WO2022206716A1 - 含有促肾上腺皮质激素或其衍生物的药物及其用途 - Google Patents
含有促肾上腺皮质激素或其衍生物的药物及其用途 Download PDFInfo
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- WO2022206716A1 WO2022206716A1 PCT/CN2022/083523 CN2022083523W WO2022206716A1 WO 2022206716 A1 WO2022206716 A1 WO 2022206716A1 CN 2022083523 W CN2022083523 W CN 2022083523W WO 2022206716 A1 WO2022206716 A1 WO 2022206716A1
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- WIPO (PCT)
- Prior art keywords
- chitosan
- salt
- acid
- chitin
- application according
- Prior art date
Links
- 101800000414 Corticotropin Proteins 0.000 title claims abstract description 73
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 title claims abstract description 72
- 229960000258 corticotropin Drugs 0.000 title claims abstract description 71
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 title claims abstract description 67
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- 229920001661 Chitosan Polymers 0.000 claims description 46
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- 229920002101 Chitin Polymers 0.000 claims description 24
- 239000002738 chelating agent Substances 0.000 claims description 21
- 229910021645 metal ion Inorganic materials 0.000 claims description 21
- 239000004094 surface-active agent Substances 0.000 claims description 20
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 17
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 6
- 108010091893 Cosyntropin Proteins 0.000 claims description 5
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- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 claims description 3
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
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- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
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- RQFQJYYMBWVMQG-IXDPLRRUSA-N chitotriose Chemical compound O[C@@H]1[C@@H](N)[C@H](O)O[C@H](CO)[C@H]1O[C@H]1[C@H](N)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)[C@@H](CO)O1 RQFQJYYMBWVMQG-IXDPLRRUSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 claims description 2
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- WPUMTJGUQUYPIV-JIZZDEOASA-L disodium (S)-malate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)CC([O-])=O WPUMTJGUQUYPIV-JIZZDEOASA-L 0.000 description 8
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- 235000019265 sodium DL-malate Nutrition 0.000 description 8
- 239000001394 sodium malate Substances 0.000 description 8
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
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- KQCBYLOBOGMDSY-OMCTUWBCSA-N n-[(2r,3r,4r,5r,6r)-5-[(2s,3r,4r,5r,6r)-3-acetamido-5-[(2s,3r,4r,5s,6r)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2,4-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide;2-hydroxybutanedioic acid Chemical class OC(=O)C(O)CC(O)=O.O[C@@H]1[C@@H](NC(=O)C)[C@H](O)O[C@H](CO)[C@@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 KQCBYLOBOGMDSY-OMCTUWBCSA-N 0.000 description 2
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- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
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- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- A61K38/35—Corticotropin [ACTH]
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Definitions
- the invention belongs to the technical field of biomedicine, and in particular relates to a medicine containing adrenocorticotropic hormone or a derivative thereof and use thereof.
- Adrenocorticotropic Hormone is a polypeptide hormone secreted by the vertebrate pituitary gland, which can promote the tissue proliferation of the adrenal cortex and the production and secretion of corticosteroids. Corticotropin production and secretion are directly regulated by hypothalamic corticotropin-releasing factor. Excessive secretion of corticosteroids can in turn affect the pituitary gland and hypothalamus, reducing their activity. Adrenocorticotropic hormone has the effect of stimulating the development and function of the adrenal cortex, mainly acting on the adrenal cortical zona fasciae and stimulating the secretion of glucocorticoids. ACTH also has the effect of regulating antibody production through the adrenal cortex.
- Adrenocorticotropic hormone is a polypeptide drug, which is easily hydrolyzed by digestive enzymes in the gastrointestinal tract, and has not been able to be administered orally;
- the clinically used medicinal preparation containing adrenocorticotropic hormone is an injection preparation: adrenocorticotropic hormone for injection (Corticotropin for injection), the indications are for active rheumatism, rheumatoid arthritis, lupus erythematosus and other collagen diseases; also for severe bronchial asthma, severe dermatitis and other allergic diseases and acute leukemia, Hodgkin's disease, etc.
- the present invention is achieved through the following technical solutions.
- the adjuvants in the oral pharmaceutical preparation are: surfactant, acrylic polymer, chitin or its derivative, and metal ion chelating agent.
- auxiliary materials in the oral pharmaceutical preparation are: surfactant, chitin or its derivative, and metal ion chelating agent.
- the surfactants mentioned therein include one or more of anionic surfactants or nonionic surfactants.
- the acrylic polymer described therein includes one or more of Carbomer, Carbomer 910, Carbomer 934 and Carbomer 934P.
- the chitin or its derivatives include chitin, chitosan, carboxymethyl chitosan, acylated chitosan, alkylated chitosan, hydroxylated chitosan, chitosan quaternary ammonium salt , one or more of chitosan oligosaccharide and chitosan sulfate.
- the metal ion chelating agent includes citric acid or its salt, tartaric acid or its salt, malic acid or its salt, maleic acid or its salt, gluconic acid or its salt, EDTA or its salt, amino acid One or more of triacetic acid or its salt, diethylenetriaminepentaacetic acid or its salt.
