dryer, the inlet air temperature is 65℃, and the material temperature is controlled at about 45℃, until the moisture content of the granules is less than 3%. The dried granules are then granulated through a 12-mesh sieve and then through a 60-mesh sieve to remove fine powder, resulting in uniform granules.

[0057] Step 4, Mixing and Packaging: Add 0.5% steviol glycosides as a flavoring agent and 0.8% magnesium stearate as a flow aid to the granules, and mix for 20 minutes. Package the mixed granules using an aluminum-plastic composite film, with each bag containing 5 grams, equivalent to 9.8 grams of the original herb. This yields the granule formulation of the drug composition for treating rheumatic pain.

[0058] 3. Product characteristics and quality indicators This product consists of yellowish-brown to brownish-yellow granules with a slightly fragrant odor and a sweet, slightly bitter taste. Particle size test: 50 grams of granules were tested according to the sieving method in the Chinese Pharmacopoeia. 2.1% of the granules failed to pass through a 12-mesh sieve, and 4.3% passed through a 60-mesh sieve. Both meet the particle size requirements for granules (no more than 10% should fail to pass through a 12-mesh sieve, and no more than 15% should pass through a 60-mesh sieve). Solubility test: 10 grams of granules were heated to 200 ml of hot water and stirred for 5 minutes until completely dissolved. Slight turbidity is permissible, and there should be no burnt residue or other foreign matter. Moisture content test: A rapid moisture analyzer was used, and the moisture content was measured to be 2.6%, lower than the moisture limit for granules (6%).

[0059] Content determination: Using the HPLC method described in Example 1, each bag contained 0.87 mg of osthol and 2.31 mg of paeoniflorin. Because this example used ultrafine grinding technology, the extraction rate of active ingredients was increased by approximately 18% and 22% respectively compared to granules prepared by ordinary grinding (passing through an 80-mesh sieve).

[0060] 4. Long-term stability assessment The product was placed in a constant temperature and humidity chamber according to its commercial packaging (aluminum-plastic composite film bag) and subjected to a long-term stability test at a temperature of 25℃±2℃ and a relative humidity of 60%±5% for 24 months. Key indicators were sampled and tested at 0, 3, 6, 9, 12, 18 and 24 months.

[0061] The stability results are as follows: At 0 months, the product is a yellowish-brown granule with a moisture content of 2.6%, osthol content of 0.87 mg / bag, and paeoniflorin content of 2.31 mg / bag; solubility is acceptable. At 6 months, the product remains unchanged, with a moisture content of 2.7%, osthol content of 0.86 mg / bag (98.9% of the initial value), and paeoniflorin content of 2.29 mg / bag (99.1% of the initial value). At 12 months, the product has slightly darkened but remains brownish-brown, with a moisture content of 2.9%, osthol content of 0.85 mg / bag (97.7% of the initial value), and paeoniflorin content of 2.26 mg / bag (97.8% of the initial value). At 24 months, the product remains a brownish-brown granule with a moisture content of 3.1%, osthol content of 0.83 mg / bag (95.4% of the initial value), and paeoniflorin content of 2.22 mg / bag (96.1% of the initial value). The microbial limits at all testing time points met the requirements (total aerobic bacteria <1000 CFU / g, total mold and yeast <100 CFU / g, and no Escherichia coli detected). These results indicate that the product remained stable in quality during the 24-month observation period, with the content of the active ingredient decreasing by less than 5%, meeting the requirements for long-term storage of traditional Chinese medicine preparations.

[0062] 5. Conclusion This embodiment utilizes ultrafine pulverization technology combined with wet granulation to prepare granules, which are characterized by uniform particle size, good solubility, and pleasant taste. A 24-month long-term stability study showed that the product quality remained stable, the active ingredients were well preserved, and it is suitable for long-term clinical use.

[0063] Example 3: Preparation of topical plaster and evaluation of transdermal absorption 1. Raw material ratio Weigh the following raw materials in the indicated weight proportions: Clematis chinensis 15 parts, Angelica pubescens 7 parts, Notopterygium incisum 11 parts, Stephania tetrandra 9 parts, Cinnamomum cassia 7 parts, Paeonia lactiflora 6 parts, Glycyrrhiza uralensis 3 parts, Ligusticum chuanxiong 7 parts, Angelica sinensis 7 parts, Boswellia carterii 2.5 parts, Commiphora myrrha 2.5 parts. Boswellia carterii and Commiphora myrrha are processed with vinegar, and Paeonia lactiflora is stir-fried with wine.

[0064] 2. Preparation method (to prepare a topical plaster) Step 1, Raw material extraction: After coarsely crushing the above-mentioned raw materials, add 10 times their total mass by volume of 70% ethanol, heat and reflux twice, 1.5 hours each time, combine the extracts, filter, and concentrate under reduced pressure to obtain a fluid extract with a relative density of 1.10 (measured at 50℃). The fluid extract is then set aside.

