CN114209815A - Pharmaceutical composition and preparation method and application thereof - Google Patents
Pharmaceutical composition and preparation method and application thereof Download PDFInfo
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- CN114209815A CN114209815A CN202111385631.6A CN202111385631A CN114209815A CN 114209815 A CN114209815 A CN 114209815A CN 202111385631 A CN202111385631 A CN 202111385631A CN 114209815 A CN114209815 A CN 114209815A
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- pharmaceutical composition
- interleukin
- osteoarthritis
- hyaluronic acid
- controlled release
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2066—IL-10
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract
The invention relates to the field of pharmaceutical compositions, in particular to a pharmaceutical composition, a preparation method and application thereof, and more particularly to a pharmaceutical composition for preventing or treating inflammatory diseases, a preparation method and application thereof. The invention provides a pharmaceutical composition and a preparation method and application thereof, aiming at solving the problems that in the prior art, the structure of an anti-inflammatory drug is complex, the drug effect of the drug is easily influenced after a carrier is added, the sustained-release time is short, and the sustained-release effect cannot be fully exerted. The controlled release polymer and the interleukin-10 are combined for the first time to prepare the pharmaceutical composition, and experiments show that the interleukin-10 combined with the specific controlled release polymer can effectively relieve the damage of articular cartilage of a rat with an osteoarthritis model and inhibit the disease process of the osteoarthritis.
Description
Technical Field
The invention relates to the field of pharmaceutical compositions, in particular to a pharmaceutical composition, a preparation method and application thereof, and more particularly to a pharmaceutical composition for preventing or treating inflammatory diseases, a preparation method and application thereof.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Osteoarthritis (OA) is one of the most common degenerative diseases of the joints, resulting from complex interactions between genetic, metabolic, biochemical and biomechanical factors, causing damage to the articular cartilage.
At present, the strategies clinically used for treating osteoarthritis mainly comprise drug treatment of non-steroidal anti-inflammatory drugs, glucocorticoids and the like, local treatment of intra-articular injection of sodium hyaluronate, autologous chondrocyte implantation and the like, but the inventor finds that the final stage of the disease usually needs surgical intervention of joint replacement, osteotomy and the like. The existing osteoarthritis drugs have limited treatment effect, high operation treatment cost, large wound and more side effects, and limit the clinical treatment effect of osteoarthritis.
Although some prior arts disclose that anti-inflammatory drugs and other carriers form a drug-carrying structure to prevent or treat osteoarthritis, the anti-inflammatory drugs are complex in structure, and the drug effect of the drugs is easily affected after the carriers are added, and the slow release time is short, so that the slow release effect cannot be fully exerted.
Disclosure of Invention
The invention provides a pharmaceutical composition and a preparation method and application thereof, aiming at solving the problems that in the prior art, the structure of an anti-inflammatory drug is complex, the drug effect of the drug is easily influenced after a carrier is added, the sustained-release time is short, and the sustained-release effect cannot be fully exerted. The controlled release polymer and the interleukin-10 are combined for the first time to prepare the pharmaceutical composition, and experiments show that the interleukin-10 combined with the specific controlled release polymer can effectively relieve the damage of articular cartilage of a rat with an osteoarthritis model and inhibit the disease process of the osteoarthritis.
Specifically, the invention is realized by the following technical scheme:
in a first aspect of the present invention, there is provided a pharmaceutical composition comprising: a controlled release polymer and interleukin-10.
In a second aspect of the present invention, there is provided a process for preparing a pharmaceutical composition, comprising: dissolving the controlled release polymer in water, stirring to form gel, and adding interleukin-10.
In a third aspect of the invention, there is provided a use of a pharmaceutical composition for the manufacture of a medicament for the treatment of an IL-10 mediated disease.
One or more of the technical schemes have the following beneficial effects:
1) one or more technical schemes of the invention construct an interleukin-10 combined controlled release polymer system as a therapeutic drug for osteoarthritis. Wherein the interleukin-10 can inhibit osteoclast function, promote chondrocyte repair, and further maintain bone homeostasis balance. The controlled release polymer system can lubricate joint cavities and play a role in filling and supporting, can delay the biodegradation rate of hydrogel, prolongs the action time of interleukin-10, and plays a role in treating osteoarthritis for a long time and relieving local pain for a long time.
2) One or more technical schemes of the invention are combined with a biomedical and pharmaceutical delivery system, and the local drug concentration is improved, the systemic toxic and side effects possibly caused by the drug are reduced, the potential trauma caused by treating osteoarthritis is greatly reduced, and the invention has wide clinical application prospect.
