WO2013177963A1 - 注射用泮托拉唑钠冻干粉组合物及其制备方法 - Google Patents
注射用泮托拉唑钠冻干粉组合物及其制备方法 Download PDFInfo
- Publication number
- WO2013177963A1 WO2013177963A1 PCT/CN2013/072101 CN2013072101W WO2013177963A1 WO 2013177963 A1 WO2013177963 A1 WO 2013177963A1 CN 2013072101 W CN2013072101 W CN 2013072101W WO 2013177963 A1 WO2013177963 A1 WO 2013177963A1
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- WIPO (PCT)
- Prior art keywords
- injection
- pantoprazole sodium
- composition
- preparation
- lyophilized powder
- Prior art date
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- 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 title claims abstract description 26
- 229960004048 pantoprazole sodium Drugs 0.000 title claims abstract description 26
- 239000000203 mixture Substances 0.000 title claims abstract description 22
- 239000008176 lyophilized powder Substances 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 18
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims abstract description 17
- 235000014852 L-arginine Nutrition 0.000 claims abstract description 16
- 229930064664 L-arginine Natural products 0.000 claims abstract description 16
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 claims abstract description 13
- 239000000243 solution Substances 0.000 claims abstract description 13
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 claims abstract description 12
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000013477 citrulline Nutrition 0.000 claims abstract description 12
- 229960002173 citrulline Drugs 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 10
- 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 9
- 229930195725 Mannitol Natural products 0.000 claims abstract description 9
- 235000010355 mannitol Nutrition 0.000 claims abstract description 9
- 239000000594 mannitol Substances 0.000 claims abstract description 9
- 239000008215 water for injection Substances 0.000 claims abstract description 9
- 239000007788 liquid Substances 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 7
- 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
- MWEQTWJABOLLOS-UHFFFAOYSA-L disodium;[[[5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-oxidophosphoryl] hydrogen phosphate;trihydrate Chemical compound O.O.O.[Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP([O-])(=O)OP(O)([O-])=O)C(O)C1O MWEQTWJABOLLOS-UHFFFAOYSA-L 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 239000007983 Tris buffer Substances 0.000 claims 1
- 238000004108 freeze drying Methods 0.000 abstract description 5
- 238000001914 filtration Methods 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 238000012545 processing Methods 0.000 abstract description 2
- 239000004480 active ingredient Substances 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 22
- 231100000397 ulcer Toxicity 0.000 description 20
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 8
- 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
- 208000007107 Stomach Ulcer Diseases 0.000 description 5
- 210000004877 mucosa Anatomy 0.000 description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 5
- 230000008439 repair process Effects 0.000 description 5
- 230000001225 therapeutic effect 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
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229940111202 pepsin Drugs 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000002183 duodenal effect Effects 0.000 description 3
- 230000000694 effects 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
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 229960005019 pantoprazole Drugs 0.000 description 3
- 230000009979 protective mechanism Effects 0.000 description 3
- 239000000126 substance Substances 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
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 2
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 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
- 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
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- 230000007246 mechanism Effects 0.000 description 2
- 230000008263 repair mechanism Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000036269 ulceration Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 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
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 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 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 241001465754 Metazoa Species 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
- 208000002847 Surgical Wound Diseases 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
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 235000001014 amino acid Nutrition 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
- 230000001580 bacterial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000003205 diastolic effect Effects 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
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 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
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical class O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 230000002503 metabolic effect 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
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 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
- 239000000843 powder Substances 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001020 rhythmical effect Effects 0.000 description 1
- 230000027849 smooth muscle hyperplasia Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- -1 stress Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000014616 translation Effects 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- 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 invention relates to the field of medicine, in particular to a 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-steroidal 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 pantoprazole sodium lyophilized powder composition for injection and a preparation thereof
- the composition is clinically capable of treating gastric ulcers, repairing ulcer wounds, and treating digestive ulcers efficiently and rapidly.
- pantoprazole sodium a 9% of pantoprazole sodium, 99. 9%
- the main drug of the composition is: a percentage by mass, 0. 1% ⁇ 99. 9% of pantoprazole sodium, 99.9% 9% ⁇ 0.
- 1% of adenosine triphosphate. 99% 9% to 0. 1% of L-arginine and 99. 9% ⁇ 0.
- 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 suppression effect is stronger and lasting. 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 pyloric screw. Bacterial therapy is therefore the first choice for gastric ulcers.
- Citrulline is a non-protein alpha-amino acid that has the ability to form peptide bonds but is not involved in protein synthesis. Citrulline is converted into the essential amino acid L-arginine in the body.
