WO2013177907A1 - 注射用左旋泮托拉唑钠冻干粉组合物及其制备方法 - Google Patents
注射用左旋泮托拉唑钠冻干粉组合物及其制备方法 Download PDFInfo
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- WO2013177907A1 WO2013177907A1 PCT/CN2012/084939 CN2012084939W WO2013177907A1 WO 2013177907 A1 WO2013177907 A1 WO 2013177907A1 CN 2012084939 W CN2012084939 W CN 2012084939W WO 2013177907 A1 WO2013177907 A1 WO 2013177907A1
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- injection
- lyophilized powder
- sodium
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- powder composition
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- 239000000203 mixture Substances 0.000 title claims abstract description 21
- 239000008176 lyophilized powder Substances 0.000 title claims abstract description 14
- 229960004048 pantoprazole sodium Drugs 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 18
- 239000004475 Arginine Substances 0.000 claims abstract description 13
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000008215 water for injection Substances 0.000 claims abstract description 9
- 238000004108 freeze drying Methods 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 5
- 229930195725 Mannitol Natural products 0.000 claims abstract description 5
- 235000010355 mannitol Nutrition 0.000 claims abstract description 5
- 239000000594 mannitol Substances 0.000 claims abstract description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 17
- 239000011734 sodium Substances 0.000 claims description 17
- 229910052708 sodium Inorganic materials 0.000 claims description 17
- 238000002347 injection Methods 0.000 claims description 13
- 239000007924 injection Substances 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 7
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 239000012982 microporous membrane Substances 0.000 claims description 5
- 238000000859 sublimation Methods 0.000 claims description 5
- 230000008022 sublimation Effects 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract 2
- 238000001914 filtration Methods 0.000 abstract 2
- 238000010792 warming Methods 0.000 abstract 2
- 238000009924 canning Methods 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 239000012528 membrane Substances 0.000 abstract 1
- 208000025865 Ulcer Diseases 0.000 description 24
- 231100000397 ulcer Toxicity 0.000 description 22
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 10
- 210000002784 stomach Anatomy 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 210000004211 gastric acid Anatomy 0.000 description 6
- 210000004877 mucosa Anatomy 0.000 description 5
- 230000008439 repair process Effects 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 102000057297 Pepsin A Human genes 0.000 description 4
- 108090000284 Pepsin A Proteins 0.000 description 4
- 208000007107 Stomach Ulcer Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229940111202 pepsin Drugs 0.000 description 4
- 235000015001 Cucumis melo var inodorus Nutrition 0.000 description 3
- 240000002495 Cucumis melo var. inodorus Species 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000002183 duodenal effect Effects 0.000 description 3
- 230000003628 erosive effect Effects 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 201000005917 gastric ulcer Diseases 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000009979 protective mechanism Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 206010010075 Coma hepatic Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 2
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000008260 defense mechanism Effects 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 201000001059 hepatic coma Diseases 0.000 description 2
- 208000007386 hepatic encephalopathy Diseases 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000008263 repair mechanism Effects 0.000 description 2
- YNWDKZIIWCEDEE-SNYZSRNZSA-N sodium;5-(difluoromethoxy)-2-[(s)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [Na+].COC1=CC=NC(C[S@](=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-SNYZSRNZSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000036269 ulceration Effects 0.000 description 2
- SCWWKKUJPHRBRV-JEDNCBNOSA-N (2s)-2,6-diaminohexanoic acid;sodium Chemical compound [Na].NCCCC[C@H](N)C(O)=O SCWWKKUJPHRBRV-JEDNCBNOSA-N 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102000004452 Arginase Human genes 0.000 description 1
- 108700024123 Arginases Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000589989 Helicobacter Species 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000002137 anti-vascular effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- NCGMIBYQHQSCGQ-PPHPATTJSA-M levofloxacin sodium Chemical compound [Na+].C([C@@H](N1C2=C(C(C(C([O-])=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 NCGMIBYQHQSCGQ-PPHPATTJSA-M 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000004678 mucosal integrity Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001020 rhythmical effect Effects 0.000 description 1
- 230000008477 smooth muscle tissue growth Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- -1 stress Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Definitions
- the present invention relates to the field of medicine, and in particular to a left-handed pantoprazole sodium lyophilized powder composition for injection and a preparation method thereof.
- Background technique :
- Gastric ulcer is one of the common and frequently-occurring diseases in the Chinese population. Its occurrence is mainly related to the imbalance between the damage factors of the gastric duodenal mucosa and the mucosal self-defense repair factors. H. pylori infection, non-anti-inflammatory drugs (NSAIDs such as aspirin), and abnormal gastric acid secretion are common causes of ulceration. Typical ulcer pain is characterized by long-term, periodic, and rhythmic.
