CN101337067A - Compound temperature sensitive type in-situ gel nasal-cavity administration preparation for treating osteoporosis - Google Patents
Compound temperature sensitive type in-situ gel nasal-cavity administration preparation for treating osteoporosis Download PDFInfo
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- CN101337067A CN101337067A CNA200810063387XA CN200810063387A CN101337067A CN 101337067 A CN101337067 A CN 101337067A CN A200810063387X A CNA200810063387X A CN A200810063387XA CN 200810063387 A CN200810063387 A CN 200810063387A CN 101337067 A CN101337067 A CN 101337067A
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Abstract
The invention belongs to a nasal cavity preparation and particularly relates to a compound temperature-sensitive type in-situ gel nasal administration preparation for curing osteoporosis. The temperature-sensitive type high molecular compound material is soaked in a proper amount of a potassium biphthalate buffer solution with the pH value being 2.5 to 4.5 for 20 to 24 hours at the room temperature, then an absorption enhancer, a solubilizing agent, a conserving agent, an odour counteracting agent and an enzyme inhibitor are added and uniformly stirred, then are shocked by an ultrasonoscope for 5 to 10 minutes to be fully dissolved, then the formula dosage of vitamin K and osteogenic growth peptide raw materials are added to the solution to be uniformly stirred, the volume is measured, and then canning and sealing are performed to obtain the nasal cavity preparation. The compound preparation has the advantages that the administration is convenient, the drug is not easy to run off from the nasal cavity, the detention time of the drug in the nasal cavity can be prolonged, and the bioavailability of the osteogenic growth peptide is enhanced, while the vitamin K can obviously enhance and promote the osteogenesis effect of the osteogenic growth peptide to ensure that the osteogenesis effect of the osteogenic growth peptide can be greatly enhanced.
Description
Technical field
The invention belongs to nasal cavity administrated preparation, especially for the compound temperature sensitive type in-situ gel nasal-cavity administration preparation that contains vitamin K and osteogenic growth peptide of treatment osteoporosis.
Background technology
The generation age of osteoporosis and degree depend on peak bone mass and bone loss speed when old at an early age, therefore improve peak bone mass at an early age or reduce that bone loss speed when old all can delay or the generation of prevention of osteoporosis.Primary osteoporosis is divided into I type and II type, and the former is postmenopausal women's osteoporosis, and pilosity is born in menopause and is begun in back 10 years.Because osteoclast hyperfunctioning, bone resorption increases, although the bone formation feedback increases, increase but still can not remedy bone resorption fully, cause bone loss, long-term accumulation forms osteoporosis, belongs to high conversion type, treatment all has clear and definite curative effect to suppress bone resorption activity as estrogens, calcitonin, parathyroid hormone etc.; The latter is a senile osteoporosis, be mainly in man or women more than 60 years old, because function of osteoblast is degenerated, bone formation reduces, although bone resorption also reduces, but still can not offset osteoplastic reduction fully, and cause sclerotin to be lost only, long-term accumulation forms osteoporosis, belong to low conversion type, and because conversion ratio descends, cause bone mass (mechanical property) to reduce, occur fracture easily, although the bone resorption inhibitor treatment also has certain effect, but unsatisfactory, generally suggestion should be promoting the bone formation activity, but still lack ideal promotion bone formation medicine at present.
Osteogenic growth peptide (Osteogenic Growth Peptide, OGP) be a kind of 14-amino acid polypeptide that can promote the osteocyte growth, sequence is Al-Leu-Lys-Arg-Glu-Arg-Gly-Thr-Leu-Tyr-Gly-Phe-Gly-Gly, treatment to low conversion type osteoporosis has effect preferably, can promote osteoblast, fibroblast and human bone marrow substrate cell propagation at external OGP, promote the marrow stromal cell alkaline phosphatase activities of osteoblast, people and rabbit; Can promote rat bone to form in vivo and raising bone trabecula quality.The influence of the external on cell proliferation of OGP is bell shape (amphicheirality), and low concentration does not have effect, and intermediate concentration promotes propagation, and high concentration then presents inhibitory action.