- L-Arginine is an amino acid drug involved in the ornithine cycle. It promotes the conversion of ammonia into non-toxic urea in the urine arginase activity, which is discharged from 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 L-Arg is a physiological prerequisite for nitric oxide (NO) and is produced by NO synthase (N0S). N0. NO has a variety of physiological activities in the body: diastolic blood vessels, anti-platelet aggregation, anti-thrombosis and anti-vascular smooth muscle hyperplasia. Therefore, as a substrate for synthesis, exogenous L-Arg is provided, and the concentration of NO in the body is promoted through the L-Arg-N0 pathway, and L-Arg can accelerate the recovery of ulcer wounds in the clinic.
- NO nitric oxide
- N0S NO synth
- Adenosine triphosphate is a high-energy compound prepared by biofermentation technology using hypoxanthine nucleotides as a substrate.
- Adenosine triphosphate is a direct source of energy required for all life activities of tissue cells in the body, and is known as intracellular energy.
- "Molecular currency" the storage and transfer of chemical energy, the synthesis of proteins, fats, sugars and nucleotides are all involved, which can promote the repair and regeneration of various cells in the body, enhance the metabolic activity of cells, and treat various diseases. Strongly targeted.
- a single pantoprazole sodium preparation can only be used as a therapeutic effect and can only be repaired by the body itself.
- Single citrulline, L-arginine, and adenosine triphosphate are not therapeutic purposes. Therefore, combining the two not only treats the gastric ulcer, but also repairs the ulcer area, thereby improving the therapeutic effect.
- the lyophilized process for producing pantoprazole sodium lyophilized powder composition for injection has the following advantages: 1) convenient liquid processing, simplifying the aseptic operation process; 2) improving the stability of the preparation; 3) no heat treatment is required It removes moisture from the product; 4) enhances the rehydration (dissolution) of the formulation. detailed description:
- Pantoprazole sodium (based on pantoprazole) 40g
- pantoprazole sodium, citrulline and mannitol To the water for injection, stir and dissolve After adding NaOH solution to adjust the pH value of 11. 0, adding 0.1% of activated carbon for 30 minutes, filtering off the activated carbon, and the solution is filtered through 0. 45 ⁇ ⁇ and 0. 22 ⁇ ⁇ microporous membrane, canned, It is sent to the freeze dryer, and the temperature is lowered to -40 ⁇ . When the temperature is kept for 2 hours, the temperature is slowly raised to -5 ° C to 0 ° C. Sublimation is dried, and then the temperature is raised to 35 ° C, and then kept warm for 3 hours, and the freeze-drying is finished, and the box is discharged.
- Example 2 preparation of pantoprazole sodium composition for lyophilized powder injection, 1000 counts
- Pantoprazole sodium (based on pantoprazole) 40g
- pantoleazole sodium, L-arginine and mannitol The solution of the pantoleazole sodium, L-arginine and mannitol is added to the water for injection, stirred and dissolved, and then added with a NaOH solution to adjust the pH value of 11. 0, added 0.1% activated carbon for 30 minutes, filtered In addition to activated carbon, the liquid is filtered through 0. 45 ⁇ ⁇ and 0.22 ⁇ microporous membrane filter, canned, sent to a freeze dryer, cooled to -40 ° C, and kept warm for 2 hours, 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 3 Preparation of pantoprazole sodium adenosine triphosphate freeze-dried powder for injection, based on 1000
- Pantoprazole sodium (based on pantoprazole) 40g
- pantoprazole sodium, adenosine triphosphate, and mannitol 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 the solution is filtered.
- Carbon, the liquid is filtered through 0.45 ⁇ and 0.22 ⁇ microporous membrane, canned, sent to the freeze dryer, cooled to -40 ° C, kept warm for 2 hours, slowly warmed to -51: ⁇ 0 ° C sublimation Dry, heat up to 35 ⁇ , keep warm for 3 hours, freeze-drying, out of the box.
- the stomach was dissected and fixed with formaldehyde.
- the stomach was dissected along the large curvature of the stomach and flattened on a glass plate.
- the transverse and vertical diameters of the ulcers were measured dl d2.
- the experimental data show that the first, second and third examples have a good therapeutic effect on ulcers.
