EP2379054A1 - Formulation pour l'administration d'hypolipemiants par voie trans-muqueuse buccale - Google Patents
Formulation pour l'administration d'hypolipemiants par voie trans-muqueuse buccaleInfo
- Publication number
- EP2379054A1 EP2379054A1 EP09805727A EP09805727A EP2379054A1 EP 2379054 A1 EP2379054 A1 EP 2379054A1 EP 09805727 A EP09805727 A EP 09805727A EP 09805727 A EP09805727 A EP 09805727A EP 2379054 A1 EP2379054 A1 EP 2379054A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- active ingredient
- formulation according
- formulation
- lipid
- alcohol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 73
- 238000009472 formulation Methods 0.000 title claims abstract description 63
- 239000003814 drug Substances 0.000 title claims description 13
- 229940079593 drug Drugs 0.000 title description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 130
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims abstract description 31
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 26
- 238000004090 dissolution Methods 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 6
- 201000005577 familial hyperlipidemia Diseases 0.000 claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims description 60
- 238000002360 preparation method Methods 0.000 claims description 32
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 27
- 239000008213 purified water Substances 0.000 claims description 18
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 16
- 239000003963 antioxidant agent Substances 0.000 claims description 15
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- 239000000725 suspension Substances 0.000 claims description 12
- 230000001681 protective effect Effects 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 claims description 4
- 229960000815 ezetimibe Drugs 0.000 claims description 4
- 229940125753 fibrate Drugs 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical class [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 235000011182 sodium carbonates Nutrition 0.000 claims description 2
- 235000019165 vitamin E Nutrition 0.000 claims description 2
- 239000011709 vitamin E Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 12
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- 239000007800 oxidant agent Substances 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 67
- 239000000243 solution Substances 0.000 description 42
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 18
- 238000010521 absorption reaction Methods 0.000 description 15
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 13
- 229960005370 atorvastatin Drugs 0.000 description 13
- 230000000694 effects Effects 0.000 description 12
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 11
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 11
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 11
- 239000003085 diluting agent Substances 0.000 description 11
- 229960004844 lovastatin Drugs 0.000 description 11
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 11
- 229960002855 simvastatin Drugs 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 235000012000 cholesterol Nutrition 0.000 description 9
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 9
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 9
- 239000003524 antilipemic agent Substances 0.000 description 8
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- -1 or <9emfibrozil Chemical compound 0.000 description 7
- 230000000144 pharmacologic effect Effects 0.000 description 7
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- 239000004743 Polypropylene Substances 0.000 description 6
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- 210000004185 liver Anatomy 0.000 description 6
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- 238000003786 synthesis reaction Methods 0.000 description 6
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- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
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- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 4
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- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 3
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- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 206010021024 Hypolipidaemia Diseases 0.000 description 2
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
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- 238000006731 degradation reaction Methods 0.000 description 2
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- 239000012895 dilution Substances 0.000 description 2
- 229960003765 fluvastatin Drugs 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 229960000672 rosuvastatin Drugs 0.000 description 2
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000024883 vasodilation Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- KJTLQQUUPVSXIM-ZCFIWIBFSA-M (R)-mevalonate Chemical compound OCC[C@](O)(C)CC([O-])=O KJTLQQUUPVSXIM-ZCFIWIBFSA-M 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 229960003627 gemfibrozil Drugs 0.000 description 1
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- 230000000302 ischemic effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
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- 150000002632 lipids Chemical class 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
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- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- 229950009116 mevastatin Drugs 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
- 238000011169 microbiological contamination Methods 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
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- 210000003240 portal vein Anatomy 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
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- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
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- 230000006641 stabilisation Effects 0.000 description 1
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- DFVFTMTWCUHJBL-BQBZGAKWSA-N statine Chemical compound CC(C)C[C@H](N)[C@@H](O)CC(O)=O DFVFTMTWCUHJBL-BQBZGAKWSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Definitions
- the present invention relates to a formulation for the instantaneous systemic administration by the oral transmucosal route of at least one lipid-lowering active ingredient, in particular of an active ingredient belonging to the family of the Statins.
- the invention also relates to a process for the preparation of this formulation and to its pharmaceutical use, in particular for the treatment of hyperlipidemia and / or for the prevention and treatment of cardiovascular diseases.
- the global pharmaceutical market is dominated by products intended to treat or prevent cardiovascular diseases. Among these products, a significant part is represented by so-called hypolipidemic molecules, intended to treat hyperlipidemias including hypercholesterolemia.
- Lipid-lowering drugs are pharmaceutical active agents capable of decreasing the level of lipids in the blood and in particular of inhibiting the production of cholesterol.
- lipid-lowering drugs The primary function of a portion of lipid-lowering drugs is to reduce the endogenous synthesis of cholesterol in its hepatic production, by inhibiting the activity of HM ⁇ 9 CoA reductase, enzyme of the hepatic cell at the origin of the synthesis Cholesterol precursor, Mevalonate.
- HM ⁇ 9 CoA reductase enzyme of the hepatic cell at the origin of the synthesis Cholesterol precursor, Mevalonate.
- lipid-lowering active ingredients More particularly known are the molecules of the family of Statins, including Atorvastatin, Pravastatin, Simvastatin, Lovastatin, Fluvastatin or Rosuvastatin.