3) According to one or more technical schemes, the interleukin-10 is added into the hyaluronic acid hydrogel and mixed to form an interleukin-10 combined hyaluronic acid hydrogel system, the preparation process is simple, the safety factor is high, the articular cavity injection administration of a medicine system is facilitated, and the toxic and side effects possibly caused by adding other organic auxiliary agents are effectively avoided.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention. Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a schematic diagram of an injectable hydrogel system of hyaluronic acid loaded with IL-10 according to example 1 of the present invention;
FIG. 2 is a schematic diagram of the knee joint surface of a rat model in example 1 of the present invention, wherein A is a blank control group, B is an osteoarthritis model group, and C is a hydrogel treatment group;
FIG. 3 is Micro-CT scanning and 3D images of a model rat knee joint in example 1 of the present invention, wherein A is a blank control group, B is a osteoarthritis model group, and C is a hydrogel treatment group;
FIG. 4 is a safranin O-fast green staining image of a pathological section of a knee joint of a model rat in example 1 of the present invention, wherein A is a blank control group, B is a osteoarthritis model group, and C is a hydrogel treatment group;
FIG. 5 is a statistical chart of OARSI scores in example 1 of the present invention;
FIG. 6 is a statistical chart of the results of the model rat pain test in example 1 of the present invention.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present disclosure. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The invention provides a pharmaceutical composition and a preparation method and application thereof, aiming at solving the problems that in the prior art, the structure of an anti-inflammatory drug is complex, the drug effect of the drug is easily influenced after a carrier is added, the sustained-release time is short, and the sustained-release effect cannot be fully exerted. The controlled release polymer and the interleukin-10 are combined for the first time to prepare the pharmaceutical composition, and experiments show that the interleukin-10 combined with the specific controlled release polymer can effectively relieve the damage of articular cartilage of a rat with an osteoarthritis model and inhibit the disease process of the osteoarthritis.
Specifically, the invention is realized by the following technical scheme:
in a first aspect of the present invention, there is provided a pharmaceutical composition comprising: a controlled release polymer and interleukin-10.
In one or more embodiments of the present invention, the controlled release polymer is a hydrogel ester.
In one or more embodiments of the present invention, the hydrogel ester is a hyaluronic acid derivative or a salt thereof, preferably hyaluronic acid.
In one or more embodiments of the present invention, the hyaluronic acid derivative is sodium hyaluronate.
Interleukin-10 is a multi-cell-derived, multifunctional cytokine that regulates the growth and differentiation of cells, participates in inflammatory and immune responses, and is a recognized inflammatory and immunosuppressive factor. Plays an important role in tumors, infections, organ transplantation, hematopoietic system and cardiovascular system, and is closely related to diseases of blood, digestion and particularly cardiovascular system.
In a second aspect of the present invention, there is provided a process for preparing a pharmaceutical composition, comprising: dissolving the controlled release polymer in water, stirring to form gel, and adding interleukin-10.
In one or more embodiments of the invention, the mass fraction of hyaluronic acid is 0.1-5%, preferably 2%; the concentration of interleukin-10 is 0.1-200. mu.g/mL, preferably 100. mu.g/mL.
The stirring temperature is 4-20 ℃, and the stirring time is 10-15 h.
In a third aspect of the invention, there is provided a use of a pharmaceutical composition for the manufacture of a medicament for the treatment of an IL-10 mediated disease.
In one or more embodiments of the invention, the IL-10 mediated disease is an inflammatory disease of the joints.
In one or more embodiments of the invention, the inflammatory disease of the joint is selected from rheumatoid arthritis, osteoarthritis and other inflammatory diseases caused by exertion, sprain, trauma, infection, cartilage damage or plastic surgery.
In one or more embodiments of the present invention, wherein the pharmaceutical composition is administered intra-articularly.
The present invention is described in further detail below with reference to specific examples, which are intended to be illustrative of the invention and not limiting.
Example 1
Preparation and characterization detection of interleukin-10 combined hyaluronic acid hydrogel system
(1) And (3) dissolving a proper amount of hyaluronic acid in distilled water, wherein the mass fraction of hyaluronic acid is 2%, and stirring at the low temperature of 10 ℃ for 12 hours to obtain the modified hyaluronic acid hydrogel.
(2) And adding the interleukin-10 into the hyaluronic acid hydrogel, and fully mixing at 250rpm for 40min, wherein the concentration of the interleukin-10 is 100 mug/mL, so as to obtain the hyaluronic acid hydrogel system loaded with the interleukin-10. The product prepared is shown in figure 1.
Example 2
Application of interleukin-10 combined hyaluronic acid water gel system in treatment of osteoarthritis
(1) Grouping experimental animals: 5 rats are randomly divided from 15 rats to serve as a blank control group, and the remaining 10 rats are subjected to joint cavity injection of sodium iodoacetate to construct a osteoarthritis model. 5 of 10 model rats were randomly selected as drug treatment groups for intra-articular administration treatment.