- gastric acid and pepsin are important digestive substances in gastric juice.
- Gastric acid is a strong acid substance and is highly aggressive; pepsin has the function of hydrolyzing proteins, which can destroy proteins on the stomach wall.
- the gastrointestinal tract can still resist and maintain mucosal integrity.
- duodenal mucosa also has a series of defense and repair mechanisms.
- the object of the present invention is to provide a lyophilized powder composition of levotoprazole sodium for injection and a preparation thereof Preparation method, the composition has a synergistic effect in the body, can clinically treat gastric ulcer, repair ulcer wound, treat digestive ulcer, and has rapid curative effect.
- a levofloxacin sodium lyophilized powder composition for injection characterized in that the main drug of the composition is: mass percentage, 0.1% to 99.9% of sodium levopantoprazole and 99.9% ⁇ 0.1% Arginine.
- a method for preparing a lyophilized powder for injection using the main drug of the above composition characterized in that the specific operation steps are:
- pantoprazole sodium acts on the key enzyme H+-K+ATPase in the terminal step of gastric acid secretion in parietal cells, making it irreversibly inactivated, and the acid-inhibiting effect is stronger and lasting.
- L-pantoprazole sodium promotes ulcer healing faster and has a higher healing rate. It is suitable for the treatment of patients with various refractory ulcers or NSAID ulcers who can not stop NSAID. It can also be used together with antibiotics to eradicate pylorus. Helicobacter treatment is therefore the first choice for gastric ulcers.
- Arginine is an amino acid drug involved in the ornithine cycle. Under the activity of liver arginase, it promotes the conversion of ammonia into non-toxic urea, which is excreted in the urine to reduce blood ammonia. It is mainly used for patients with hepatic coma caused by elevated blood ammonia and various types of hepatic coma. New pharmacological studies have found that Arg is a physiological prerequisite for nitric oxide (NO), which is produced by NO synthase (N0S). NO has a variety of physiological activities in the body: diastolic blood vessels, anti-platelet aggregation, anti-thrombosis and anti-vascular smooth muscle growth. Therefore, as a substrate for the synthesis of NO, exogenous Arg is provided, and the concentration of NO in the body is promoted through the Arg-NO pathway, and Arg can accelerate the recovery of ulcer wounds in the clinic.
- NO nitric oxide
- a single left-handed pantoprazole sodium preparation can only play a therapeutic role and can only be repaired by the body itself.
- a single arginine does not serve the purpose of treatment. Therefore, combining the two not only treats the gastric ulcer, but also repairs the ulcer area, thereby improving the treatment effect.
- the invention discloses the use of the freeze-drying process for producing a lyophilized powder composition of L-pound torazole sodium for injection has the following advantages: 1) convenient liquid processing, simplifies the aseptic operation process; 2) improves the stability of the preparation; 3) does not need to go through Heat treatment removes moisture from the product; 4) enhances rehydration (dissolution) of the formulation. detailed description:
- Example 1 Preparation of a freeze-dried powder needle for levopantoprazole sodium composition for injection, based on 1000
- the sterilized sodium lysine is added to the water for injection, and the solution is stirred and dissolved, and then the NaOH solution is added to adjust the pH value of 11.0, and 0.1% of the activated carbon is stirred for 30 minutes, and filtered.
- Activated carbon the liquid is filtered through 0. 45 ⁇ ⁇ and 0. 22 ⁇ ⁇ microporous membrane, canned, sent to the freeze dryer, cooled to -40 ° C, after 2 hours of incubation, slowly warmed to -5 After sublimation at °C ⁇ 0°C, heat up to 35°C, heat for 3 hours, freeze-drying, and out of the box.
- Example 2 Preparation of a freeze-dried powder needle for a sodium edetazine sodium injection for injection, based on 1000
- Example 3 Preparation of a freeze-dried powder needle for sodium levopantoprazole composition for injection, based on 1000
- the prescription amount of levotoprazole sodium, arginine and mannitol is added to the water for injection, stirred and dissolved, and then the NaOH solution is added to adjust the pH value of 11.0, and 0.1% activated carbon is added and stirred for 30 minutes, and the activated carbon is filtered out. It is filtered through 0.45 ⁇ and 0.22 ⁇ microporous membrane, canned, sent to a freeze dryer, and cooled to -40 ° C. After 2 hours of incubation, slowly warm to -5 ° C ⁇ 0 ° C sublimation drying, and then After heating to 35 ° C, keep warm for 3 hours, freeze-drying, and out of the box.