- the weight ratio of surfactant, acrylic polymer, chitin or its derivatives and metal ion chelating agent is 19-21:6-7:6-7:60-70.
- the weight ratio of surfactant, chitin or its derivatives and metal ion chelating agent is 19-21:6-7:60-70.
- the weight ratio of ACTH (or its derivatives), surfactant, acrylic polymer, chitin or its derivatives and metal ion chelating agent is 1.5-2.5:19-21:6-7:6-7:60 -70.
- the weight ratio of ACTH (or its derivatives), surfactant, chitin or its derivatives and metal ion chelating agent is 1.5-2.5:19-21:6-7:60-70.
- the weight ratio of ACTH (or its derivatives), surfactant, acrylic polymer, chitin or its derivatives and metal ion chelating agent is 0.20-0.30:19-21:6-7:6-7:60 -70.
- the weight ratio of ACTH (or its derivatives), surfactant, chitin or its derivatives and metal ion chelating agent is 0.20-0.30:19-21:6-7:60-70.
- the weight ratio of ACTH (or its derivatives), surfactant, acrylic polymer, chitin or its derivatives and metal ion chelating agent is 0.25-2.0:19-21:6-7:6-7:60 -70.
- the weight ratio of ACTH (or its derivatives), surfactant, chitin or its derivatives and metal ion chelating agent is 0.25-2.0:19-21:6-7:60-70.
- the preferred proportional relationship is: the weight ratio of ACTH (or its derivative), surfactant, chitin or its derivative and metal ion chelating agent is 0.25-2.0:19-21:6- 7:60-70.
- the concentration of the adrenocorticotropic hormone described therein is 0.05 mg/ml or higher in the solution formulation, and 0.4 mg or higher in the capsule formulation.
- Described solution preparation formula concentration refers to more than or equal to 0.05mg/ml, to the saturated concentration in the aqueous solution;
- the capsule preparation refers to that the filling amount in each capsule is greater than or equal to 0.4 mg, up to the maximum filling amount of one capsule.
- the adrenocorticotropic hormone or its derivatives include ACTH(1-39), ACTH(1-24) and ACTH(1-17).
- the adrenocorticotropic hormone (ACTH) of the present invention is a polypeptide hormone secreted by the vertebrate pituitary gland, which can promote the tissue proliferation of the adrenal cortex and the production and secretion of corticosteroids.
- ACTH contains 39 amino acids, of which amino acids 1 to 24 are essential amino acids for biological activity, and amino acids 25 to 39 are protective amino acids.
- adrenocorticotropic hormone (ACTH)
- corticotropin for injection corticotropin for injection
- the present invention obtains adrenocorticotropic hormone (ACTH) or its derivative by oral administration
- Oral pharmaceutical composition as the active ingredient for the treatment of arthritis, including gout.
- the adrenocorticotropic hormone derivatives described in the present invention include but are not limited to: ACTH(1-24), ACTH(1-24) is the N-terminal 24 peptide of adrenocorticotropic hormone.
- ACTH (1-24) because amino acids 1-24 are essential amino acids for biological activity, therefore, it has the same physiological activity as ACTH, and the preparation of oral drugs must have the same ability to treat arthritis, including gout caused by high uric acid. effect.
- Arthritis generally refers to inflammatory diseases that occur in human joints and their surrounding tissues, caused by inflammation, infection, degeneration, trauma or other factors, and can be divided into dozens of types.
- the clinical manifestations are joint redness, swelling, heat, pain, dysfunction and joint deformity, and severe cases lead to joint disability and affect the quality of life of patients.
- the etiology of arthritis is complex, mainly related to autoimmune reactions, infections, metabolic disorders, trauma, degenerative diseases and other factors. According to the etiology, arthritis can be divided into bone, rheumatoid, rheumatic, gout and so on. There are more than 100 million arthritis patients in my country, and the number is increasing, especially gouty arthritis.
- Gout is a common and complex type of arthritis that can affect all age groups, with a higher incidence in men than in women.
- Patients with gout often experience sudden joint pain at night. The onset is acute, with severe pain, edema, redness, and inflammation in the joints. The pain gradually decreases until it disappears, lasting several days or weeks. When the pain strikes (acute gout), the patient wakes up in the middle of the night with pain, and some patients describe the pain as similar to the burning of the big toe.
- the most commonly affected joint is the big toe (medical term: first metatarsal), but the affected joint is not limited to this, and is also commonly found in the joints of the hands, knees, elbows, and the like. The affected joint will eventually become red, swollen and inflamed. After edema, the tissue becomes soft and the movement is limited, which finally affects daily life. These symptoms will recur.
- anionic surfactants, nonionic surfactants, etc. described in the present invention can all be purchased through commercial channels.
- the acrylic polymers described in the present invention include carbomer, carbomer 910, carbomer 934, and carbomer 934P, which can be purchased through commercial channels.
- the chitin or its derivatives of the present invention include chitin, chitosan, carboxymethyl chitosan, acylated chitosan, alkylated chitosan, hydroxylated chitosan, quaternary ammonium chitosan Salts, chitosan oligosaccharides, and chitosan sulfates can all be purchased commercially.