- the cure rate of the treatment group 1, 2, 3 was higher than that of pantoprazole sodium (control group 2) alone, and it has a good therapeutic effect on gastric ulcer and can repair the ulcer area.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
一种注射用泮托拉唑钠冻干粉组合物及其制备方法，涉及医药领域，该组合物的主药为：泮托拉唑钠、瓜氨酸、、L—精氨酸和三磷酸腺苷，制备冻干粉组合物的具体步骤为：将组分比为0.1%～99.9%的泮托拉唑钠、99.9%～0.1% 的瓜氨酸、99.9%～0.1%的L-精氨酸、99.9%～0.1%的三磷酸腺苷，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11.0；加入活性炭搅拌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℃，保温2小时后，缓慢升温至—5 ℃～0℃升华干燥，再升温至35℃后，保温3小时；冷冻干燥结束，出箱。本发明的优点：液体加工方便，简化了无菌作业过程；提高了制剂的稳定性；无需经过热处理就能去除产品中的水分；增强了制剂的复水（溶解）性。
Description
说 明 书 注射用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、 非甾体抗炎药 (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， 幽门螺杆菌和非甾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泮托拉唑钠冻干粉组合物及其制备方
法， 该组合物在临床上能治疗胃溃疡， 修复溃疡伤口， 高效迅速的治疗消化 道溃疡。
本发明的具体技术方案为：
一种注射用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%的泮托拉唑钠、 99. 9%〜0. 1%的瓜氨酸、 99. 9%〜0. 1% 的 L-精氨酸和 99. 9%〜0. 1%的三磷酸腺苷。
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 ) 将组分比为 0. 1%〜99. 9%的泮托拉唑钠、 99. 9%〜0. 1%的瓜氨酸、 99. 9%〜0. 1%的 L-精氨酸、 99. 9%〜0. 1%的三磷酸腺苷， 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 μ πι和 0. 22 μ πι微孔滤膜过滤；
( 5) 罐装， 送入冷冻干燥机中；
( 6) 降温至 -4CTC , 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。
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。 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。
瓜氨酸是一种非蛋白质 α _氨基酸， 它具有肽键形成的能力， 但是不参与 蛋白质的合成。 瓜氨酸在体内转化为人体必需氨基酸 L-精氨酸。
L-精氨酸 （L-Arginine， L-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: L-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 )的底物， 提供外源性的 L-Arg， 通过 L-Arg-N0通路， 促进体内 NO浓度增加， L- Arg在临床中能起到加速溃疡伤口 复原的作用。
三磷酸腺苷 (ATP)是以次黄嘌吟核苷酸为底物， 经生物发酵的技术制得的 高能化合物， 三磷酸腺苷是体内组织细胞一切生命活动所需能量的直接来源， 被誉为细胞内能量的 "分子货币"， 储存和传递化学能， 蛋白质、 脂肪、 糖和 核苷酸的合成都需它参与， 可促使机体各种细胞的修复和再生， 增强细胞代 谢活性， 对治疗各种疾病均有较强的针对性。
单一的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 一的瓜氨酸、 L-精氨酸、 三磷酸腺苷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、 注射用泮托拉唑钠组合物冻干粉针的制备， 以 1000支计
1.处方
泮托拉唑钠 （按泮托拉唑计） 40g
瓜氨酸 40g
L-精氨酸 40g
三磷酸腺苷 20g
甘露醇 250g
注射用水 2000ml
2.制备工艺
将处方量的的泮托拉唑钠、 瓜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 ιη和 0. 22 μ πι微孔滤膜过滤， 罐装， 送入冷冻干燥机中， 降温 至 -40Ό， 保温 2小时候， 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、 注射用泮托拉唑钠组合物冻干粉针的制备， 以 1000支计
1.处方
泮托拉唑钠 （按泮托拉唑计） 40g
瓜氨酸 40g
L-精氨酸 40g
三磷酸腺苷 40g
甘露醇 250g
注射用水 2000ml
2.制备工艺
将处方量的的泮托拉唑钠、 L-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 ιη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小时候， 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、 注射用泮托拉唑钠三磷酸腺苷冻干粉针的制备， 以 1000支计
1.处方
泮托拉唑钠 （按泮托拉唑计） 40g
瓜氨酸 40g
L-精氨酸 40g
三磷酸腺苷 60g
甘露醇 250g
注射用水 2000ml
2.制备工艺
将处方量的的泮托拉唑钠、 三磷酸腺苷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 μΐϋ和 0.22 μιη微孔滤膜过滤， 罐装， 送入冷冻干燥机中， 降温至 -40°C， 保温 2小时候， 缓慢升温至 -51：〜 0°C升华干燥， 再升温至 35Ό 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 30 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= r 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
通过实验资料表明， 实施例一、 二、 三均对溃疡有良好的治疗作用， 治
疗组 1、 2、 3的治愈率比单用泮托拉唑钠 （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%的泮托拉唑钠、 99.9%〜0.1%的瓜氨酸、 99.9%〜 0.1%的 L-精氨酸和 99.9%〜0.1%的三憐酸腺苷。
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) 将组分比为 0.1%〜99.9%的泮托拉唑钠、 99.9%〜0.1%的瓜氨酸、 99.9%〜0.1%的 L-精氨酸、 99.9%〜0.1%的三磷酸腺苷， 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 ρΗ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 μηι微孔滤膜过滤；
(5) 罐装， 送入冷冻干燥机中；
(6) 降温至 -4CTC, 保温 2小时后， 缓慢升温至 -5Τ〜 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。
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