- the stomach was dissected along the large curvature of the stomach and flattened on a glass plate.
- the transverse and vertical diameters dl and d2 of the ulcer were measured.
- Control group 2 1.3 (left-handed tolazole) 9 90 5.7 ⁇ 5.5 67.3
- Treatment group 1 9 90 2.8 ⁇ 3.0 86.2
- Treatment group 2 10 100 2 ⁇ 0 ⁇ 2 ⁇ 7 88.5
- Treatment group 3 9 90 2.1 ⁇ 2 ⁇ 8 87.9
- the examples - , 2, and 3 have a good therapeutic effect on the ulcer.
- the cure rate of the treatment group 1, 2, 3 is higher than that of the left-handed pantoprazole sodium (control group 2). It has a good therapeutic effect and can repair the ulcer area.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种注射用左旋泮托拉唑钠冻干粉组合物及其制备方法。该组合物的主药为：左旋泮托拉唑钠和精氨酸。制备该冻干粉组合物的具体步骤为：将质量百分比为0.1%〜99.9%的左旋泮托拉唑钠、99.9%〜0.1%的精氨酸，和主药5〜10倍的甘露醇加到注射用水中；搅拌溶解后加入NaOH溶液调节pH值为11.0；加入总体积0.1%的活性炭搅拌30分钟；滤除活性炭，药液再经0.45μm和0.22μm微孔滤膜过滤；罐装，送入冷冻干燥机中；降温至-40°C，保温2小时后，缓慢升温至-5°C〜0°C升华干燥，再升温至35°C后，保温3小时；冷冻干燥结束，出箱，即得注射用左旋泮托拉唑钠冻干粉组合物。
Description
注射用左旋泮托拉唑钠冻干粉组合物及其制备方法
技术领域- 本发明涉及医药领域， 尤其涉及一种注射用左旋泮托拉唑钠冻干粉组合 物及其制备方法。 背景技术：
胃溃疡是我国人群中常见病、 多发病之一。 其发生主要与胃十二指肠黏 膜的损害因素和黏膜自身防御修复因素之间失平衡有关。 幽门螺杆菌（H. pylori)感染、 非 体抗炎药 (NSAID, 如阿司匹林）、 胃酸分泌异常是引起溃 疡的常见病因。 典型的溃疡疼痛具有长期性、 周期性和节律性的特点。
胃腔内， 胃酸和胃蛋白酶是胃液中重要的消化物质。 胃酸为强酸性物质， 具有较强的侵蚀性； 胃蛋白酶具有水解蛋白质的作用， 可破坏胃壁上的蛋白 质， 然而， 在这些侵蚀因素的存在下， 胃肠道仍能抵抗而维持黏膜的完整性 及自身的功能， 其主要是因为胃、 十二指肠黏膜还具有一系列防御和修复机 制。 我们将胃酸及胃蛋白酶的有害侵蚀性称之为损伤机制， 而将胃肠道自身 具有的防御和修复机制称之为保护机制。 目前认为， 正常人的胃十二指肠黏 膜的保护机制， 足以抵抗胃酸及胃蛋白酶的侵蚀。 但是， 当某些因素损害了 保护机制中的某个环节就可能发生胃酸及蛋白酶侵蚀自身黏膜而导致溃疡的 形成。 当过度胃酸分泌远远超过黏膜的防御和修复作用也可能导致溃疡发生。 近年的研究已经表明， 幽门螺杆菌和非 体抗炎药是损害胃肠保护机制导致 溃疡发病的最常见病因， 胃酸在溃疡形成中起关键作用。 此外， 药物， 应激， 激素也可导致溃疡的产生， 各种心理因素及不良的饮食生活习惯可诱发溃疡 的出现。 发明内容：
本发明的目的在于提供一种注射用左旋泮托拉唑钠冻干粉组合物及其制
备方法， 该组合物在体内有协同作用， 在临床上能治疗胃溃疡， 修复溃疡伤 口， 治疗消化道溃疡， 疗效迅速。