The special anatomical structure of nasal cavity is for the medicine that orally is difficult to absorb, drug administration by injection is inconvenient again provides good selection.The nasal-cavity administration advantage shows:
(1) mammal nasal cavity position exists abundant blood capillary and lymphatic vessel, the nasal cavity epithelium closely links to each other with blood vessel wall, the epithelial cell gap is bigger, the inner membrance of blood capillary has pane sample space around mucous epithelium blood capillary and the body of gland, the basement membrane of all blood capillaries is leakage hole shape, though the venule inner membrance is complete, but its basement membrane and smooth muscle cell are highly porous property, the above-mentioned characteristic of intranasal blood vessel, make between blood vessel and the tissue and carry out body fluid and mass exchange easily, medicine can absorb rapidly and enter the body circulation, realizes quick-acting.
(2) nasal membrane is because of existing abundant cilium, and medicine can contact mucosa on a large scale, has increased the effective surface area of drug absorption widely.
(3) medicine of Xi Shouing directly enters systemic circulation, the first pass effect when having avoided drug oral, and bioavailability is higher relatively;
(4) nasal cavity position protease content is few, and albumen, polypeptide class biopharmaceutical macromolecular drug are not easy by enzymolysis, can realize absorbing preferably in the presence of absorption enhancer;
(5) compare with injection, but patient's autonomy use, particularly, have more superiority to the chronic disease that needs long-term prescription or handicapped old people, be easy to be accepted by the patient.
The existing simple report that carries out the nasal spray administration with solution state, but during the solution spray administration, medicinal liquid is easy to flow out from nasal cavity or medicinal liquid enters the oral cavity easily with fluid state, cause drug wastage, declined bioavailability of oral administration, therefore need to seek more suitably an administering mode or a route of administration, in order to overcome simple deficiency with the solution administration.
Situ-gel claims gel on the throne again, is meant with after the solution state administration, takes place rapidly to change mutually at medicine-feeding part, forms a class I liquid I preparation of semi-solid gel.Responsive to temperature type situ-gel, its gelation mechanism are the situ-gels that the variation by ambient temperature forms, and this system contains the temperature-responsive polymer chemical compound, and administration post polymerization thing solution forms non-chemically crosslinked gel because of the inside and outside variation of temperature.It is in the external liquid condition that is, viscosity is little, make medicine be scattered on the nasal mucosa uniformly by spray delivery with atomised form, under the temperature environment of nasal cavity, the formation even gel that droplet is very fast, prolong drug helped medicine and fully absorbs in the time of staying of nasal cavity, had improved the bioavailability of osteogenic growth peptide.
Nineteen sixty Bouckare etc. reports that at first vitamin K can promote experimental union of fracture.After this various countries scholar studies the relation of vitamin K and bone metabolism in succession, thinks at present, and vitamin K can increase the synthetic and secretion of Bone Gla protein, is the mechanism of its osteoporosis.In the present invention, we have carried out vitamin K situ-gel, osteogenic growth peptide situ-gel, have contained the function of resisting osteoporosis of the compound recipe osteogenic growth peptide situ-gel nose spray administration of vitamin K, after finding the vitamin K nasal-cavity administration, compare with model, function of resisting osteoporosis is also not obvious, no significant difference, and in the osteogenic growth peptide situ-gel, add the vitamin K of above-mentioned same amount, behind the nasal-cavity administration, the function of resisting osteoporosis of osteogenic growth peptide improves greatly than single effect with the osteogenic growth peptide situ-gel.
Osteogenic growth peptide is a polypeptide compounds, and oral administration can be by the enzymatic degradation in the gastrointestinal tract; And for the osteoporosis patient, need long-term prescription, the drug administration by injection inconvenience, and can bring misery to patient, and patient must receive treatment under doctor's management, and poor compliance need be sought a kind of determined curative effect for this reason, use more convenient form of administration.
Summary of the invention
The purpose of this invention is to provide a kind of compound temperature sensitive type in-situ gel nasal-cavity administration preparation that contains vitamin K and osteogenic growth peptide that is used for the treatment of osteoporosis.By spray delivery medicine is scattered on the nasal mucosa uniformly with atomised form, under the temperature environment of nasal cavity, the formation even gel that droplet is very fast, prolong drug have improved the bioavailability of osteogenic growth peptide in the time of staying of nasal cavity; The utilization temperature sensitive type macromolecular compound that contains vitamin K and osteogenic growth peptide prepares situ-gel, and vitamin K can obviously improve and the ossification that promotes osteogenic growth peptide, and osteogenic growth peptide skeletonization effect is improved greatly.
