CN102805865A - Eye drop administration device system and preparation - Google Patents
Eye drop administration device system and preparation Download PDFInfo
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- CN102805865A CN102805865A CN 201110148148 CN201110148148A CN102805865A CN 102805865 A CN102805865 A CN 102805865A CN 201110148148 CN201110148148 CN 201110148148 CN 201110148148 A CN201110148148 A CN 201110148148A CN 102805865 A CN102805865 A CN 102805865A
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- tnfr2
- preparation
- eye
- treatment
- antibody
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000003889 eye drop Substances 0.000 title abstract description 7
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 25
- 206010061218 Inflammation Diseases 0.000 claims abstract description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 18
- 230000004054 inflammatory process Effects 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 239000004475 Arginine Substances 0.000 claims abstract description 16
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims abstract description 16
- 206010010741 Conjunctivitis Diseases 0.000 claims abstract description 16
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229960000686 benzalkonium chloride Drugs 0.000 claims abstract description 16
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000001768 carboxy methyl cellulose Substances 0.000 claims abstract description 16
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims abstract description 16
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims abstract description 16
- 229960001340 histamine Drugs 0.000 claims abstract description 16
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 16
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 16
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 16
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 16
- 239000011780 sodium chloride Substances 0.000 claims abstract description 9
- 208000021386 Sjogren Syndrome Diseases 0.000 claims abstract description 5
- 239000008363 phosphate buffer Substances 0.000 claims description 15
- 208000005494 xerophthalmia Diseases 0.000 claims description 11
- 208000003084 Graves Ophthalmopathy Diseases 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 208000010217 blepharitis Diseases 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000030533 eye disease Diseases 0.000 abstract 1
- 239000008055 phosphate buffer solution Substances 0.000 abstract 1
- 210000001685 thyroid gland Anatomy 0.000 abstract 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 14
- 229940079593 drug Drugs 0.000 description 11
- 239000006196 drop Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 238000010254 subcutaneous injection Methods 0.000 description 6
- 210000000795 conjunctiva Anatomy 0.000 description 5
- 239000007929 subcutaneous injection Substances 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 241000130764 Tinea Species 0.000 description 4
- 208000002474 Tinea Diseases 0.000 description 4
- 210000002808 connective tissue Anatomy 0.000 description 4
- 230000009261 transgenic effect Effects 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940073621 enbrel Drugs 0.000 description 2
- 210000004744 fore-foot Anatomy 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- CKMXBZGNNVIXHC-UHFFFAOYSA-L ammonium magnesium phosphate hexahydrate Chemical compound [NH4+].O.O.O.O.O.O.[Mg+2].[O-]P([O-])([O-])=O CKMXBZGNNVIXHC-UHFFFAOYSA-L 0.000 description 1
- 239000000607 artificial tear Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 102000009634 interleukin-1 receptor antagonist activity proteins Human genes 0.000 description 1
- 108040001669 interleukin-1 receptor antagonist activity proteins Proteins 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910052567 struvite Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an eye drop preparation, which comprises 1.0-10mg/ml of antibody protein, 10-20mM of a phosphate buffer solution, 0.005 percent mg/ml of benzalkonium chloride, 0.5 percent mg/ml of carboxymethyl cellulose, 0.005-0.01mg/ml of Tween 80, 0.05-0.1 percent mg/ml of arginine, 5-15mM of histamine and 4.0-9.0mg/ml of NaCl. The pH of the eye drop preparation is 7.0-7.5. The antibody protein is TNFR2-Fc-IL-1ra or TNFR2-Fc or an anti-IL-12/23 antibody or IL-1ra-Fc-IL-18bp. The eye drop preparation is applied to preparation of a medicament for treating excessive inflammatory reactions after xeroma, a computer disease, a sicca syndrome, a thyroid gland-relevant eye disease, blepharitis, conjunctivitis and ophthalmologic operation.
Description
Technical field
The invention belongs to drug world, the eye conjunctiva that is specifically related to several kinds of antibody-pharmaceutical grade proteins drips drug-delivery preparation, the method and apparatus of medicine.
Background technology
Struvite ocular disease comprises that inflammation of causing behind xerophthalmia (computeritis) and the ophthalmologic operation etc. is multiple; The main at present Therapeutic Method such as artificial tears and hormone that adopt, the specific inhibitor that need find the little specific inflammation inflammation factor of side effect (like TNF, IL-1, IL-18, IL-12 and IL-23) at present is to avoid the using side effect that causes repeatedly.Antibody and pharmaceutical grade protein generally all are subcutaneous or intravenous injections, and local the use also do not seen in present business method, and the antibody that warp eye conjunctiva uses and the preparation of pharmaceutical grade protein and penetration enhancers or method also need attempt just knowing.