本发明的具体技术方案为：
一种注射用左旋泮托拉唑钠冻干粉组合物， 其特征在于， 该组合物的主 药为： 质量百分比， 0.1%〜99.9%的左旋泮托拉唑钠和 99.9%〜0.1%的精氨酸。
一种以上述组合物的主药制备注射用冻干粉针的方法， 其特征在于， 具 体操作步骤为：
(1) 将质量百分比为 0.1%〜99.9%的左旋泮托拉唑钠、 99.9%〜0.1%精氨 酸， 和主药 5〜10倍的甘露醇加到注射用水中；
(2) 搅拌溶解后加入 NaOH溶液调节 pH值 11.0;
(3) 加入总体积 0.1%的活性炭搅拌 30分钟；
(4) 滤除活性炭， 药液再经 0.45 μπι和 0.22 μπι微孔滤膜过滤；
(5) 罐装， 送入冷冻干燥机中；
(6) 降温至 -40°C， 保温 2小时后， 缓慢升温至 _5°C〜0°C升华干燥， 再 升温至 35 °C后， 保温 3小时；
(7) 冷冻干燥结束， 出箱， 即得注射用左旋泮托拉唑钠冻干粉组合物。 左旋泮托拉唑钠作用于壁细胞胃酸分泌终末步骤中的关键酶 H+-K+ATP 酶， 使其不可逆失活， 抑酸作用更强且作用持久。 左旋泮托拉唑钠促进溃疡 愈合的速度较快、 愈合率较高， 适用于各种难治性溃疡或 NSAID溃疡患者不能 停用 NSAID时的治疗， 还可与抗生素的协同作用可用于根除幽门螺杆菌治疗， 因此是胃溃疡的首选用药。
精氨酸 （Arg)为氨基酸类药， 参与鸟氨酸循环， 在肝精氨酸酶活力下促 进氨转化为无毒的尿素由尿中排出， 以降低血氨。 主要用于血氨增高引起的 肝昏迷及各类肝昏迷忌用谷氨酸钠的病人。 新的药理研究发现： Arg是一氧化 氮 （NO) 的生理性前提， 经 NO合成酶 （N0S)作用后生成 N0。 NO在体内具有 多种生理活性作用：舒张血管， 抗血小板聚集， 抗血栓形成和抗血管平滑肌增 生等。 因而作为合成 NO的底物， 提供外源性的 Arg, 通过 Arg-NO通路， 促进体 内 NO浓度增加， Arg在临床中能起到加速溃疡伤口复原的作用。
单一的左旋泮托拉唑钠制剂只能起到治疗的作用， 只能靠人体自身修复。
单一的精氨酸却不能起到治疗的目的。 所以将两者结合不仅治疗了胃溃疡， 还能做到修复溃疡面积， 从而提高治疗效果。
本发明用冻干工艺生产注射用左旋泮托拉唑钠冻干粉组合物有以下优 点： 1 ) 液体加工方便， 简化了无菌作业过程； 2 ) 提高了制剂的稳定性； 3 ) 无需经过热处理就能去除产品中的水分； 4) 增强了制剂的复水 （溶解） 性。 具体实施方式：
为了使本发明实现的技术手段、 创作特征、 达成目的与功效易于明白了 解， 下面结合具体实施例， 进一步阐述本发明。
实施例一、 注射用左旋泮托拉唑钠组合物冻干粉针的制备， 以 1000支计
1.处方
左旋泮托拉唑钠 （按左旋泮托拉唑计） 40g
甘露 250g
注射用水 2000ml
2.制备工艺
将处方量的的左旋泮托拉唑钠、 精氨酸和甘露醇加到注射用水中， 搅拌 溶解后加入 NaOH溶液调节 pH值 11. 0， 加入 0. 1%的活性炭搅拌 30分钟， 滤除活 性炭， 药液再经 0. 45 μ πι和 0. 22 μ πι微孔滤膜过滤， 罐装， 送入冷冻干燥机中， 降温至 -40°C， 保温 2小时后， 缓慢升温至 -5°C〜0°C升华干燥， 再升温至 35°C 后， 保温 3小时， 冷冻干燥结束， 出箱。
实施例二、 注射用左旋泮托拉唑钠组合物冻干粉针的制备， 以 1000支计
1.处方
左旋泮托拉唑钠 （按左旋泮托拉唑计） 40g
甘露 250g
注射用水 2000ml
2.制备工艺
将处方量的的左旋泮托拉唑钠、 精氨酸和甘露醇加到注射用水中， 搅拌
溶解后加入 NaOH溶液调节 pH值 11.0， 加入 0.1%的活性炭搅拌 30分钟， 滤除活 性炭， 药液再经 0.45 μπι和 0.22 μπι微孔滤膜过滤， 罐装， 送入冷冻干燥机中， 降温至 -40°C， 保温 2小时后， 缓慢升温至 -5°C〜0°C升华干燥， 再升温至 35°C 后， 保温 3小时， 冷冻干燥结束， 出箱。
