WO2002069971A1

WO2002069971A1 - Pharmaceutical compositions and dietary supplements for treatment or improvement of arthitis

Info

Publication number: WO2002069971A1
Application number: PCT/CN2001/000316
Authority: WO
Inventors: Deru Lu
Original assignee: Molecular Biology Limited
Priority date: 2001-03-05
Filing date: 2001-03-05
Publication date: 2002-09-12
Also published as: CN1218697C; CN1523990A; WO2002069971A8

Abstract

The present invention provides pharmaceutical compositions and dietary supplements for treatment or improvement of arthritis, especially rheumatoid arthritis, and each of them contains, base on weight of the total composition, 30-50mg/g sinomemine, 8-15mg/g TGP and 1.5-3mg/g ferolic acid as active ingredients, in combination with pharmaceutically acceptable carriers. It also provides methods for preparation of pharmaceutical compositions and dietary supplements according to the present invention have significant effects on rheumatoid arthritis.

Description

Pharmaceutical composition and dietary supplement for treating or improving arthritis Field of the Invention

The present invention relates to a pharmaceutical composition and a dietary supplement for treating or improving arthritis, especially rheumatoid arthritis, and a preparation method thereof. Related background technology

Rheumatoid arthritis (RA) is a common disease. Frequently. It is more common in temperate and cold regions and can occur at any age. Its incidence will increase with age. Women are susceptible to this disease, with a male-to-female ratio of 1: 3.5. The incidence in economically developed countries ranges from 0.4% to 1%, compared with 1% in the United States, which is approximately 18 million patients. My country is 0.6%, with about 80 million patients.

Rheumatoid arthritis is an autoimmune disease with complex etiology. It is generally believed that the cause is some genetically susceptible people. Under the influence of some inducements (cold, humid), certain microorganisms can invade the synovial membrane and lymphocytes of the joint. In this case, when the suppressor T cells are low in function, they can induce B cell proliferation and immunoglobulin degeneration, and this degenerate immunoglobulin becomes an antigen, which causes immune cells to produce an immune response and cause synovial tissue. A series of symptoms such as inflammation, joint swelling, and pain.

At present, the commonly used drugs for treating rheumatoid arthritis in clinical practice are anti-inflammatory drugs, steroids and immunosuppressive agents. After using these drugs, symptoms can usually be relieved, but the side effects are large.

In terms of treating rheumatoid arthritis, China has accumulated rich experience in Chinese medicine and traditional Chinese medicine. Basically, there are two types of compound prescriptions and single prescriptions. Although some compound traditional Chinese medicines have good effects, they often use more than 10 or even 20 Medicinal herbs. For example, in the Chinese invention patent CN1175433 entitled "A drug for treating rheumatoid arthritis and its production method" (application on August 30, 1996, public announcement on March 11, 1998), a therapeutic class is disclosed Oral preparation of rheumatoid arthritis and rheumatoid arthritis, which contains black snake (10 servings), green wind rattan (15 servings), white peony (10 servings), angelica (10 servings), cooked land (15 servings), Twelve flavor drugs such as safflower (3 servings), sea breeze rattan (15 parts), whole scorpion (5 parts), chicken blood rattan (15 parts), black ants (5 parts) (weight ratio), among which The weight accounts for 15/133 (about 11%) of all medicinal materials. With the exception of black ants, other drugs are extracted with water. However, there is basically no systematic research on which medicinal materials play a role in treatment, and there is some blindness. In addition, although some unilateral medicines also have certain effects, due to the complex etiology of rheumatoid arthritis, the efficacy of unilateral medicine is very limited.

Modern western medicine has made important contributions to treating diseases and maintaining human health, but for some diseases, some western medicines cannot cure, can only relieve symptoms, and are more expensive and may cause serious side effects. Confirmed in recent years In the future, dietary supplements have gradually attracted people's interest and created a multi-billion dollar market. The so-called dietary supplement is a product made from plants. It also undergoes rigorous scientific and clinical research like chemical drugs. Generally speaking, it is cheaper and safer. It is more effective in treating chronic diseases than western medicine, and it does not require FDA approval in the United States. Can be listed. The development of dietary supplements with efficacy in treating rheumatoid arthritis has also gradually become a research focus in the field.