The present invention carries out vitamin K situ-gel, osteogenic growth peptide situ-gel, contains the function of resisting osteoporosis of the compound recipe osteogenic growth peptide situ-gel nose spray administration of vitamin K, after finding the vitamin K nasal-cavity administration, compare with model, function of resisting osteoporosis is also not obvious, no significant difference, and in the osteogenic growth peptide situ-gel, adding the vitamin K of above-mentioned same amount, behind the nasal-cavity administration, the function of resisting osteoporosis of osteogenic growth peptide improves greatly than single effect with the osteogenic growth peptide situ-gel.
The present invention placed 20～24 hours being immersed under the temperature sensitive type macromolecular compound material room temperature condition in the potassium hydrogen phthalate buffer of an amount of pH2.5～3.5, add absorption enhancer, solubilizing agent, antiseptic, aromatic, enzyme inhibitor then, stir, with ultrasonoscope concussion 5-10 minute, make whole dissolvings, in solution, add the vitamin K and the osteogenic growth peptide raw material of recipe quantity again, stir, standardize solution, canned sealing promptly.It is in the external liquid condition that is, and viscosity is little, makes medicine be scattered on the nasal mucosa uniformly with atomised form by spray delivery, under the temperature environment of nasal cavity, the formation even gel that droplet is very fast, prolong drug have improved the bioavailability of osteogenic growth peptide in the time of staying of nasal cavity; And vitamin K can obviously improve and the ossification that promotes osteogenic growth peptide, and osteogenic growth peptide skeletonization effect is improved greatly.
Used temperature-responsive polymer polymeric material is N one N-isopropylacrylamide analog copolymer (PNIPAM) poloxamer (poloxamer), polyoxyethylene-polylactic-co-glycolic acid copolymer (PEO-PLGA-PEO), xylan, chitosan in the preparation of the present invention.
The absorption enhancer that adds in the preparation of the present invention is beta cyclodextrin class, chelating agen class, glucoside, the phospholipids compounds that cholic acid salt, saturated or unsaturated fatty acid and esters, alcohols, ethers, sulfoxide class, amide and lactams, ion-type and nonionic surfactant, cyclodextrin and alkyl replace.
Contain solubilizing agent, antiseptic, aromatic, pH buffer, enzyme inhibitor in the preparation of the present invention.
The present invention exists with liquid condition external, uses the sprayer unit administration, and medicine is scattered on the nasal mucosa uniformly with atomised form, under the temperature environment of nasal cavity, and the uniform semi-solid gel of formation that droplet is very fast.
Principal agent vitamin K content of the present invention is 0.5-2mg/ml, and the content of osteogenic growth peptide is 0.05-1mg/ml.
The concrete steps of vitamin K situ-gel, osteogenic growth peptide situ-gel and compound recipe situ-gel osteoporosis are as follows:
1. placed 20～24 hours being immersed under the temperature sensitive type macromolecular compound material room temperature condition in the potassium hydrogen phthalate buffer of an amount of pH2.5～4.5.
2. add absorption enhancer, solubilizing agent, antiseptic, aromatic, the enzyme inhibitor of recipe quantity, stir,, make whole dissolvings with ultrasonoscope concussion 5-10 minute.
3. add the vitamin K and the osteogenic growth peptide raw material of recipe quantity at last, stir, make whole dissolvings, the standardize solution filling and sealing promptly.
Preparation contains the situ-gel (A) of vitamin K 1mg/ml, the situ-gel (B) of osteogenic growth peptide 0.2mg/ml and both compound recipe situ-gels (C) of above-mentioned same concentration, spray with the isolated plant nose and state A, B, each 10 μ l of C every day, sooner or later each once is provided with model control group (OVX).In administration 4 with measure rat body bone ore deposit total amount (BMC) July and bone mineral density (BMD) and bone biomechanical intensity etc.The results are shown in following table:
Table 1 nose spray A, B, C are to the influence of old rats BMC and BMD
Compare with OVX group, A group BMC and BMD when 4 months and 7 months do not have significant change, and there was no significant difference, B were organized in the time of 4 months, and BMC and BMD improve respectively and improved 8% and 15.3% in 7.1% and 9.0%, 7 month respectively, with the model comparison, utmost point significant difference are arranged; The C group is in the time of 4 months, and BMC and BMD improve respectively and improved 15.9% and 23.0% in 15.6% and 15.1%, 7 month respectively, compares with model, and utmost point significant difference is arranged, and C group BMC and BMD raising obviously are greater than the B group and organize sum with A.