实施例三、 注射用左旋泮托拉唑钠组合物冻干粉针的制备， 以 1000支计
1.处方
左旋泮托拉唑钠 （按左旋泮托拉唑计） 40g
甘露 250g
注射用水 2000ml
2.制备工艺
将处方量的的左旋泮托拉唑钠、 精氨酸和甘露醇加到注射用水中， 搅拌 溶解后加入 NaOH溶液调节 pH值 11.0， 加入 0.1%的活性炭搅拌 30分钟， 滤除活 性炭， 药液再经 0.45 μπι和 0.22 μπι微孔滤膜过滤， 罐装， 送入冷冻干燥机中， 降温至 -40°C， 保温 2小时后， 缓慢升温至 -5°C〜0°C升华干燥， 再升温至 35°C 后， 保温 3小时， 冷冻干燥结束， 出箱。 实验资料
SD大白鼠 50只。 试验前禁食 24h。 在乙醚麻醉下打开腹腔， 将内径 5mm、 长 30mm的玻璃管垂直放置于胃体部浆膜面上， 向管腔内加入冰醋酸 0. 2ml, 1.5min后用棉签蘸出冰醋酸， 缝合手术切口。 术后正常饮食， 第二天将动物 随机分为 5组： 对照组 1( 蒸馏水）， 对照组 2( 注射用左旋泮托拉唑钠）， 治疗 组 1(实施例一）、 治疗组 2 (实施例二）、 治疗组 3 (实施例三）； 连续给药 15d。 解剖取出胃， 并用甲醛固定， 沿胃大弯剖开胃， 平展在玻璃板上， 测量溃疡 横竖径 dl、 d2。 用公式 S= X (dl/2) X (d2/2)计算溃疡面积 S( mm2) 作为溃 疡指数， 并计算溃疡愈合率和溃疡抑制率。 结果见下表
治愈动物数 治愈率 溃疡指数 溃疡抑制率 组别 齐糧 (mg/kg)
(只） （％) ( X士 s，mm2) (%)
对照组 1 0 0 18.3±8· 7
对照组 2 1.3 (左旋泮托拉唑） 9 90 5.7±5.5 67.3
1.3 (左旋泮托拉唑）
治疗组 1 9 90 2.8±3.0 86.2
1.3 (精氨酸）
1.3 (左旋泮托拉唑）
治疗组 2 10 100 2·0±2·7 88.5
1.5 (精氨酸）
1.3 (左旋泮托拉唑）
治疗组 3 9 90 2.1 ±2· 8 87.9
2.0 (精氨酸）
舰实验资料表明， 实施例- 、 二、 三均对 疡有良好的治疗作用， 治 疗组 1、 2、 3的治愈率比单用左旋泮托拉唑钠 （对照组 2) 高， 对胃溃疡有良 好的治疗效果， 并且能修复溃疡面积。
以上显示和描述了本发明的基本原理、 主要特征以及本发明的优点。 本 行业的技术人员应该了解， 本发明不受上述实施例的限制， 上述实施例和说 明书中描述的只是说明本发明的原理， 在不脱离本发明精神和范围的前提下， 本发明还会有各种变化和改进， 这些变化和改进都落入要求保护的本发明范 围内。 本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims
1.一种注射用左旋泮托拉唑钠冻干粉组合物， 其特征在于， 该组合物的 主药为： 质量百分比， 0.1%〜99.9%的左旋泮托拉唑钠和 99.9%〜0.1%的精氨 酸。
2.一种以权利要求 1所述组合物的主药制备注射用冻干粉针的方法， 其特 征在于， 具体操作步骤为：
(1) 将质量百分比为 0.1%〜99.9%的左旋泮托拉唑钠、 99.9%〜0.1%精氨 酸， 和主药 5〜10倍的甘露醇加到注射用水中；
(2) 搅拌溶解后加入 NaOH溶液调节 pH值 11.0;
(3) 加入总体积 0.1%的活性炭搅拌 30分钟；
(4) 滤除活性炭， 药液再经 0.45 μπι和 0.22 μπι微孔滤膜过滤；
(5) 罐装， 送入冷冻干燥机中；
(6) 降温至 -40°C， 保温 2小时后， 缓慢升温至 _5°C〜0°C升华干燥， 再 升温至 35 °C后， 保温 3小时；
(7) 冷冻干燥结束， 出箱， 即得注射用左旋泮托拉唑钠冻干粉组合物。
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