- the metal ion chelating agent of the present invention includes citric acid or its salt, tartaric acid or its salt, malic acid or its salt, maleic acid or its salt, gluconic acid or its salt, EDTA or its salt, Aminotriacetic acid or its salt, diethylenetriaminepentaacetic acid or its salt can all be purchased through commercial channels.
- ACTH or its derivatives, surfactants, chitin or its derivatives, and metal ion chelating agents are formed into new compositions, which are used for the treatment of arthritis after oral administration, Especially gout caused by high uric acid.
- ACTH or its derivatives, surfactants, acrylic polymers, chitin or its derivatives, and metal ion chelating agents are formed into new compositions, and after oral administration, with For the treatment of arthritis, especially gout caused by high uric acid.
- the preferred composition for oral treatment of gout of the present invention is: ACTH or its derivatives, and surfactants, chitin or its derivatives, and metal ion chelating agents to form a new composition; the reason is: three components are selected and ACTH After the combination of its derivatives, it has a good therapeutic effect on arthritis (including gout caused by high uric acid), and on the basis of reducing the components in the composition, it has better safety, and at the same time, it reduces the cost, reduces the burden on patients, etc. advantage.
- the following tests of the present invention are conclusive tests of researchers and researchers based on the technical solutions to be protected by the present invention on the basis of many creative tests.
- the quantitative experiments in the following test examples are all set up three repeated experiments, and the data are the average or the mean ⁇ standard deviation of the three repeated experiments.
- Test 1 Effect test on joint swelling (gout) caused by hyperuric acid in mouse model
- adrenocorticotropic hormone 0.5mg/ml
- sodium lauryl sulfate 4mg/ml
- chitosan 1.3mg/ml
- sodium citrate 13mg/ml.
- the small intestine administration volume was 4 ml/kg.
- Five-component low-dose group adrenocorticotropic hormone 0.05mg/ml, sodium lauryl sulfate 4mg/ml, carbomer 1.3mg/ml, chitosan 1.3mg/ml, sodium citrate 13mg/ml ml.
- the small intestine administration volume was 4 ml/kg.
- Single active ingredient group adrenocorticotropic hormone 0.5mg/ml.
- the small intestine administration volume was 4 ml/kg.
- Positive control group normal saline.
- the small intestine administration volume was 4 ml/kg.
- Test method After 6-8 weeks of C57 male mice were anesthetized by chloral hydrate and xylazine, 50 ⁇ l of 20 mg/ml sodium urate was injected into the right hind paw, and 50 ⁇ l of normal saline was injected into the left hind paw. Half an hour later, according to the grouping situation, a small mouth was opened in the abdominal cavity, and 4 ml/kg of the test drug was administered through the small intestine, with 6 mice in each group. Taking the sodium urate administration as the 0 point, the diameters of the left and right hind paws were measured at 0, 6, 12 and 24 h, and each animal was measured three times at each time point to reduce the operation error. The effectiveness of the drug was assessed by comparing the ratio of the diameter of the right hind paw to the diameter of the left hind paw.
- a p valu ⁇ 0..05 vs positive control group (no drug); b: p value ⁇ 0.01 vs positive control group (no drug)
- the four-component group (the combination of ACTH and sodium lauryl sulfate, chitosan, and sodium citrate) has a 24-hour effect on joint swelling caused by high uric acid; similarly, the five-component high-dose group also has an effect that lasts 24 hours.
- Test 2 The effect of hyperuric acid-induced joint swelling (gout) on the Beagle dog model
- Five-component drug group Enteric-coated capsule No. 3, containing adrenocorticotropic hormone 4mg, sodium lauryl sulfate 40mg, carbomer 13mg, chitosan 13mg, and sodium citrate 130mg. oral.
- Single active ingredient group Enteric-coated capsule No. 3, containing 4 mg of adrenocorticotropic hormone. oral.
- Positive control group No. 3 hollow enteric-coated capsules. oral.
- Test method Male beagle dogs of 6-8 weeks were orally administered different test drugs according to the grouping. After 1 h, the animals were immobilized, and 1 ml of 20 mg/ml sodium urate was injected into the right hind paw, and 1 ml of normal saline was injected into the left hind paw. 3 animals per group. Taking the sodium urate administration as the 0 point, the diameters of the left and right hind paws were measured at 0, 6, 12 and 24 h, and each animal was measured three times at each time point to reduce the operation error. The effectiveness of the drug was assessed by comparing the ratio of the diameter of the right hind paw to the diameter of the left hind paw.
- a p valu>0.05 vs positive control group (no drug); b: p value ⁇ 0.01 vs positive control group (no drug)
- Test results The test shows (as shown in Table 2) that the preparation of adrenocorticotropin into an oral preparation has a very good relieving effect on joint swelling (gout) caused by high uric acid in beagle dogs.
- Adrenocorticotropic hormone 4g sodium lauryl sulfate 40g, carbomer 13g, chitosan 13g, sodium citrate 130g.