Therefore, there is an urgent need in the art to develop new drugs and / or dietary supplements for treating rheumatoid arthritis and methods for preparing the same. Object of the invention

The purpose of the present invention is to provide a medicine and / or dietary supplement containing pure Chinese medicine extract, which has significant effects on treating rheumatoid arthritis and rheumatoid arthritis. Summary of invention

In a first aspect of the present invention, a pharmaceutical composition is provided, which contains the following active ingredients based on the total weight of the composition:

Sinomenine 30-50 mg / g;

Paeoniflorin 8-15mg / g;

Ferulic acid 1. 5-3mg / g,

And pharmaceutically acceptable carriers.

Preferably, the content of sinomenine is 40-50 mg / g, and paeoniflorin is 10-15 mg / g.

In addition, a pharmaceutical composition of the present invention can also be limited by the number of medicinal materials. In other words, the pharmaceutical composition of the present invention contains necessary components selected from the group consisting of:

45-85 parts by weight of blue wind rattan;

8-20 parts by weight

3- 10 parts by weight of angelica,

In addition, the weight of Qingfengteng + Baiji + Angelica sinensis accounts for 30-99% of the total weight of the composition, and the balance of the pharmaceutically acceptable carrier.

Preferably, the medicinal composition contains 55-85 parts by weight of green wind rattan; 10-20 parts by weight of white pupa; 4-10 parts by weight of angelica, and the weight of green wind vine + white pupa + angelica 50-99% of the total composition. More preferably, the medicinal composition contains 60-85 parts by weight of green wind rattan; 12-15 parts by weight of white peony, and 5-8 parts by weight of angelica. In a second aspect of the present invention, there is provided a dietary supplement containing essential components selected from the group consisting of:

45-85 parts by weight of blue wind rattan;

8-20 parts by weight

3- 10 parts by weight of angelica,

In addition, the weight of Qing Feng Teng + Bai Zhi + Angelica sinensis accounts for 30-99% of the total weight of the supplement, and the balance of the pharmaceutically acceptable carrier.

Preferably, the dietary supplement contains 55-85 parts by weight of green wind rattan; 10-20 parts by weight of white pupa; 4-10 parts by weight of angelica, and the weight of green wind vine + white pupa + angelica SO-99% of the total weight of the composition.

In a third aspect of the present invention, a method for preparing a pharmaceutical composition or dietary supplement of the present invention is provided, which comprises the steps of:

(1) extracting the green wind rattan medicinal material by infiltration with water to obtain an aqueous solution containing sinomenine, and then concentrating the green wind rattan extract with a sinomenine content of 10-20%;

(2) Extracting Angelica sinensis and Baiji extract by water extraction;

(3). Mixing the extract of Qingfeng Rattan with Angelica sinensis and Baiji extract to obtain a pharmaceutical composition having an active ingredient at a desired concentration,

The order of steps (1) and (2) is interchangeable.

Preferably, the medicinal material used for the green wind rattan is a green wind rattan coarse powder with a high sinomenine content. Detailed description of the invention

After extensive and intensive research, the inventors have designed and developed an effective target site related to the onset of rheumatoid arthritis based on the "multi-target" theory under the guidance of the pathogenesis of rheumatoid arthritis. "The compound traditional Chinese medicine preparation, the formula is basically composed of the following effective components: Qingfeng Rattan, Bai Zhi, Angelica. Sinomenine and paeony total glycosides in the preparation have anti-inflammatory, analgesic, and multiple immunomodulatory effects, can eliminate symptoms and prevent the development of the disease, and ferulic acid can both improve the activity of T cells and prevent allergies and prevent side effects . Clinical tests have shown that this is a scientific and effective formula. As used herein, the term "essential component" refers to the essential Chinese medicinal material, namely Qingfengteng i? ), S ^ {Paeomia lacti flora) ¾ jl3 (Angelica sinensis).

As used herein, the term "essential ingredient" refers to a chemical substance necessary as an active ingredient, i.e.Ivy Base (Sinomemine), total glucosides of paecony (TGP) and ferrolic acid.

As used herein, the terms "paeonyin" and "paeoniflorin" are used interchangeably, and both refer to the glucosides in paeony.

As used herein, the term "consisting essentially of" means that in the composition, in addition to the essential ingredients or essential ingredients, minor ingredients that do not affect the active ingredients and / Or impurities. For example, sweeteners may be included to improve taste, antioxidants to prevent oxidation, and other commonly used additives in the art! Usually blue wind rattan (■ SV JO He Hii / ZB acutum), white pheasant (corpse aecwia _ / 3c iij ara) and angelica C½ ic3

It accounts for at least 70%, preferably at least 80%, and more preferably at least 90% of the total weight of Chinese medicinal materials.

