CN105982911A - Preparation method of high-viscoelasticity injection composed of glucosamine and sodium hyaluronate - Google Patents
Preparation method of high-viscoelasticity injection composed of glucosamine and sodium hyaluronate Download PDFInfo
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Abstract
The invention relates to a preparation method of a high-viscoelasticity injection composed of glucosamine and sodium hyaluronate. The injection mainly includes the components of glucosamine sulfate/sodium chloride double salt and the sodium hyaluronate with sodium dihydrogen phosphate and disodium hydrogen phosphate, as auxiliary materials, being used as a pH regulator. Sodium chloride is employed as an osmotic pressure regulator. The injection is greatly reduced in hygroscopicity and enhanced in flowability, is improved in stability, has good treatment effects, low drug resistance rate and less adverse reaction, and can be used in intra-articular injection therapy on arthritis.
Description
Technical field
The present invention relates to the preparation method of the high viscoelasticity injection of a kind of glucosamine and hyaluronic acid sodium combination, it is provided that a kind of medicinal composition for injections in articular cavity, belong to pharmaceutical technology field.
Background technology
Osteoarthritis be a kind of with Articular cartilage degeneration and Secondary cases hyperosteogeny the chronic joint diseases as characteristic.Being more common in middle-aged and elderly people, women is more than male.It is apt to occur in the positions such as bigger knee joint, hip joint, lumbosacral region joint of vertebral column and the first toe joint of bearing a heavy burden, and the DIPJ of hand, proximal interphalangeal joint.This disease also known as osteoarthritis, degenerative osteoarthritis, hypertrophy row arthritis, osteoarthritis, osteoarthritis etc..Along with the aging and fat ratio of population rises, the prevalence rate of osteoarthritis will improve.
Osteoarthritis can start morbidity from 20 years old, but most of asymptomatic, is typically difficult to find.World Health Organization (WHO) adds up, and in more than 50 years old crowd, the sickness rate of osteoarthritis is 50%, and in the crowd of more than 55 years old, sickness rate is 80%.The incidence of China's osteoarthritis accounts for the 10% of total population, is about 100,000,000 people.Nineteen ninety, China only has ten thousand Human Osteoarthritis more than 4000, and within 2000, has reached 80,000,000, patient numbers has reached people more than 100,000,000, predicting according to WHO, being up to 1.5 hundred million to Chinese patient with bone disease in 2015, China will become one of most country of world's osteoarthritis number of patients.
The cause of disease of osteoarthritis is owing to having lacked the synovial fluid of viscosity (joint fluid) in articular cavity, causes originally should serving as the abnormal friction of cartilage as cushion in osteoarthrosis, damages and degenerate.When, after cartilage degradation, just protecting bone surface, when walking or standing, body wt makes the joint degenerated more painful.Owing to fearing misery, naturally decreasing motion, then the muscle of there also follows atrophy, and ligament also can become more loose.
The main pathological change of osteoarthritis is cartilage degeneration and disappearance, and at joint margins ligament attachment and subchondral bone qualitative response hypertrophy forms hyperosteogeny, and thus causes arthralgia, stiff deformity and dysfunction.This disease clinically, can be divided into constitutional and Secondary cases two class.Spontaneous osteoarthritis means year old age ageing and the relevant arthropathy of other diseases of getting along well, and secondary osteoarthritis is then by caused by damage, inflammation, heredity and the disease such as metabolism, endocrine.
Osteoarthritis is the performance that osteoarthrosis physiological is degenerated, and there is no the medicine reversing or stopping this disease progression.The purpose for the treatment of is to ease the pain, and relief of symptoms stops and delay advancing of disease, Saving cortilage function, in case maimed.Use Comprehensive Treatment, including patient education, Drug therapy, physical therapy and surgical operation therapy.
At present, the Drug therapy of common osteoarthritis has following four kinds.
(1) medicine of symptom is improved: analgesics such as acetaminophen has analgesic activity, but antiinflammatory action is weak.NSAID (non-steroidal anti-inflammatory drug) has the feature of anti-inflammatory analgesic, can alleviate arthralgia, improve range of motion after medication.
(2) glucocorticoid: unsuitable systemic administration, only invalid to other treatment, there is acute inflammation outbreak performance in joint or has joint surrounding synovial membrane scorching, in skin inflammation etc. can give articular cavity or diseased region local injection.Unsuitable Reusability.Same position biphasic injection interval time is at least more than 3 months.
(3) use Chondroprotective agents: can relief of symptoms, maintain and recover function of joint.Such as poly-glucosamine.