- Preparation method take sodium lauryl sulfate, carbomer, chitosan, and sodium citrate respectively, crush and sieve, mix them with adrenocorticotropic hormone, and put them into enteric-coated capsules to get it.
- Adrenocorticotropic hormone 4g sodium lauryl sulfate 40g, Bohm 934P 13g, carboxymethyl chitosan 13g, sodium malate 130g.
- Preparation method take sodium lauryl sulfate, pomer 934P, carboxymethyl chitosan, and sodium malate respectively, crush and sieve, mix with adrenocorticotropic hormone evenly, and put them into enteric-coated capsules.
- Adrenocorticotropic hormone 4g sodium lauryl sulfate 40g, Bohm 934 13g, acylated chitosan 13g, sodium malate 130g.
- Preparation method take sodium lauryl sulfate, pomer 934, acylated chitosan and sodium malate respectively, crush and sieve, mix with adrenocorticotropic hormone, and put them into enteric-coated capsules to get it.
- Adrenocorticotropic hormone 5g sodium lauryl sulfate 400g, carbomer 130g, chitosan 130g, sodium citrate 1300g.
- Preparation method take sodium lauryl sulfate, carbomer, chitosan, and sodium citrate respectively, crush and sieve, mix them with adrenocorticotropic hormone, and put them into enteric-coated capsules to get it.
- Adrenocorticotropic hormone 4g sodium lauryl sulfate 40g, chitosan 13g, sodium citrate 130g.
- Preparation method take sodium lauryl sulfate, chitosan and sodium citrate respectively, crush and sieve, mix them with adrenocorticotropic hormone evenly, and put them into enteric-coated capsules.
- Adrenocorticotropic hormone 4g sodium lauryl sulfate 40g, carboxymethyl chitosan 13g, sodium malate 130g.
- Preparation method take sodium lauryl sulfate, carboxymethyl chitosan and sodium malate respectively, crush and sieve, mix with adrenocorticotropic hormone, and put them into enteric-coated capsules to get it.
- Adrenocorticotropic hormone 4g sodium lauryl sulfate 40g, acylated chitosan 13g, sodium malate 130g.
- Preparation method take sodium lauryl sulfate, acylated chitosan and sodium malate respectively, crush and sieve, mix them with adrenocorticotropic hormone evenly, and put them into enteric-coated capsules.
- Adrenocorticotropic hormone 0.5g, sodium lauryl sulfate 40g, chitosan 13g, sodium citrate 130g.