The present invention relates to use the eye conjunctiva of several kinds of antibody-pharmaceutical grade proteins to drip drug-delivery preparation, the method and apparatus of medicine.
Summary of the invention
In order to solve the problem that above-mentioned prior art exists, the purpose of this invention is to provide a kind of preparation of putting drops in one's eyes.That mainly to be tested is the binary medicine TNFR2-Fc-IL-1ra and the TNFR2-Fc of treatment inflammatory skin disease.
For realizing goal of the invention of the present invention, the technical scheme that the inventor provides is following:
Summary of the invention
The present invention also provides a kind of preparation of putting drops in one's eyes, and its composition comprises following component:
TNFR2-Fc-IL-1ra 1-10mg/ml, phosphate buffer (Phosphate buffer) 10-20mM, benzalkonium chloride (Benzalkonium chloride) 0.005% (mg/ml), carboxymethyl cellulose (Carboxy methyl cellulose) 0.5% (mg/ml), Tween 80 (Tween 80) 0.005-0.01 (mg/ml), arginine (Arginine) 0.05-0.1% (mg/ml), histamine (Histamine) 5-15mM, NaCl 4.0-9.0mg/ml, the pH of the described preparation of putting drops in one's eyes is 7.0-7.5.
The present invention also provides a kind of preparation of putting drops in one's eyes, and its composition comprises following component:
TNFR2-Fc 1-10mg/ml, phosphate buffer (Phosphate buffer) 10-20mM, benzalkonium chloride (Benzalkonium chloride) 0.005% (mg/ml), carboxymethyl cellulose (Carboxy methyl cellulose) 0.5% (mg/ml), Tween 80 (Tween 80) 0.005-0.01 (mg/ml), arginine (Arginine) 0.05-0.1% (mg/ml), histamine (Histamine) 5-15mM, NaCl 4.0-9.0mg/ml, the pH of the described preparation of putting drops in one's eyes is 7.0-7.5.
The present invention also provides a kind of preparation of putting drops in one's eyes, and its composition comprises following component:
IL-1ra-Fc-IL-18bp 1-10mg/ml, phosphate buffer (Phosphate buffer) 10-20mM, benzalkonium chloride (Benzalkonium chloride) 0.005% (mg/ml), carboxymethyl cellulose (Carboxy methyl cellulose) 0.5% (mg/ml), Tween 80 (Tween 80) 0.005-0.01 (mg/ml), arginine (Arginine) 0.05-0.1% (mg/ml), histamine (Histamine) 5-15mM, NaCl 4.0-9.0mg/ml, the pH of the described preparation of putting drops in one's eyes is 7.0-7.5.
The present invention also provides the described preparation of putting drops in one's eyes to cross the application in the strong inflammatory reaction medicine in preparation treatment xerophthalmia, computeritis, sjogren syndrome, thyroid-associated ophthalmopathy, lid inflammation, eye conjunctivitis disease and ophthalmologic operation (like corneal transplantation) back.
Detailed Description Of The Invention
Eye drip treatment preparation and method:
Eye drip treatment antibody protein (including but not limited to TNFR2-Fc-IL-1ra, TNFR2-Fc and IL-1ra-Fc-IL-18bp etc.) preparation as:
◆TNFR2-Fc-IL-1ra?1-10mg/ml
◆ phosphate buffer (Phosphate buffer) 10-20mM
◆ benzalkonium chloride (Benzalkonium chloride) 0.005%mg/ml
◆ carboxymethyl cellulose (Carboxy methyl cellulose) 0.5%mg/ml
◆ Tween 80 (Tween 80) 0.005-0.01mg/ml
◆ arginine (Arginine) 0.05-0.1%mg/ml
◆ histamine (Histamine) 5-15mM
◆NaCl?4.0-9.0mg/ml
◆pH?7.0-7.5。
With:
◆TNFR2-Fc?1-10mg/ml
◆ phosphate buffer (Phosphate buffer) 10-20mM
◆ benzalkonium chloride (Benzalkonium chloride) 0.005%mg/ml
◆ carboxymethyl cellulose (Carboxy methyl cellulose) 0.5%mg/ml
◆ Tween 80 (Tween 80) 0.005-0.01mg/ml
◆ arginine (Arginine) 0.05-0.1%mg/ml
◆ histamine (Histamine) 5-15mM
◆NaCl?4.0-9.0mg/ml
◆pH?7.0-7.5。
With:
◆IL-1ra-Fc-IL-18bp?1-10mg/ml
◆ phosphate buffer (Phosphate buffer) 10-20mM
◆ benzalkonium chloride (Benzalkonium chloride) 0.005%mg/ml
◆ carboxymethyl cellulose (Carboxy methyl cellulose) 0.5%mg/ml
◆ Tween 80 (Tween 80) 0.005-0.01mg/ml
◆ arginine (Arginine) 0.05-0.1%mg/ml
◆ histamine (Histamine) 5-15mM
◆NaCl?4.0-9.0mg/ml
◆pH?7.0-7.5。
The eye drip Therapeutic Method is directly the eye drip preparation to be dropped on the eye.