[0065] Step 2, Base Preparation: Weigh the following plaster base materials according to the following weight ratios: 3 parts sodium polyacrylate, 0.1 parts aluminum hydroxyl, 0.2 parts tartaric acid, 20 parts glycerin, 15 parts purified water, 1 part carbomer, and 1.5 parts polyvinylpyrrolidone. Disperse the sodium polyacrylate, aluminum hydroxyl, and tartaric acid in glycerin and stir for 30 minutes until homogeneous to obtain phase A. Dissolve the carbomer and polyvinylpyrrolidone in purified water and allow them to swell completely to obtain phase B. Mix phase A and phase B and stir in a vacuum mixer for 20 minutes to obtain a homogeneous base adhesive.

[0066] The third step, drug addition and application: Mix the above fluid extract and base adhesive at a mass ratio of 1:5, add 1% azone (by mass of the total drug composition) as a transdermal absorption enhancer, and continue vacuum stirring for 15 minutes until the drug and base are completely homogeneous. Apply the drug-containing base to a non-woven fabric backing layer to a thickness of 0.8 mm, then cover with a release film, and dry in a 40°C oven for 4 hours to remove excess moisture. Cut into 7 cm × 10 cm patches, each containing approximately 4.5 grams of raw drug. This yields a topical patch formulation for treating rheumatic pain.

[0067] 3. Product characteristics and quality control This product is a light brown gel patch, applied to a non-woven fabric backing layer and covered with a polyethylene release film. The patch surface is smooth and free of air bubbles. Adhesion test: Measured using the rolling ball ramp method, the rolling ball number is 15, which meets the adhesion requirements for gel patches (generally not lower than 10). Formability test: After placing the patch at 37℃ for 30 minutes, there was no dripping. Patch content test: Three patches were taken, the release film removed, and accurately weighed; each patch contained 2.85 ± 0.12 grams of patch.

[0068] Content determination: One plaster was taken, cut into pieces, and extracted with methanol by ultrasonication for 30 minutes. After filtration, the content was determined by HPLC according to Example 1. Each plaster contained 0.28 mg of osthol and 0.79 mg of paeoniflorin.

[0069] 4. Transdermal absorption test The in vitro transdermal properties of this product were evaluated using the Franz diffusion cell method. Abdominal skin was collected from healthy male SD rats, subcutaneous fat and tissue were removed, and the skin was rinsed thoroughly with physiological saline. The patch sample was cut into 1.5 cm diameter discs and applied to the stratum corneum side of the skin, with the dermis facing the receiving cell. 15 mL of pH 7.4 phosphate buffer (37°C) was injected into the receiving cell, and the mixture was magnetically stirred at 300 rpm. Samples (1 mL) were taken at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours, and an equal volume of fresh receiving solution was immediately added. The concentration of osthol in the receiving solution was determined by HPLC, and the cumulative permeation and transdermal rate were calculated.

[0070] The results showed that osthol had a cumulative permeation rate of 7.82 μg / cm² over 24 hours, with a transdermal rate of 0.33 μg / cm²·h. Paeoniflorin had a cumulative permeation rate of 4.56 μg / cm² over 24 hours, with a transdermal rate of 0.19 μg / cm²·h. The transdermal rates of the azone-containing samples were 2.8-fold and 2.3-fold higher than those of the azone-free control samples, respectively, indicating that azone has a significant permeation-enhancing effect on the pharmaceutical compositions of the present invention.

[0071] 5. Local irritation test Six healthy New Zealand rabbits (half male and half female), weighing 2.0–2.5 kg, were selected. Hair was shaved symmetrically on both sides of the spine, covering an area of ​​approximately 10 cm × 10 cm. A self-comparison method was used, with the product (3 cm × 3 cm) applied to the shaved area on the left side and a blank substrate applied to the right side as a control. The patches were secured with non-irritating medical tape. After 4 hours, the patches were removed, and any remaining residue was washed off with warm water. The rabbits were observed for irritation reactions such as erythema and edema on their skin at 1, 24, 48, and 72 hours after patch removal.

[0072] Results: No abnormal reactions such as erythema, edema, pigmentation, or tissue degeneration were observed at either the administration or control sites in any of the experimental rabbits. According to the skin irritation reaction scoring standard, the average score for this product was 0, indicating it is non-irritating. This demonstrates that the topical patch of this invention does not cause local irritation to normal skin and is safe to use.