- Preparation method take sodium lauryl sulfate, chitosan and sodium citrate respectively, crush and sieve, mix them with adrenocorticotropic hormone evenly, and put them into enteric-coated capsules.
- Adrenocorticotropic hormone 1g sodium lauryl sulfate 40g, chitosan 13g, sodium citrate 130g.
- Preparation method take sodium lauryl sulfate, chitosan and sodium citrate respectively, crush and sieve, mix them with adrenocorticotropic hormone evenly, and put them into enteric-coated capsules.
- Adrenocorticotropic hormone 3g sodium lauryl sulfate 40g, chitosan 13g, sodium citrate 130g.
- Preparation method take sodium lauryl sulfate, chitosan and sodium citrate respectively, crush and sieve, mix them with adrenocorticotropic hormone evenly, and put them into enteric-coated capsules.
- the examples include, but are not limited to, the above-mentioned preparation examples.
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Abstract
本发明提供一种含有促肾上腺皮质激素或其衍生物的口服药物在制备治疗关节炎药物中的应用，特别是将所述口服药物用于治疗高尿酸引起的痛风。
Description
本发明属于生物医药技术领域，具体涉及一种含有促肾上腺皮质激素或其衍生物的药物及其用途。
促肾上腺皮质激素(Adrenocorticotropic Hormone，ACTH)是脊椎动物脑垂体分泌的一种多肽类激素，它能促进肾上腺皮质的组织增生以及皮质激素的生成和分泌。促肾上腺皮质激素的生成和分泌受下丘脑促肾上腺皮质激素释放因子的直接调控。分泌过盛的皮质激素反过来也能影响垂体和下丘脑，减弱它们的活动。促肾上腺皮质激素具有刺激肾上腺皮质发育和机能的作用，主要作用于肾上腺皮质束状带，刺激糖皮质类固醇的分泌。促肾上腺皮质激素还具有通过肾上腺皮质来调节抗体生成作用。
促肾上腺皮质激素属于多肽类药物，易被胃肠道的消化酶等酶解，一直无法实现口服给药；临床上应用的含有促肾上腺皮质激素的药物制剂为注射制剂：注射用促肾上腺皮质激素(注射用促皮质素)，适应症为用于活动性风湿病、类风湿性关节炎、红斑性狼疮等胶原性疾患；亦用于严重的支气管哮喘、严重皮炎等过敏性疾病及急性白血病、何杰金氏病等。
检索现有技术，未检索到口服给药的促肾上腺皮质激素的制剂以及该口服制剂的新用途。
发明内容
基于上述原因，申请人经过多次创造性研究，得到一种含有促肾上腺皮质激素或其衍生物的口服药物及其新用途。研究表明，含有促肾上腺皮质激素或其衍生物的口服药物对于关节炎，包括高尿酸引起的痛风，具有很好的治疗作用。
本发明是通过下述技术方案实现的。
含有促肾上腺皮质激素或其衍生物的口服药物在制备治疗关节炎药物中的应用。
特别是对于高尿酸引起的急性痛风具有很好的治疗作用。
其中所述的口服药物制剂中的辅料为：表面活性剂、丙烯酸类聚合物、甲壳素或其衍生物、金属离子螯合剂。
其中所述的口服药物制剂中的辅料为：表面活性剂、甲壳素或其衍生物、金属离子螯合剂。
其中所述的表面活性剂包括阴离子表面活性剂或非离子表面活性剂中一种或几种。
其中所述的丙烯酸类聚合物包括卡波姆、卡波姆910、卡波姆934、卡波姆934P中一种或几种。
其中所述的甲壳素或其衍生物包括甲壳素、壳聚糖、羧甲基壳聚糖、酰化壳聚糖、烷基化壳聚糖、羟基化壳聚糖、壳聚糖季铵盐、壳聚寡糖、壳聚糖硫酸酯中的一种或几种。
其中所述的金属离子螯合剂包括枸橼酸或其盐、酒石酸或其盐、苹果酸或其盐、马来酸或其盐、葡萄糖酸或其盐、乙二胺四乙酸或其盐、氨基三乙酸或其盐、二亚乙基三胺五乙酸或其盐中的一种或几种。
其中表面活性剂、丙烯酸类聚合物、甲壳素或其衍生物与金属离子螯合剂的重量比为19-21：6-7：6-7：60-70。
其中表面活性剂、甲壳素或其衍生物与金属离子螯合剂的重量比为19-21：6-7：60-70。
其中ACTH(或其衍生物)、表面活性剂、丙烯酸类聚合物、甲壳素或其衍生物与金属离子螯合剂的重量比为1.5-2.5：19-21：6-7：6-7：60-70。
其中ACTH(或其衍生物)、表面活性剂、甲壳素或其衍生物与金属离子螯合剂的重量比为1.5-2.5：19-21：6-7：60-70。
其中ACTH(或其衍生物)、表面活性剂、丙烯酸类聚合物、甲壳素或其衍生物与金属离子螯合剂的重量比为0.20-0.30：19-21：6-7：6-7：60-70。