Use TNFR2-Fc-IL-1ra and eye drip medication to treat xerophthalmia appearance eye conjunctivitis disease.Eye conjunctivitis disease disappeared complete obiteration (see figure 1) in a hour basically after experimental result showed one-time treatment in the time of 45 minutes.Inflammation was crossed the active drug of strong reaction after above experimental result also pointed out TNFR2-Fc-IL-1ra might become the treatment ocular operation, and other also comprise makes the anti-inflammatory eye drop.
Use TNFR2-Fc (or IL-1ra-Fc-IL-18bp) and eye drip medication to treat xerophthalmia appearance eye conjunctivitis disease.Eye conjunctivitis disease complete obiteration in a hour behind the experimental result demonstration one-time treatment.
TNFR2-Fc and TNFR2-Fc-IL-1ra are in the rat body behind the identical molar dose subcutaneous injection, and it is as shown in Figure 2 that the plasma drug level of effectively treating fore paw inflammation edema is measured the result.These two experimental results show in blood, to distribute to distribute in blood than TNFR2-Fc far away after the TNFR2-Fc-IL-1ra intravenous injection and lack, but drug effect is suitable.The IL-1ra of these results suggest TNFR2-Fc-IL-1ra part maybe and connective tissue, especially subcutaneous connective tissue combine, drive TNFR2-Fc and play therapeutic effect to connective tissue.
Research in the delay of injection site behind the Enbrel of labelled with radioisotope and the TNFR2-Fc-IL-1ra subcutaneous injection is as shown in Figure 3.Experimental result shows TNFR2-Fc-IL-1ra really in subcutaneous delay, the necessity of prompting local skin administration (microneedle transdermal or subcutaneous injection).
Non-treatment of transgenic cow tinea mice pattern and binary medicine TNFR2-Fc-IL-1ra treatment conventional organization section statining result are as shown in Figure 4.Non-treatment of transgenic cow tinea mice pattern and binary medicine TNFR2-Fc-IL-1ra treat back markers of inflammation CD45, CD4, the result is as shown in Figure 5 for the CD8 immunohistochemical staining.More than two experimental results show that TNFR2-Fc-IL-1ra is effective to the abundant inflammatory skin diseases of connective tissue really.
Compared with prior art, advantage of the present invention has:
Protein antibody medicine TNFR2-Fc-IL-1ra and TNFR2-Fc eye drip are not seen the commercialization report in the world; We have set up the novel TNFR2-Fc-IL-1ra and the TNFR2-Fc eye drip medicine that can be used for doing eye table inflammation diseases such as treatment xerophthalmia first through repeatedly experiments such as binary new drug TNFR2-Fc-IL-1ra.
Description of drawings
Fig. 1 is before the treatment of an eye conjunctivitis disease and treatment back photo as a result.
Fig. 2 is that TNFR2-Fc behind the identical molar dose subcutaneous injection, effectively treats the plasma drug level of fore paw inflammation edema and measures the result in the rat body with TNFR2-Fc-IL-1ra.
Fig. 3 is in the delay case study result of injection site behind Enbrel (TNFR2-Fc) and the TNFR2-Fc-IL-1ra subcutaneous injection of labelled with radioisotope.
Fig. 4 is non-treatment of transgenic cow tinea mice pattern and binary medicine TNFR2-Fc-IL-1ra treatment conventional organization section statining result.
Fig. 5 is markers of inflammation CD45 after non-treatment of transgenic cow tinea mice pattern and the binary medicine TNFR2-Fc-IL-1ra treatment, CD4, CD8 immunohistochemical staining result.
The specific embodiment
Below in conjunction with embodiment, content of the present invention is described more specifically.Should be appreciated that enforcement of the present invention is not limited to following embodiment, all will fall into protection domain of the present invention any pro forma accommodation and/or the change that the present invention made.
In the present invention, if not refer in particular to, all part, percentage ratios are unit of weight, and all equipment and raw material etc. all can be buied from market or the industry is commonly used.Do not specialize if having, the method that embodiment adopts is this area current techique.
Some explanation to embodiment:
(1) the eye drip Therapeutic Method among the embodiment is directly the eye drip preparation to be dropped on the eye.
(2) treatment of the eye drip among embodiment antibody protein preparation:
◆ TNFR2-Fc-IL-1ra 1.0-10mg/ml (TNFR2-Fc-IL-1ra is replaceable to be TNFR2-Fc, anti-IL-12/23 antibody, IL-1ra-Fc-IL-18bp etc.)