The spray of table 2 nose A, B, C are to old rats femur, the influence of calcium salt relative volume mass
Compare with the OVX group, A group femur relative volume mass and the raising of calcium salt density there are no significant difference, B, C group femur relative volume mass improves 3.8% and 6.6% respectively, and B, C group calcium salt relative volume mass improves 12.2% and 20.5% respectively, and the C group improves particularly remarkable.
Table 3 nose spray A, B, C are to the influence of old rats femur biomechanical property
Compare with the OVX group, A group femur peak load and femur structure intensity improve does not all have significant difference, and B, C group femur peak load improves 13.3% and 23.1%; B, C group femur structure intensity improves 9.0% and 15.6%.The C group improves all very obvious, be obviously greater than A group and B group.
Can draw to draw a conclusion from above three experiments, nose is sprayed into the osteogenic growth peptide situ-gel and has good function of resisting osteoporosis, and add a certain amount of vitamin K therein, and the function of resisting osteoporosis effect of osteogenic growth peptide is improved greatly, this is a key of the present invention.
Good effect of the present invention
1, at present the osteogenic growth peptide injection of external development to have entered the II phase clinical, but disease for osteoporosis and so on, patient needs long term administration, and drug administration by injection has brought great misery to patient, and nasal-cavity administration can overcome the inconvenience that drug administration by injection brings.
2. with the dosage form nasal-cavity administration of situ-gel, many deficiencies of having brought when having overcome solution-type dosage form spray delivery, medicine is difficult for flowing out from the nostril or medicine enters the oral cavity decomposition failure, has improved the biological utilisation of medicine, reduces untoward reaction.
3. compared merely with osteogenic growth peptide situ-gel (A), merely with vitamin K situ-gel (B), contain the function of resisting osteoporosis that compound recipe osteogenic growth peptide situ-gel (C) nasal spray of vitamin K produces, find: 1. nose spray A, B all have certain function of resisting osteoporosis, but the function of resisting osteoporosis of osteogenic growth peptide is far longer than vitamin K; 2. behind the nose spray C, the sum when function of resisting osteoporosis of generation obviously is greater than both simple administrations, possible vitamin K can further promote the ossification of osteogenic growth peptide, and osteogenic growth peptide skeletonization effect is improved greatly.
That this compound preparation has is easy to use, medicine be difficult for from nasal cavity run off, can prolong drug in time of staying of nasal cavity, improve the bioavailability of osteogenic growth peptide, and vitamin K can obviously improve and the ossification that promotes osteogenic growth peptide, and osteogenic growth peptide skeletonization effect is improved greatly.
The specific embodiment
Embodiment 1
Osteogenic growth peptide 0.02g
Vitamin K 0.15g
Citric acid 0.2g
Tween 80 0.5g
Bacitracin 0.5g
Poloxamer 20g
The potassium hydrogen phthalate buffer of pH2.5 adds to 100ml
The poloxamer room temperature condition is immersed in place in the potassium hydrogen phthalate buffer of an amount of pH2.5 and spends the night, and then in above-mentioned solution, add citric acid, tween 80, bacitracin, stir, with ultrasonoscope concussion 5-10 minute, make whole dissolvings, add vitamin K and osteogenic growth peptide at last, stir, the potassium hydrogen phthalate buffer standardize solution that adds pH2.5 is to 100ml, and fill promptly.