其中ACTH(或其衍生物)、表面活性剂、甲壳素或其衍生物与金属离子螯合剂的重量比为0.20-0.30：19-21：6-7：60-70。
其中ACTH(或其衍生物)、表面活性剂、丙烯酸类聚合物、甲壳素或其衍生物与金属离子螯合剂的重量比为0.25-2.0：19-21：6-7：6-7：60-70。
其中ACTH(或其衍生物)、表面活性剂、甲壳素或其衍生物与金属离子螯合剂的重量比为0.25-2.0：19-21：6-7：60-70。
所述的比例关系中，优选的比例关系为：ACTH(或其衍生物)、表面活性剂、甲壳素或其衍生物与金属离子螯合剂的重量比为0.25-2.0：19-21：6-7：60-70。
其中所述的促肾上腺皮质激素在溶液制剂配方中浓度为0.05mg/ml及更高浓度，在胶囊制剂中含量为0.4mg及更高含量。
所述的溶液制剂配方浓度是指大于等于0.05mg/ml，至水溶液中饱和浓度；
所述的胶囊制剂是指每一粒胶囊中装量大于等于0.4mg，至一粒胶囊最大装量为止。
其中所述的促肾上腺皮质激素或其衍生物包括ACTH(1-39)、ACTH(1-24)和ACTH(1-17)。
本发明所述的促肾上腺皮质激素(ACTH)是脊椎动物脑垂体分泌的一种多肽类激素，它能促进肾上腺皮质的组织增生以及皮质激素的生成和分泌。ACTH含39个氨基酸，其中1～24位氨基酸是构成生物活性的必备氨基酸，25～39位为保护性氨基酸。
现有临床上应用的以“促肾上腺皮质激素(ACTH)”为活性成分产品为注射用促皮质素；而本发明是通过口服给药的方式，获得促肾上腺皮质激素(ACTH)或其衍生物为活性成分口服药物组合物，用于治疗关节炎，包括痛风。
本发明所述的促肾上腺皮质激素衍生物包括但不限于：ACTH(1-24)，ACTH(1-24)是促肾上腺皮质激素的N端24肽。ACTH(1-24)因为1～24位氨基酸是构成生物活性的必备氨基酸，因此，与ACTH具有同样的生理活性，制备口服药物，肯定具有同样具有治疗关节炎，包括高尿酸引起的痛风的作用。
关节炎泛指发生在人体关节及其周围组织，由炎症、感染、退化、创伤或其他因素引起的炎性疾病，可分为数十种。临床表现为关节的红、肿、热、痛、功能障碍及关节畸形，严重者导致关节残疾、影响患者生活质量。关节炎的病因复杂，主要与自身免疫反应、感染、代谢紊乱、创伤、退行性病变等因素有关。根据病因可将关节炎分为骨性、类风湿性、风湿性、痛风性等。我国的关节炎患者有1亿以上，且人数在不断增加，其中尤其以痛风性关节炎居多。
痛风是一种常见且复杂的关节炎类型，各个年龄段均可能罹患本病，男性发病率高于女性。痛风患者经常会在夜晚出现突然性的关节疼，发病急，关节部位出现严重的疼痛、水肿、红肿和炎症，疼痛感慢慢减轻直至消失，持续几 天或几周不等。当疼痛发作时(急性痛风)，患者会在半夜熟睡中疼醒，有患者描述疼痛感类似于大脚趾被火烧一样。最常发病的关节是大脚趾(医学术语：第一跖骨)，但发病的关节不限于此，还常见于手部的关节、膝盖、肘部等。发病的关节最终会红肿、发炎，水肿后组织变软，活动受限，最后影响日常生活。这些症状会反复出现。
本发明所述的阴离子表面活性剂、非离子表面活性剂等均可以通过商业途径购买。
本发明所述的丙烯酸类聚合物包括卡波姆、卡波姆910、卡波姆934、卡波姆934P均可以通过商业途径购买。
本发明所述的甲壳素或其衍生物包括甲壳素、壳聚糖、羧甲基壳聚糖、酰化壳聚糖、烷基化壳聚糖、羟基化壳聚糖、壳聚糖季铵盐、壳聚寡糖、壳聚糖硫酸酯均可以通过商业途径购买。
本发明所述的金属离子螯合剂包括枸橼酸或其盐、酒石酸或其盐、苹果酸或其盐、马来酸或其盐、葡萄糖酸或其盐、乙二胺四乙酸或其盐、氨基三乙酸或其盐、二亚乙基三胺五乙酸或其盐均可以通过商业途径购买。
本发明对于现有技术贡献在于：将ACTH或其衍生物，与表面活性剂、甲壳素或其衍生物、金属离子螯合剂形成新的组合物，通过口服给药后，用于治疗关节炎，特别是高尿酸引起的痛风。
本发明对于现有技术贡献在于：将ACTH或其衍生物，与表面活性剂、丙烯酸类聚合物、甲壳素或其衍生物、金属离子螯合剂形成新的组合物，通过口服给药后，用于治疗关节炎，特别是高尿酸引起的痛风。
本发明优选的口服治疗痛风的组合物为：ACTH或其衍生物，与表面活性剂、甲壳素或其衍生物、金属离子螯合剂形成新的组合物；其原因为：选用三种成分与ACTH或其衍生物组合之后，对于关节炎(包括高尿酸引起的痛风)具有很好的治疗作用基础上，组合物中成分减少，具有更好的安全性，同时降低成本，减少患者的负担等等优点。
以下以具体试验例来说明本发明的技术方案，但本发明的保护范围不限于此。
本说明书试验例所述的内容仅仅是对发明构思的实现形式的列举，本发明的保护范围不应当被视为仅限于试验案例所陈述的具体形式，本发明的保护范 围也及于本领域技术人员根据本发明构思所能够想到的等同技术手段。尽管以下本发明的实施方案进行了描述，但本发明并不局限于上述的具体实施方案和应用领域，下述的具体实施方案仅仅是示意性的、指导性的，而不是限制性的。
试验例
本发明下述试验，是在多次创造性试验的基础上，以本发明所要保护的技术方案为基础，总结的研发人员的结论性试验。以下试验例中的定量试验，均设置三次重复实验，数据为三次重复实验的平均值或平均值±标准差。
试验1：小鼠模型上对高尿酸导致的关节肿胀(痛风)的影响试验
分组如下：
1、药物四成分组：促肾上腺皮质激素0.5mg/ml、十二烷基硫酸钠4mg/ml、壳聚糖1.3mg/ml、枸橼酸钠13mg/ml。小肠给药体积4ml/kg。