[0073] 6. Conclusion The preparation process of the topical patch in this embodiment is feasible, resulting in a smooth patch surface and suitable adhesion. Transdermal absorption experiments show that, with the aid of azone, the active ingredients can continuously penetrate the skin and enter the body. Local irritation experiments confirm that this product is safe and non-irritating to the skin. This patch is convenient to use, provides a high local concentration at the application site, and is suitable for long-term external use by patients with rheumatic pain to relieve joint and muscle pain.

[0074] It should be noted that, in this document, relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, the phrase "comprising an element defined as..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0075] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for treating rheumatic pain, characterized in that, This composition is made from the following parts by weight of active pharmaceutical ingredient: Clematis chinensis 8-16 parts, Angelica pubescens 6-12 parts, Notopterygium incisum 6-12 parts Stephania tetrandra 5-10 parts, Cinnamomum cassia 4-8 parts, Paeonia lactiflora 5-10 parts Licorice root 3-6 parts, Sichuan lovage rhizome 4-8 parts, Angelica sinensis root 6-12 parts Frankincense 2-5 parts, myrrh 2-5 parts.

2. The pharmaceutical composition for treating rheumatic pain according to claim 1, characterized in that, The weight parts of the active pharmaceutical ingredient are: Clematis chinensis 12 parts, Angelica pubescens 9 parts, Notopterygium incisum 9 parts, Fangji 8 parts, Guizhi 6 parts, Baishao 8 parts Licorice 4 parts, Ligusticum chuanxiong 6 parts, Angelica sinensis 9 parts Frankincense 3 parts, myrrh 3 parts.

3. The pharmaceutical composition for treating rheumatic pain according to claim 1, characterized in that, The weight parts of the active pharmaceutical ingredient are: Clematis chinensis 10 parts, Angelica pubescens 10 parts, Notopterygium incisum 8 parts Fangji 6 parts, Guizhi 5 parts, Baishao 10 parts Licorice root 5 parts, Sichuan lovage rhizome 5 parts, Angelica sinensis root 10 parts Frankincense 4 parts, myrrh 4 parts.

4. The pharmaceutical composition for treating rheumatic pain according to claim 1, characterized in that, The weight parts of the active pharmaceutical ingredient are: Clematis chinensis 15 parts, Angelica pubescens 7 parts, Notopterygium incisum 11 parts Fangji 9 parts, Guizhi 7 parts, Baishao 6 parts Licorice root 3 parts, Sichuan lovage rhizome 7 parts, Angelica sinensis root 7 parts Frankincense 2.5 parts, myrrh 2.5 parts.

5. A pharmaceutical composition for treating rheumatic pain according to claims 1 to 4, characterized in that, Both the frankincense and myrrh are processed with vinegar, and the white peony root is stir-fried with wine.

6. A method for preparing a pharmaceutical composition for treating rheumatic pain, used to prepare the pharmaceutical composition according to claims 1 to 5, characterized in that, The preparation method includes the following steps: Step A: Weigh each raw material according to the stated weight proportions, dry them, pulverize them into coarse powder, mix them evenly, and obtain mixed coarse powder; Step B: Add 6 to 10 times the total mass of the mixed coarse powder to ethanol with a volume fraction of 60% to 80%, and reflux extract at 60 to 80°C 1 to 3 times, 1 to 2 hours each time. Combine the extracts, filter, and obtain the alcohol extract. Step C: The alcohol extract is concentrated under reduced pressure at 50-70°C to a clear extract with a relative density of 1.10-1.20, and then dried under vacuum or by spray drying to obtain a dried extract; Step D: Crush the dried extract, pass it through an 80-120 mesh sieve, add conventional excipients according to pharmaceutical methods, and prepare a clinically acceptable dosage form.

7. A method for preparing a pharmaceutical composition for treating rheumatic pain according to claim 6, characterized in that, The dosage form is tablet, capsule, granule, pill, powder, oral liquid, ointment, plaster or spray.

8. A method for preparing a pharmaceutical composition for treating rheumatic pain according to claim 6, characterized in that, The reflux extraction described in step B adopts a segmented temperature-variable extraction process: the first extraction stage is carried out at 65°C for 1.5 hours, and the second extraction stage is carried out at 75°C for 1 hour, with the volume fractions of ethanol in the two extractions being 70% and 60%, respectively.

9. The use of a pharmaceutical composition for treating rheumatic pain according to any one of claims 1 to 5 in the preparation of a medicament for treating rheumatic pain caused by rheumatoid arthritis, osteoarthritis or gouty arthritis.

10. The application of the pharmaceutical composition for treating rheumatic pain according to claim 9, characterized in that, The drug is also used to prepare topical preparations for relieving rheumatic pain of the cold-dampness obstruction type or the blood stasis obstruction type. The topical preparations contain the drug composition and a transdermal absorption enhancer. The transdermal absorption enhancer is azone or propylene glycol, and its dosage is 0.5% to 2% of the total mass of the drug composition.

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