Embodiment 2
Osteogenic growth peptide 0.06g
Vitamin K 0.05g
Hydroxypropyl beta cyclodextrin 2g
Bacitracin 0.5g
Chitosan 10g
The potassium hydrogen phthalate buffer of pH3.0 adds to 100ml
The chitosan room temperature condition is immersed in place in the potassium hydrogen phthalate buffer of an amount of pH3.0 and spends the night, and then in above-mentioned solution, add hydroxypropyl beta cyclodextrin, bacitracin, stir, with ultrasonoscope concussion 5-10 minute, make whole dissolvings, add vitamin K and osteogenic growth peptide at last, stir, the potassium hydrogen phthalate buffer standardize solution that adds pH3.0 is to 100ml, and fill promptly.
Embodiment 3
Osteogenic growth peptide 0.05g
Vitamin K 0.1g
Hydroxypropyl beta cyclodextrin 2g
Bacitracin 0.5g
Poloxamer 2g
Xylan 15g
The potassium hydrogen phthalate buffer of pH3.5 adds to 100ml
Xylan, poloxamer room temperature condition are immersed in place in the potassium hydrogen phthalate buffer of an amount of pH3.5 and spend the night, and then in above-mentioned solution, add hydroxypropyl beta cyclodextrin, bacitracin, stir, with ultrasonoscope concussion 5-10 minute, make whole dissolvings, add vitamin K and osteogenic growth peptide at last, stir, the potassium hydrogen phthalate buffer standardize solution that adds pH3.5 is to 100ml, and fill promptly.
Claims (6)
1, a kind of compound temperature sensitive type in-situ gel nasal-cavity administration preparation for the treatment of osteoporosis, it is characterized in that placing 20～24 hours with being immersed under the temperature sensitive type macromolecular compound material room temperature condition in the potassium hydrogen phthalate buffer of an amount of pH2.5～3.5, in the temperature sensitive type macromolecular solution, add absorption enhancer then, solubilizing agent, antiseptic, aromatic, enzyme inhibitor, stir, with ultrasonoscope concussion 5-10 minute, make whole dissolvings, the vitamin K and the osteogenic growth peptide raw material that in solution, add recipe quantity again, stir, standardize solution, canned sealing gets final product.
2,, it is characterized in that the temperature sensitive type macromolecular compound is N one N-isopropylacrylamide analog copolymer, poloxamer, polyoxyethylene-polylactic-co-glycolic acid copolymer, xylan, chitosan according to claims 1 described nasal cavity administrated preparation.
3, according to claims 1 described nasal cavity administrated preparation, it is characterized in that containing in the solution absorption enhancer, solubilizing agent, antiseptic, aromatic, PH buffer, enzyme inhibitor.
4,, it is characterized in that principal agent vitamin K content is 0.5-2mg/ml according to claims 1 described nasal cavity administrated preparation
5, according to claims 1 described nasal cavity administrated preparation, the content that it is characterized in that osteogenic growth peptide is 0.05-1mg/ml.
6, according to claims 1 described nasal cavity administrated preparation, it is characterized in that preparation exists with liquid condition external, use the sprayer unit administration, medicine is scattered on the nasal mucosa with atomised form uniformly, under the temperature environment of nasal cavity, the uniform semi-solid gel of formation that droplet is very fast.
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| CNA200810063387XA CN101337067A (en) | 2008-08-12 | 2008-08-12 | Compound temperature sensitive type in-situ gel nasal-cavity administration preparation for treating osteoporosis |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104721234A (en) * | 2013-12-20 | 2015-06-24 | 舒梅 | Periplaneta Americana extract product ion-activated in-situ gel and preparation method thereof |
| CN115403658A (en) * | 2022-05-19 | 2022-11-29 | 首都医科大学 | Arbuterol-Tyr-Gly-Phe-Gly-Gly, synthesis, activity and application thereof |
-
2008
- 2008-08-12 CN CNA200810063387XA patent/CN101337067A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104721234A (en) * | 2013-12-20 | 2015-06-24 | 舒梅 | Periplaneta Americana extract product ion-activated in-situ gel and preparation method thereof |
| CN115403658A (en) * | 2022-05-19 | 2022-11-29 | 首都医科大学 | Arbuterol-Tyr-Gly-Phe-Gly-Gly, synthesis, activity and application thereof |
| CN115403658B (en) * | 2022-05-19 | 2024-04-23 | 首都医科大学 | Ursolic acid-Tyr-Gly-Phe-Gly-Gly, synthesis, activity and application thereof |
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Open date: 20090107 |