2、药物五成分低剂量组：促肾上腺皮质激素0.05mg/ml、十二烷基硫酸钠4mg/ml、卡波姆1.3mg/ml、壳聚糖1.3mg/ml、枸橼酸钠13mg/ml。小肠给药体积4ml/kg。
3、药物五成分高剂量组：促肾上腺皮质激素0.5mg/ml、十二烷基硫酸钠4mg/ml、卡波姆1.3mg/ml、壳聚糖1.3mg/ml、枸橼酸钠13mg/ml。小肠给药体积4ml/kg。
4、药物单一活性成分组：促肾上腺皮质激素0.5mg/ml。小肠给药体积4ml/kg。
5、药物四成分辅料组：十二烷基硫酸钠4mg/ml、卡波姆1.3mg/ml、壳聚糖1.3mg/ml、枸橼酸钠13mg/ml。小肠给药体积4ml/kg。
6、阳性对照组(不给药)：生理盐水。小肠给药体积4ml/kg。
试验方法：6-8周的C57雄性小鼠，经水合氯醛和赛拉嗪联合麻醉后，右后足注射50μl 20mg/ml的尿酸钠，左后足注射50μl生理盐水。半小时后，根据分组情况，腹腔开小口，经小肠给入4ml/kg的试验药物，每组6只小鼠。以给入尿酸钠为0点，于0、6、12和24h测量左右后足的直径，每只动物在各时间点测量3次，以减小操作误差。通过比较右后足直径/左后足直径的比值，来评价药物的有效性。
表1对高尿酸导致的关节肿胀(痛风)的影响
a：p valu＜0
..05vs阳性对照组(不给药)；b：p value＜0.01vs阳性对照组(不给药)
试验结论：试验显示(如表1所示)，将促肾上腺素皮质激素制备成口服制剂之后，对于小鼠上高尿酸导致的关节肿胀(痛风)具有很好的缓解作用(急性痛风)。研究表明四成分组(ACTH与十二烷基硫酸钠、壳聚糖、枸橼酸钠的组合物)对于对高尿酸导致的关节肿胀具有持续24小时的作用；同理，五成分高剂量组也具有持续24小时的作用。
试验2：比格犬模型上对高尿酸导致的关节肿胀(痛风)的影响试验
分组如下：
1、药物五成分组：3号肠溶胶囊内，含促肾上腺皮质激素4mg、十二烷基硫酸钠40mg、卡波姆13mg、壳聚糖13mg、枸橼酸钠130mg。口服。
2、药物单一活性成分组：3号肠溶胶囊内，含促肾上腺皮质激素4mg。口服。
3、阳性对照组(不给药)：3号空心肠溶胶囊。口服。
试验方法：6-8周的雄性比格犬，根据分组情况，口服不同试验药物。1h后，固定动物，右后足注射1ml 20mg/ml的尿酸钠，左后足注射1ml生理盐水。每组3只动物。以给入尿酸钠为0点，于0、6、12和24h测量左右后足的直径，每只动物在各时间点测量3次，以减小操作误差。通过比较右后足直径/左后足直径的比值，来评价药物的有效性。
表2比格犬模型上对高尿酸导致的关节肿胀(痛风)的影响
a:p valu＞0.05vs阳性对照组(不给药)；b:p value＜0.01vs阳性对照组(不给药)
试验结果：试验显示(如表2所示)，将促肾上腺素皮质激素制备成口服制剂之后，对于比格犬上高尿酸导致的关节肿胀(痛风)具有很好的缓解作用。
制备实施例
实施例1
促肾上腺皮质激素4g、十二烷基硫酸钠40g、卡波姆13g、壳聚糖13g、枸橼酸钠130g。
制备方法：取十二烷基硫酸钠、卡波姆、壳聚糖、枸橼酸钠分别粉碎过筛，与促肾上腺皮质激素混合均匀，放入肠溶胶囊中，即得。
实施例2
促肾上腺皮质激素4g、十二烷基硫酸钠40g、波姆934P 13g、羧甲基壳聚糖13g、苹果酸钠130g。
制备方法：取十二烷基硫酸钠、波姆934P、羧甲基壳聚糖、苹果酸钠分别粉碎过筛，与促肾上腺皮质激素混合均匀，放入肠溶胶囊中，即得。
实施例3
促肾上腺皮质激素4g、十二烷基硫酸钠40g、波姆934 13g、酰化壳聚糖13g、苹果酸钠130g。
制备方法：取十二烷基硫酸钠、波姆934、酰化壳聚糖、苹果酸钠分别粉碎过筛，与促肾上腺皮质激素混合均匀，放入肠溶胶囊中，即得。
实施例4
促肾上腺皮质激素5g、十二烷基硫酸钠400g、卡波姆130g、壳聚糖130g、枸橼酸钠1300g。
制备方法：取十二烷基硫酸钠、卡波姆、壳聚糖、枸橼酸钠分别粉碎过筛，与促肾上腺皮质激素混合均匀，放入肠溶胶囊中，即得。
实施例5
促肾上腺皮质激素4g、十二烷基硫酸钠40g、壳聚糖13g、枸橼酸钠130g。
制备方法：取十二烷基硫酸钠、壳聚糖、枸橼酸钠分别粉碎过筛，与促肾上腺皮质激素混合均匀，放入肠溶胶囊中，即得。
实施例6
促肾上腺皮质激素4g、十二烷基硫酸钠40g、羧甲基壳聚糖13g、苹果酸钠130g。
制备方法：取十二烷基硫酸钠、羧甲基壳聚糖、苹果酸钠分别粉碎过筛，与促肾上腺皮质激素混合均匀，放入肠溶胶囊中，即得。
实施例7
促肾上腺皮质激素4g，十二烷基硫酸钠40g、酰化壳聚糖13g、苹果酸钠130g。
制备方法：取十二烷基硫酸钠、酰化壳聚糖、苹果酸钠分别粉碎过筛，与促肾上腺皮质激素混合均匀，放入肠溶胶囊中，即得。
实施例8
促肾上腺皮质激素0.5g、十二烷基硫酸钠40g、壳聚糖13g、枸橼酸钠130g。
制备方法：取十二烷基硫酸钠、壳聚糖、枸橼酸钠分别粉碎过筛，与促肾上腺皮质激素混合均匀，放入肠溶胶囊中，即得。
实施例9
促肾上腺皮质激素1g、十二烷基硫酸钠40g、壳聚糖13g、枸橼酸钠130g。
制备方法：取十二烷基硫酸钠、壳聚糖、枸橼酸钠分别粉碎过筛，与促肾上腺皮质激素混合均匀，放入肠溶胶囊中，即得。
实施例10
促肾上腺皮质激素3g、十二烷基硫酸钠40g、壳聚糖13g、枸橼酸钠130g。
制备方法：取十二烷基硫酸钠、壳聚糖、枸橼酸钠分别粉碎过筛，与促肾上腺皮质激素混合均匀，放入肠溶胶囊中，即得。