As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier for the administration of a therapeutic agent, including various excipients and diluents. The term refers to pharmaceutical carriers that are not essential active ingredients per se and are not excessively toxic after administration. Suitable vectors are well known to those of ordinary skill in the art. A full discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (Mack Pub. Co., N. J. 1991). Pharmaceutically acceptable carriers in the composition may contain liquids such as water, saline, glycerol, and ethanol. In addition, there may be auxiliary substances in these carriers, such as wetting or emulsifying agents, pH buffering substances, and the like. Non-essential ingredients other than essential ingredients (Sinomemine, Total glucosides of paecony (TGP), and Ferolic acid) from Qingfengteng, Baiji, Angelica sinensis. Ingredients, as well as other non-essential ingredients (such as other auxiliary medicinal materials), are also included in the definition of a pharmaceutically acceptable carrier.

As used herein, the term "composition of the invention" includes pharmaceutical compositions and dietary supplements as long as they contain or consist essentially of (1) Sinomenine or Sinomenine; (2) Paeonia lactiflora or Paeonia lactiflora; And (3) Angelica or ferulic acid. In general, the weight of Qingfeng Rattan + Baiji + Angelica sinensis is 30-99%, preferably 50-99%, and more preferably 60-90% of the total weight of the composition. In a preferred example, the composition of the present invention usually does not contain other traditional Chinese medicines currently contained in compound traditional Chinese medicines for treating rheumatoid arthritis, such as black ants, salvia miltiorrhiza, whole scorpion and the like. In the pharmaceutical composition of the present invention, the three traditional Chinese medicinal materials as an essential component are (1) Sinome ium acutum, wherein the active ingredient is Sinomemine; (2) Paeomia lacti flora); The active ingredient is Total glucosides of paecony (TGP); and (3) Angelica sinensis), and the active ingredient is Ferolic acid. The onset of rheumatoid arthritis is related to immune abnormalities, which are mainly manifested by low inhibitory T cell function and abnormal increase in monocyte macrophage function. Clinically, it is a series of symptoms including inflammation of synovial tissue, joint swelling and pain. For this reason, the inventors specially designed a medicine consisting of green wind rattan, white peony, and angelica. The active component of Sinomenine is to promote the release of histamine to relieve pain, and to inhibit the activated macrophages to play an anti-inflammatory effect. The total glycosides of paeony in Paeonia lactiflora can restore the function of inhibitory T cells. And reduce inflammatory factors, thereby restoring immune function; the role of ferulic acid in angelica is to regulate histamine release, thereby reducing side effects caused by Sinomenine, and reducing the amount of prostaglandin E2 (an inflammatory factor) release, Thereby anti-inflammatory. Therefore, the pharmaceutical composition of the present invention can comprehensively target various causes of rheumatoid arthritis, and thus can effectively treat or improve the symptoms of rheumatoid arthritis.

The therapeutic effect of the medicine of the present invention on rheumatoid arthritis is closely related to the content of necessary active ingredients. Studies have shown that in order to achieve a stable effect of treating rheumatoid arthritis, the active ingredient content of the drug should be brought to a certain range. The range of reasonable content of each active ingredient in the drug is:

Sinomenine 30-50 mg / g, preferably 40-50 mg / g,

Paeoniflorin 8-15 mg / g, preferably 10-15 mg / g,

Ferulic acid 1. 5- 3 mg / g. In addition to defining the composition of the present invention according to the necessary active ingredients, the composition of the present invention can also be defined by the ratio of the necessary components (medicines).

In the composition of the present invention, a suitable ratio of the three essential medicinal materials is -45-85 parts by weight, preferably 55-85 parts by weight, and more preferably 60-85 parts by weight. vine;

8-20 parts by weight, preferably 10-20 parts by weight, more preferably 12-15 parts by weight of white peony; 3-10 parts by weight, preferably 4-10 parts by weight, more preferably 5-8 parts by weight of Angelica sinensis, and the weight of the green wind rattan + white lotus + angelica sinensis accounts for 30-99%, preferably 50-99%, more preferably 60-95% of the total weight of the composition. The balance is a pharmaceutically acceptable carrier, such as starch, maltodextrin, and the like. In order for the preparation to have a good therapeutic effect, the effective active ingredient content in the preparation is the key. To this end, the inventors have also established a set of high-performance liquid phase (HPLC) measurement methods for detecting active ingredients in various Chinese medicinal materials in the preparation to monitor various active ingredients in raw materials and preparations.