(2) Constructing an animal model: 1% sodium pentobarbital was administered intraperitoneally (40mg/kg) for anesthesia, skin preparation at the knee joint of rats was performed in a sterile environment, iodophor was sterilized, and sodium iodoacetate solution was taken up with a micro syringe for intra-luminal injection of knee joint, at a dose of 3mg (50 μ L) per rat. The blank control was not subjected to other treatments.
(3) The administration mode comprises the following steps:
first group (blank control group): and (5) normally breeding.
Second group (model group): and (5) normally breeding.
Third group (hydrogel administration group): the treatment is carried out by injecting 20 mu L of interleukin-10 into the joint cavity on the 3 rd, 7 th, 14 th and 21 th days after the molding.
(4) And (3) pain measurement: the rats were behaviorally measured for hind paw pain threshold on days 0, 3, 7, 14, 21, 28 of the experiment. Rats were evaluated for pain tolerance using a dynamic plantar tactile meter and were acclimatized for 15 minutes on a metal mesh surface in a temperature-controlled chamber prior to the start of the experiment. The touch stimulation device was placed under the rat and stimulation microwires were placed under the plantar surface of the hind paw with an adjustable angle scope. When the instrument is activated, the microwire advances at a constant speed and contacts the proximal metatarsal region of the paw. The microfilament gradually applies pressure to the plantar surface of the foot from the detection threshold until the stimulus becomes painful and the rat retracts the paw. The force required to trigger the paw withdrawal reflex was recorded.
(5) Collecting a specimen: rats were anesthetized at week 4 of the experiment and CT images of the knee joints were taken using small animal micro-CT. The rats are sacrificed later, the knee joints are dissected to observe the pathological change degree of the joint surfaces and carry out pathological section on the knee joints, and the pathological histological change of the knee joints of the rats in each group is evaluated and the histological score is carried out.
(6) The Osteoarthritis Research Society International (OARSI) score is shown in Table 1, and the score chart is shown in FIG. 5.
TABLE 1 OARSI scoring Table
| Grading | Bone |
| 0 | Articular cartilage with intact morphology |
| 1 | Critical state of osteoarthritis, |
| 2 | Local discontinuity of articular |
| 3 | The cartilage matrix enters the middle layer to form vertical fissures |
| 4 | Erosion of cartilage tissue |
| 5 | The cartilage tissue is stripped off, and the hyaline cartilage is completely destroyed to reach the level of |
| 6 | Cartilage deformation, cartilage contour change |
(7) The statistical method comprises the following steps: the experimental data were statistically analyzed using GraphPad Prism software, and the metrology data were expressed as x ± s. P <0.05 considered a statistical difference between the two groups, and p <0.01 considered a significant statistical difference between the two groups.
(8) The experimental results are as follows: according to fig. 2, 3 and 4, the CT image and the general image of the articular surface of the rat knee joint show that the rat knee joint of the model group produces osteoarthritis-like changes, narrowing of the joint space, destruction of the articular cartilage, osteophyte formation, and reduction of the number of chondrocytes, compared to the blank control group. Compared with the model group, the hydrogel administration group rats have obviously reduced knee joint lesion degree and obviously reduced articular cartilage damage. From the results of the behavioral experiments (fig. 6), the threshold of pain induction was significantly reduced in the rats of the model group compared to the rats of the blank control group, while the threshold of pain induction was significantly higher in the rats of the hydrogel administration group than in the rats of the model group. In summary, the present embodiment considers that the injection of interleukin-10 into the joint cavity in combination with the hyaluronic acid hydrogel system can effectively delay the disease process of osteoarthritis, and has a significant therapeutic effect on rat osteoarthritis models.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A pharmaceutical composition, comprising: a controlled release polymer and interleukin-10.
2. The pharmaceutical composition of claim 1, wherein the controlled release polymer is a hydrogel ester.
3. The pharmaceutical composition according to claim 2, wherein the hydrogel ester is a hyaluronic acid derivative or a salt thereof, preferably hyaluronic acid.
4. The pharmaceutical composition of claim 3, wherein the hyaluronic acid derivative is sodium hyaluronate.
5. A process for preparing a pharmaceutical composition according to any one of claims 1 to 4, comprising: dissolving the controlled release polymer in water, stirring to form gel, and adding interleukin-10.
6. The process for preparing a pharmaceutical composition according to claim 5, wherein the mass fraction of hyaluronic acid is 0.1-5%, preferably 2%; the concentration of interleukin-10 is 0.1-200. mu.g/mL, preferably 100. mu.g/mL.
7. Use of a pharmaceutical composition according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of an IL-10 mediated disease.
8. The use according to claim 7, wherein the IL-10 mediated disease is an inflammatory disease of the joints.
9. Use according to claim 8, characterized in that the inflammatory disease of the joints is selected from rheumatoid arthritis, osteoarthritis and other inflammatory diseases caused by fatigue, sprains, trauma, infections, cartilage damage or plastic surgery.
10. The use of claim 8, wherein the pharmaceutical composition is administered intra-articularly.
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