所述实施例包括但不限于上述制备实施例。
本领域的普通技术人员在本说明书的启示下和在不脱离本发明权利要求所保护的范围的情况下，还可以做出很多种的形式，这些均属于本发明保护之列。
Claims (12)
- 含有促肾上腺皮质激素或其衍生物的口服药物在制备治疗关节炎药物中的应用。
- 根据权利要求1所述的应用，其中所述的关节炎包括高尿酸引起的痛风。
- 根据权利要求1所述的应用，其中所述的口服药物制剂中的辅料为：表面活性剂、丙烯酸类聚合物、甲壳素或其衍生物、金属离子螯合剂。
- 根据权利要求1所述的应用，其中所述的口服药物制剂中的辅料为：表面活性剂、甲壳素或其衍生物、金属离子螯合剂。
- 根据权利要求3或4所述的应用，其中所述的表面活性剂包括阴离子表面活性剂或非离子表面活性剂中一种或几种。
- 根据权利要求3所述的应用，其中所述的丙烯酸类聚合物包括卡波姆、卡波姆910、卡波姆934、卡波姆934P中一种或几种。
- 根据权利要求3或4所述的应用，其中所述的甲壳素或其衍生物包括甲壳素、壳聚糖、羧甲基壳聚糖、酰化壳聚糖、烷基化壳聚糖、羟基化壳聚糖、壳聚糖季铵盐、壳聚寡糖、壳聚糖硫酸酯中的一种或几种。
- 根据权利要求3或4所述的应用，其中所述的金属离子螯合剂包括枸橼酸或其盐、酒石酸或其盐、苹果酸或其盐、马来酸或其盐、葡萄糖酸或其盐、乙二胺四乙酸或其盐、氨基三乙酸或其盐、二亚乙基三胺五乙酸或其盐中的一种或几种。
- 根据权利要求3所述的应用，其中表面活性剂、丙烯酸类聚合物、甲壳素或其衍生物与金属离子螯合剂的重量比为19-21：6-7：6-7：60-70。
- 根据权利要求4所述的应用，其中表面活性剂、甲壳素或其衍生物与金属离子螯合剂的重量比为19-21：6-7：60-70。
- 根据权利要求1所述的应用，其中所述的促肾上腺皮质激素口服药物制剂中溶液制剂配方中浓度为0.05mg/ml及更高浓度，在胶囊制剂中含量为0.4mg及更高含量。
- 根据权利要求1所述的应用，其中所述的促肾上腺皮质激素或其衍生物包括ACTH(1-39)、ACTH(1-24)和ACTH(1-17)。
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| GB1064263A (en) * | 1963-06-28 | 1967-04-05 | Sandoz Ltd | Improvements in or relating to a pentacosapeptide |
| US20180169191A1 (en) * | 2016-12-19 | 2018-06-21 | Eton Pharmaceuticals, Inc. | Adrenocorticotropic hormone-based pharmaceutical formulations and methods for fabricating and using thereof |
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| GB1064263A (en) * | 1963-06-28 | 1967-04-05 | Sandoz Ltd | Improvements in or relating to a pentacosapeptide |
| US20180169191A1 (en) * | 2016-12-19 | 2018-06-21 | Eton Pharmaceuticals, Inc. | Adrenocorticotropic hormone-based pharmaceutical formulations and methods for fabricating and using thereof |
| US20190134163A1 (en) * | 2016-12-19 | 2019-05-09 | Eton Pharmaceuticals, Inc. | Adrenocorticotropic hormone-based pharmaceutical formulations and methods for fabricating and using thereof |
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| KHANNA PUJA P.; GLADUE HEATHER S.; SINGH MANJIT K.; FITZGERALD JOHN D.; BAE SANGMEE; PRAKASH SHRADDHA; KALDAS MARIAN; GOGIA MANEES: "Treatment of acute gout: A systematic review", SEMINARS IN ARTHRITIS AND RHEUMATISM., ELSEVIER, AMSTERDAM, NL, vol. 44, no. 1, 13 February 2014 (2014-02-13), AMSTERDAM, NL , pages 31 - 38, XP029012861, ISSN: 0049-0172, DOI: 10.1016/j.semarthrit.2014.02.003 * |
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