The pharmaceutical composition or dietary supplement of the present invention can be made into any conventional preparation form by a conventional method, preferably a tablet or capsule preparation. In another aspect of the present invention, a method for preparing a pharmaceutical composition or dietary supplement of the present invention is provided.

It is difficult for conventional Chinese medicine extraction methods to achieve a higher concentration of active ingredients in the extract to ensure the efficacy of the preparation. The inventors have found that when using Qingfeng Teng to treat rheumatoid arthritis according to pharmacological research, the effective dose for adults is preferably 40-80mg / day, so that each gram of preparation should contain 40-50mg of sinomenine, and this concentration This is not possible with normal extraction methods. An effective method for extracting sinomenine was designed for this purpose.

In this extraction method, the sinomenine coarse powder with high sinomenine content is first extracted with water to infiltrate to obtain the sinomenine-containing aqueous solution, and then concentrated in a rotary evaporator to 10% -20% Blue Wind Vine Extract. In this way, a raw material with high sinomenine content can be obtained.

At the same time, the conventional water extraction method was used to obtain the extract of Angelica sinensis and Baiji. For example, angelica is mixed with water and heated, and then the obtained solution is concentrated to obtain an angelica concentrate (such as an extract). In addition, angelica concentrate powder was obtained after spray drying. Similarly, extracts of Paeonia lactiflora can be obtained. Of course, preferably, it is possible to obtain a concentrate (such as an extract) containing both angelica and paeoniae effective components.

Finally, according to the needs of the formulation, a certain proportion of these extracts are formulated together, so that the required concentration can be achieved.

In one embodiment, a method for preparing a medicament of the present invention includes the steps:

(1) Select the sinomenine coarse powder with high sinomenine content, extract with water infiltration to obtain the sinomenine-containing aqueous solution, and then concentrate to the sinomenine content of sinomenine 10-20% extract.

(2) Obtain Angelica sinensis and Baiji extract by conventional water extraction method.

(3) Finally, according to the requirements of the preparation, these two extracts are mixed together, so that the required concentration can be achieved, and the order of steps (1) and (2) can be interchanged. The advantages of the invention are:

(1) The composition is simple, the active ingredients are clear and targeted;

(2) The active ingredients can be quantitatively controlled to ensure the quality;

(3) Low cost;

(4) The effect is obvious. The present invention is further described below in conjunction with the examples. It should be understood that these examples are only used to illustrate the present invention and not to limit the present invention. In the examples, percentages are percentages by weight, and parts are parts by weight unless otherwise specified. Example 1

Preparation of pharmaceutical composition

In this embodiment, a pharmaceutical composition (composition A) is provided, wherein the ratio of the three traditional Chinese medicines is:

Blue wind rattan 82 parts by weight (820 g)

White peony 12 parts by weight (120 g)

Angelica 6 parts by weight (60 g)

The three traditional Chinese medicines used in this example are all tested by HPLC, and the quality meets the requirements.

Weigh a certain amount of green wind vine, extract the water with sinomenine from the water by infiltration method to obtain an aqueous solution containing sinomenine, and then concentrate it on a rotary evaporator to obtain green wind vine with a sinomenine content of 10-20%. extract.

Weigh a certain amount of angelica and peony, add 10 times the amount of water, heat and boil for 2 hours, pour out the liquid medicine, add 8 times the amount of water to the residue, heat and boil for 2 hours, combine the liquids, and also concentrate 5 克的原药材。 Into an extract, its concentration is equivalent to 1. 0-1. 5 grams of the original medicinal material per 1ml.

The green wind rattan water extract concentrate and angelica and white peony water extract concentrate are thoroughly mixed into a mixed stream extract, and vacuum dried (60 ~ 70 Ό) 3. 5-4. 0 hours to make a dry extract, The dry extract was pulverized, sieved with 60 mesh, and filled with capsules. In this example, Green Wind Vine + Baiji + Angelica sinensis accounted for about 80% of the total weight of the composition. Example 2

Effect on Arthritis

1. Dosage form: The medicine in the form of capsules is manufactured according to the method described in Example 1, each capsule containing 400 mg of the pharmaceutical composition.

2. Medication method: Patients diagnosed with rheumatoid arthritis are administered by a doctor, 2 capsules twice a day, 2 months as a course of treatment.

3. Efficacy evaluation:

Significant effect: Joint pain, bloating disappeared, and functional activities returned to normal. Laboratory indicators such as ESR and rheumatoid factor were normal.