(4) viscosupplementation: be the sodium hyaluronate solution to intraarticular injection macromolecule, alleviates synovial membrane inflammation, cartilage destruction and improve function of joint, blocks the vicious cycle of local patholoic change.
Viscoelasticity thing replacement therapy is a kind of clinical new method that the medical science new ideas proposed the seventies in last century, i.e. intraarticular injection have viscoelastic Substance treatment osteoarthritis.Visco-elastic material used so far is mainly hyaluronic acid sodium.Hyaluronic acid sodium is a kind of macromolecule glycosaminoglycans, there is height viscoelasticity, good biocompatibility, enter internal after can not only play increase joint lubrication, reduce the physical action such as joint-friction, the internal microenvironment of joint repair can also be created, and being regulated and controled by cell CD44 receptor, thus reparative regeneration joint synovial cell.
As the visco-elastic material of a kind of intraarticular injection, hyaluronic acid sodium possesses following performance: one, tissue and blood compatibility are good, and non-immunogenicity, without chemotactic factor, does not cause allogenic immune to react, do not has an effect with the cell in blood and protein；Its two, histiocytic metabolite and little molecule are had permeability, and polymer network concentration and hyperhydrated effect make most blood proteins and little molecule may diffuse through its molecular network region；Its three, there is the rheological property as natural joint liquid, but its content or concentration be apparently higher than natural joint liquid；Its four, extend the hyaluronic acid half-life in vivo, extend its protective effect to joint, and internal synovial cell can be stimulated to produce endogenous hyaluronic acid sodium, promote the recovery of function of joint.
Glucosamine, molecular formula C6H13O5N, the compound that a hydroxyl of glucose is replaced by an amino.Being widely present and nature, 2-amino-2-deoxy-D-Glucose is generally with N-acetyl derivative (such as chitin) or be present in microorganism, the polysaccharide of animal origin with N-sulfuric ester and 3-O-.alpha.-carboxyethyl-D-glucosamine. form and combine in polysaccharide.Glucosamine is in human body and the material become, and is the important nutrient of formation chondrocyte, is the natural tissues composition of healthy articular cartilage.With advancing age, the shortage of the glucosamine in human body is increasingly severe, and articular cartilage is constantly degenerated and weares and teares.The U.S., European and Japanese a large amount of medical researches show: glucosamine can help repair and safeguard cartilage, and can stimulate the growth of chondrocyte.
Aminoglucose saccharide compound is mainly presented in hydrochlorate, sulfate and double salt thereof and N-acetylglucosamine.Glucosamine currently on the market is broadly divided into glucosamine hydrochloride and glucosamine sulphate two kinds, in the clinical trial of China, glucosamine sulphate is similar with hydrochlorate therapeutic effect, but for health side effect, glucosamine hydrochloride health has uncomfortable one group more, being mainly reflected in stomach pain, healing crisis is many, and effect is the most inconspicuous.In the world, the solid power of dimension of numerous well-known glucosamine product such as Ireland Luo Da pharmaceutical factory, the U.S. step on the brands such as happiness is strong, times strong and all select the glucosamine sulfate of superior performance.
Treatment osteoarthritis is preferred with glucosamine sulfate effect, but is free from the glucosamine sulphate easily moisture absorption and the oxidation of metal chloride, and the double salt being composited by glucosamine sulphate and metal chloride, molecular formula is C6H12NNaO8S, is compared to glucosamine sulphate, has a good chemical stability, and the most nonhygroscopic, not brown stain, preparation method are simple, meet medicinal standard, particularly the double salt product of low sodium content, as medicinal the most widely clinical practice.
Summary of the invention
1.
Present invention is primarily targeted at the deficiency overcoming technical background, it is provided that the preparation method of the high viscoelasticity injection of a kind of good stability, curative effect are good, resistant rate is low, untoward reaction is few glucosamine and hyaluronic acid sodium combination.
2.
It is an object of the invention to provide a kind of stable glucosamine pharmaceutical composition, it is characterized in that this pharmaceutical composition is mainly composed of glucosamine sulfate sodium chloride double salt and hyaluronic acid sodium, selected adjuvant is sodium dihydrogen phosphate and disodium hydrogen phosphate, as pH adjusting agent；Sodium chloride, as osmotic pressure regulator.Advantage of the invention is that change glucosamine height draw moist, oxidizable, be difficult to ensure the characteristic deposited, glucosamine draw moist being substantially reduced, mobility strengthens, and the stability of product improves, and curative effect is good, and resistant rate is low, and untoward reaction is few.
3.
Aforementioned pharmaceutical compositions can be made into any dosage form for intraarticular injection, first-selected liquid preparation and gel preparation.
4.
Aforementioned pharmaceutical compositions can be used for intra-articular injection therapy osteoarthritis.