◆ phosphate buffer (Phosphate buffer) 10-20mM
◆ benzalkonium chloride (Benzalkonium chloride) 0.005%mg/ml
◆ carboxymethyl cellulose (Carboxy methyl cellulose) 0.5%mg/ml
◆ Tween 80 (Tween 80) 0.005-0.01mg/ml
◆ arginine (Arginine) 0.05-0.1%mg/ml
◆ histamine (Histamine) 5-15mM
◆NaCl?4.0-9.0mg/ml
pH?7.0-7.5。
Embodiment 1 TNFR2-Fc-IL-1ra eye drip administration
Use TNFR2-Fc-IL-1ra eye drip treatment antibody protein preparation and eye drip medication to treat xerophthalmia appearance eye conjunctivitis disease, each dosage 1.0-10.0mg.Experimental result shows that in surprise protein macromolecule TNFR2-Fc-IL-1ra can absorb through conjunctiva, and behind the one-time treatment, eye conjunctivitis disease disappeared in the time of 45 minutes basically, complete obiteration in a hour (Fig. 1).Above experimental result also points out TNFR2-Fc-IL-1ra might become the active drug of crossing strong inflammatory reaction behind treatment xerophthalmia, computeritis, sjogren syndrome, thyroid-associated ophthalmopathy, lid inflammation, eye conjunctivitis disease and the ophthalmologic operation, and other also comprise makes the anti-inflammatory eye drop.
Embodiment 2 TNFR2-Fc eye drip administrations
Use TNFR2-Fc eye drip treatment antibody protein preparation and eye drip medication to treat xerophthalmia appearance eye conjunctivitis disease, each dosage 1.0-10.0mg.Experimental result shows that in surprise protein macromolecule TNFR2-Fc can absorb through conjunctiva, and behind the one-time treatment, eye conjunctivitis disease disappeared in the time of 45 minutes basically, complete obiteration in a hour.Above experimental result also points out TNFR2-Fc might become the active drug of crossing strong inflammatory reaction behind treatment xerophthalmia, computeritis, sjogren syndrome, thyroid-associated ophthalmopathy, lid inflammation, eye conjunctivitis disease and the ophthalmologic operation, and other also comprise makes the anti-inflammatory eye drop.
The administration of embodiment 3IL-1ra-Fc-IL-18bp eye drip
Use IL-1ra-Fc-IL-18bp (breathe out the biological preparation of medicine, be prepared into eye drip treatment antibody protein preparation) and eye drip medication to treat xerophthalmia appearance eye conjunctivitis disease, each dosage 1.0-5.0mg by the inventive method.Eye conjunctivitis disease complete obiteration in a hour behind the experimental result demonstration one-time treatment.
Claims (3)
1. preparation of putting drops in one's eyes, its composition comprises following component:
Antibody protein 1.0-10mg/ml, phosphate buffer 1 0-20mM, benzalkonium chloride 0.005%mg/ml, carboxymethyl cellulose 0.5%mg/ml, Tween 80 0.005-0.01mg/ml, arginine 0.05%-0.1%mg/ml, histamine 5-15mM, NaCl 4.0-9.0mg/ml, the pH of the described preparation of putting drops in one's eyes are 7.0-7.5.
2. the described antibody protein medicine of claim 1 is TNFR2-Fc-IL-1ra or TNFR2-Fc or anti-IL-12/23 antibody or IL-1ra-Fc-IL-18bp.
3. the described preparation of putting drops in one's eyes of claim 1 is crossed the application in the strong inflammatory reaction medicine behind preparation treatment xerophthalmia, computeritis, sjogren syndrome, thyroid-associated ophthalmopathy, lid inflammation, eye conjunctivitis disease and ophthalmologic operation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110148148 CN102805865A (en) | 2011-05-31 | 2011-05-31 | Eye drop administration device system and preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110148148 CN102805865A (en) | 2011-05-31 | 2011-05-31 | Eye drop administration device system and preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102805865A true CN102805865A (en) | 2012-12-05 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110148148 Pending CN102805865A (en) | 2011-05-31 | 2011-05-31 | Eye drop administration device system and preparation |
Country Status (1)
| Country | Link |
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| CN (1) | CN102805865A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023125483A1 (en) * | 2021-12-28 | 2023-07-06 | 山东先声生物制药有限公司 | Anti-tnfr2 antibody pharmaceutical composition |
-
2011
- 2011-05-31 CN CN 201110148148 patent/CN102805865A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023125483A1 (en) * | 2021-12-28 | 2023-07-06 | 山东先声生物制药有限公司 | Anti-tnfr2 antibody pharmaceutical composition |
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Application publication date: 20121205 |