Improvement: joint pain, swelling reduced, and functional activity improved.

Ineffective: No change compared to before treatment.

4. Statistics: A total of 50 cases were observed, and the results are as follows:

80 cases were markedly effective in 80%, 9 cases were improved in 18%, 1 case was ineffective in 2%, the total effective rate was 981 5. Toxic side effects: Liver and kidney function tests were performed before and after treatment on 50 patients taking the drug of the present invention, and the results were normal before and after treatment. In addition, it was reported that when taking Sinomenine tablets for rheumatoid arthritis, 1/3 Patients had redness, sweating, and other side effects at the beginning of taking the drug, but none of them had such reactions.

6. Typical case: Patient Mao XX, female, 82 years old, is a domestic woman, unable to walk down due to joint pain and swelling of the upper and lower extremities. She was diagnosed with rheumatoid arthritis. The swelling index and tenderness index were both 21. After taking the medicine of the present invention for a course of treatment, the swelling subsided, there was no more pain, and it was possible to get out of bed and take care of themselves, and the ESR also decreased from 34 to 20 mm / h. Follow-up for one and a half years has not recurred. Example 3

Relationship between the content of essential components or active ingredients and the effect of treatment

In this example, the relationship between the content of each medicinal material or its active ingredient in the pharmaceutical composition of the present invention and the effect on the efficacy of treating rheumatoid arthritis was analyzed.

A method similar to that described in Example 1 was used to prepare a composition with the following proportions, in which the total amount of green wind vine + white peony + angelica and the content of excipients were the percentage of the total weight of the composition. And test its efficacy according to the method described in Example 2.

The results show that these compositions can all have obvious effects on rheumatoid arthritis, and the effects can be improved and improved.

More than 80%.

Compositions 1-4 and Composition A in Example 1 were tested by high performance liquid phase (HPLC), the content of sinomenine was 30-50 mg / g; the content of paeoniflorin was 8-15 mg / g; the content of ferulic acid It is 1.5 to 3 mg / g. Example 4

Preparation of dietary supplements

According to a method similar to that in Example 1, a dietary supplement was prepared, in which the ratio of the three traditional Chinese medicines was-60 parts by weight of Qingfengteng (600 g)

10 parts by weight (100 g)

Angelica 5 parts by weight (50 g)

The prepared dry extract was pulverized, sieved with 60 mesh, and filled with capsules. In this example, Green Wind Vine + Baiji + Angelica sinensis accounted for about 70% of the total weight of the composition.

Claims

Claim

A pharmaceutical composition, characterized in that it contains the following active ingredients based on the total weight of the composition:

Sinomenine 30-50 mg / g;

Paeoniflorin 8-15mg / g;

Ferulic acid 1. 5-3mg / g,

And pharmaceutically acceptable carriers.

The pharmaceutical composition according to claim 1, wherein the content of sinomenine is 40-50 mg / g, and the paeoniflorin is 10-15 mg / g.

The pharmaceutical composition according to claim 1, which is a tablet or capsule preparation.

4. A pharmaceutical composition, characterized in that it contains essential components selected from the group consisting of:

45-85 parts by weight of blue wind rattan;

8-20 parts by weight

3-10 parts by weight of angelica,

The pharmaceutical composition according to claim 4, characterized in that it contains

55-85 parts by weight of blue wind rattan;

10-20 parts by weight

4- 10 parts by weight of angelica,

In addition, the weight of the green wind rattan + white peony + angelica is 50-99% of the total weight of the composition.

6. The pharmaceutical composition according to claim 4, characterized in that it contains

60-85 parts by weight of blue wind rattan;

12-15 parts by weight

5- 8 parts by weight of angelica.

The pharmaceutical composition according to claim 4, which is a tablet or capsule preparation.

8. A dietary supplement, characterized in that it contains the necessary components selected from the group consisting of:

45-85 parts by weight of blue wind rattan;

8-20 parts by weight

3- 10 parts by weight of angelica,

And the weight of Qingfengteng + Baiji + Angelica sinensis accounts for 30-99% of the total weight of the supplement, and the remaining amount Accepted vectors.

The dietary supplement according to claim 8, which contains

55-85 parts by weight of blue wind rattan;

10-20 parts by weight

4-10 parts by weight of angelica,

10. A method for preparing a pharmaceutical composition according to claim 1, characterized in that it comprises the steps-

(2) Extracting Angelica sinensis and Baiji extract by water extraction;

The order of steps (1) and (2) is interchangeable.