5.
The consumption of aforementioned pharmaceutical compositions is: in each articular cavity, ampoule is 2ml～3ml, preferably 2.0～2.5, first-selected 2.0ml.
6.
Aforementioned pharmaceutical compositions according to Human Osteoarthritis state of an illness difference, its medicine frequency and cycle is: once, each treatment cycle is 4～7 weeks in medication in a week.
7.
The pH scope of aforementioned pharmaceutical compositions is 6.5～7.5, and preferably pH scope is 6.8～7.2；Osmolarity ranges be 250～350 milli infiltration capacities/liter, preferably 260～320 milli infiltration capacities/liter.
8.
Two kinds of main components in case of the present invention, Glucosamine sulfate sodium chloride can be made into injection usually used as solid dosage forms, hyaluronic acid sodium, and the injection dosage form of two kinds of main component combinations is novel invention.
9.
Further object is that the preparation method providing a kind of stable glucosamine pharmaceutical composition, the purpose of the present invention is achieved through the following technical solutions.
10.
The technical scheme that the present invention provides is: glucosamine sulfate sodium chloride double salt and the high viscoelasticity injection of two kinds of compositions of hyaluronic acid sodium.
Described pharmaceutical composition consists of the following composition by ratio of weight and the number of copies:
Glucosamine sulfate sodium chloride
5—25
Hyaluronic acid sodium
35—55
Sodium dihydrogen phosphate
0.5—5.5
Disodium hydrogen phosphate
0.5—3.5
Sodium chloride
25—45
Its preparation method is characterised by that its preparation process is:
(1)
Each supplementary material is crossed 80 mesh sieves pulverize, standby;
(2)
Precision weighs in the sodium dihydrogen phosphate of recipe quantity, disodium hydrogen phosphate, sodium chloride to enough aquesterilisa, and stirring makes it be completely dissolved, and prepares phosphate buffer；
(3)
Buffer is degerming through 0.22 millimeter of filtering with microporous membrane；
(4)
Precision weighs glucosamine sulfate sodium chloride double salt and the hyaluronic acid sodium of recipe quantity, adds in the phosphate buffer after filtering；
(5)
Being positioned over shaking table, room temperature 200rmp rotating speed shakes 48 hours so that it is be fully dissolved to without visible flocks block, stands to bubble-free, obtains clear, colorless viscoelasticity injection；
(6)
Under aseptic condition, subpackage is in syringe, jumps a queue, packaging.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further described, but following example are not as the restriction of the present invention,
Embodiment 1
Glucosamine sulfate sodium chloride 4.2g
Hyaluronic acid sodium 13.5g
Sodium dihydrogen phosphate 0.9g
Disodium hydrogen phosphate 0.6g
Sodium chloride 10.8g
Water
300ml
Its preparation method is characterised by that its preparation process is:
(1)
Each supplementary material is crossed 80 mesh sieves pulverize, standby;
(2)
Precision weighs in 0.9g sodium dihydrogen phosphate, 0.6g disodium hydrogen phosphate, 10.8g sodium chloride to 400ml aquesterilisa, and stirring makes it be completely dissolved, and prepares phosphate buffer；
(3)
Buffer is degerming through 0.22 millimeter of filtering with microporous membrane, takes the 300ml sterile buffer after filtration standby；
(4)
Precision weighs 4.2g glucosamine sulfate sodium chloride double salt and 13.5g hyaluronic acid sodium, adds in the phosphate buffer after filtering；
(5)
Being positioned over shaking table, room temperature 200rmp rotating speed shakes 48 hours so that it is be fully dissolved to without visible flocks block, stands to bubble-free, obtains clear, colorless viscoelasticity injection；
(6)
Under aseptic condition, subpackage is in syringe, jumps a queue, packaging.
Embodiment 2
Glucosamine sulfate sodium chloride
4.2g
Hyaluronic acid sodium 13.5g
Sodium dihydrogen phosphate 0.9g
Disodium hydrogen phosphate 0.6g
Sodium chloride 11.0g
Water
300ml
Its preparation method is characterised by that its preparation process is:
(1)
Each supplementary material is crossed 80 mesh sieves pulverize, standby;
(2)
Precision weighs in 0.9g sodium dihydrogen phosphate, 0.6g disodium hydrogen phosphate, 11.0g sodium chloride to 400ml aquesterilisa, and stirring makes it be completely dissolved, and prepares phosphate buffer；
(3)
Buffer is degerming through 0.22 millimeter of filtering with microporous membrane, takes the 300ml sterile buffer after filtration standby；
(4)
Precision weighs 4.2g glucosamine sulfate sodium chloride double salt and 13.5g hyaluronic acid sodium, adds in the phosphate buffer after filtering；
(5)
Being positioned over shaking table, room temperature 200rmp rotating speed shakes 48 hours so that it is be fully dissolved to without visible flocks block, stands to bubble-free, obtains clear, colorless viscoelasticity injection；
(6)
Under aseptic condition, subpackage is in syringe, jumps a queue, packaging.
Claims (8)
1. a good stability, curative effect is good, resistant rate is low, untoward reaction is few glucosamine and the joint cavity injection liquid of hyaluronic acid sodium combination, it is characterised in that be mainly composed of glucosamine sulfate sodium chloride double salt and hyaluronic acid sodium.
2. the pharmaceutical composition described in claim 1 consists of the following composition by ratio of weight and the number of copies:
Glucosamine sulfate sodium chloride
5—25
Hyaluronic acid sodium
35—55
Sodium dihydrogen phosphate
0.5—5.5
Disodium hydrogen phosphate
0.5—3.5
Sodium chloride
25—45。
3., described in claim 2, adjuvant is sodium dihydrogen phosphate and disodium hydrogen phosphate, as pH adjusting agent；Sodium chloride, as osmotic pressure regulator.
4. the pharmaceutical composition described in claim 1 is for making any dosage form of intraarticular injection, includes but not limited to liquid preparation and gel preparation.
5. the consumption of pharmaceutical composition described in claim 1 is: in each articular cavity, ampoule is 2ml～3ml, preferably 2.0～2.5, first-selected 2.0ml.
6. pharmaceutical composition described in claim 1 according to Human Osteoarthritis state of an illness difference, its medicine frequency and cycle is: once, each treatment cycle is 4～7 weeks in medication in a week.
7. the pH scope of pharmaceutical composition described in claim 1 is 6.5～7.5, and preferably pH scope is 6.8～7.2；Osmolarity ranges be 250～350 milli infiltration capacities/liter, preferably 260～320 milli infiltration capacities/liter.
8. pharmaceutical composition described in claim 1, its preparation process is:
(1) each supplementary material is crossed 80 mesh sieves pulverize, standby;
(2) during precision weighs the sodium dihydrogen phosphate of recipe quantity, disodium hydrogen phosphate, sodium chloride to enough aquesterilisa, stirring makes it be completely dissolved, and prepares phosphate buffer；
(3) buffer is degerming through 0.22 millimeter of filtering with microporous membrane；
(4) precision weighs glucosamine sulfate sodium chloride double salt and the hyaluronic acid sodium of recipe quantity, adds in the phosphate buffer after filtering；
(5) being positioned over shaking table, room temperature 200rmp rotating speed shakes 48 hours so that it is be fully dissolved to without visible flocks block, stands to bubble-free, obtains clear, colorless viscoelasticity injection；
(6) under aseptic condition, subpackage, in syringe, is jumped a queue, packaging.
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Cited By (3)
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| CN106491530A (en) * | 2016-12-13 | 2017-03-15 | 湖北远大天天明制药有限公司 | A kind of medical composite for eye |
| CN110193006A (en) * | 2019-05-22 | 2019-09-03 | 四川农业大学 | Aminoglucose hydrochloride Bones and joints intelligent aqueous gel and its preparation method and application |
| CN114886915A (en) * | 2022-05-06 | 2022-08-12 | 广州医科大学附属第三医院（广州重症孕产妇救治中心、广州柔济医院） | Sodium hyaluronate injection of compound eicosapentaenoic acid for treating osteoarthritis |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106491530A (en) * | 2016-12-13 | 2017-03-15 | 湖北远大天天明制药有限公司 | A kind of medical composite for eye |
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| CN110193006A (en) * | 2019-05-22 | 2019-09-03 | 四川农业大学 | Aminoglucose hydrochloride Bones and joints intelligent aqueous gel and its preparation method and application |
| CN110193006B (en) * | 2019-05-22 | 2022-11-25 | 四川农业大学 | Glucosamine hydrochloride bone joint intelligent hydrogel and preparation method and application thereof |
| CN114886915A (en) * | 2022-05-06 | 2022-08-12 | 广州医科大学附属第三医院（广州重症孕产妇救治中心、广州柔济医院） | Sodium hyaluronate injection of compound eicosapentaenoic acid for treating osteoarthritis |
| CN114886915B (en) * | 2022-05-06 | 2023-12-26 | 广州医科大学附属第三医院（广州重症孕产妇救治中心、广州柔济医院） | Sodium hyaluronate injection of compound eicosapentaenoic acid for treating osteoarthritis |
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Application publication date: 20161005 |