- St ⁇ tine molecules Like all hypolipidaemia, St ⁇ tine molecules reduce cholesterol synthesis by inhibiting the activity of HM ⁇ 9 CoA reductase, but they also have potential for reducing atheromatous plaque in the arterial endothelium, attenuating ischemic syndromes. In addition, long-term treatments with Statins are able to significantly prevent the primary onset of myocardial infarction and secondary relapse events after a first ischemic stroke. Fibrates are also known, such as, for example, fenofibrate, or ⁇ 9emfibrozil, as well as Ezetimibe, which belongs to another class.
- Lipid-lowering drugs in general, and Statins in particular are typically administered orally.
- the intravenous mode of administration by infusion has been the subject of experimental work, but although it is fast and effective, it is not adapted to a daily background treatment of hypercholesterolemia or to the prevention of cardiac accidents. Indeed, an infusion administration requires dedicated personnel and the use of specific equipment. It is expensive and its implementation is too burdensome for the patient who wants the simplest and most available ambulatory treatment possible.
- hypolipidaemia in particular the statins, have physicochemical and pharmacological characteristics which make their systemic bioavailability and their activity often problematic, some of which cause intolerance disorders, mainly digestive and muscular, depending on the doses administered orally.
- Hepatic which causes their metabolism and / or their degradation more or less intense, asec constitution of many metabolites, some of which inactive or toxic may be constitutive of side effects.
- the dose of truly bioactive active ingredient is therefore low: only a residual part of the quantity administered is distributed to the liver to inhibit the activity of HM ⁇ 9 CoA reductase and reduce the endogenous synthesis of cholesterol.
- the bioavailability of these active ingredients may still vary according to the individual, both in terms of absorption times and in terms of the ratio of active principle (s) absorbed.
- the known average residual bioavailabilities are:
- a first difficulty lies in the administration of a sufficient dose of lipid-lowering agent to the patient, taking into account the weight status of the subject, the dilution and the dispersion of this active principle in the body, so that the only significantly active part that acts on the HM ⁇ 9 CoA reductase is sufficiently available to be effective.
- a second problem is the lag time due to metabolism and diffusion in the body before the hypolipidemic molecule acts.
- Another problem lies in the appearance of side effects and intolerances mainly digestive and muscular, related to certain products of the metabolism of the administered molecules. Enteral administration of lipid-lowering drugs, the only mode currently used, is therefore not satisfactory, and it would be advisable to have a form of administration offering a better pharmacokinetic, pharmacological and therapeutic performance.
- the present invention proposes a lipid-lowering formulation which makes it possible to deliver to the body directly and without delay, the only effective dosage required without bioavailability hazards, with a dose / effect ratio as close as possible to the fraction that is ideally suited for the pharmacological activity sought.
- hydroalcoholic solution consisting of water and ethanol, containing at least 30 degrees of alcohol, wherein said active ingredient is present in a stable and complete dissolution state, and optionally a pH-correcting agent and / or a antioxidant agent.
- the invention also provides a method of preparation and the use of this formulation for the treatment of hypercholesterolemia and / or the prevention and / or treatment of a cardiovascular event.
- the formulation according to the invention makes it possible to obtain the best lipid-lowering and / or preventive cardiovascular effect that can be obtained with a lipid-lowering and / or cardiovascular protective active ingredient, and with the lowest possible dose. It enables the instantaneous and complete oral mucosal passage of a therapeutic preparation based on at least one hypolipart ⁇ nte molecule, including a Statin, preventing any salivary dilution and swallowing molecules and therefore any inappropriate passage through the digestive tract.
- statins are delivered almost instantaneously and directly to the liver via the arterial vascular system, where they play their role as an inhibitor of HM ⁇ 9 CoA reductase. They are distributed directly and initially to the whole of the macro and micro-arterial vascular tree which transports them, where they can thus and before any organic and tissue dispersion of said active principle, play their potential reductive role of atheromatosis directly. in contact with parietal lesions of the network.
- the subject of the invention is therefore a formulation for the oral transmucosal administration of at least one lipid-lowering and / or cardiovascular protective active ingredient, in particular an active principle of the family of the statins, comprising :
- said lipid-lowering and / or cardiovascular protective active ingredient in base form or in salt form,
- hydroalcoholic solution consisting of water and ethanol, containing at least 30 degrees of alcohol, in which said active ingredient is present in a stable and complete dissolution state
- the formulation according to the invention consists solely of the active ingredient (s), the hydroalcoholic solution consisting of water and ethanol, and optionally a pH-correcting agent and / or an antioxidant.
- lipid-lowering active ingredient and / or cardiovascular protector is meant:
- the lipid-lowering active principles that is to say any molecule capable of inhibiting the HM ⁇ 9 CoA reductase and of acting against an excess of cholesterol and / or triglycerides in the blood, - the cardiovascular protective active ingredients, that is to say, any molecule capable of reducing cardiovascular risks, in particular capable of reducing cardiac attacks, the thickness of atheromatous arterial and coronary plaque, etc., and
- the active principles considered to be both lipid-lowering and cardiovascular protective that is to say which, in addition to their capacity to significantly reduce hypercholesterolemia, are also capable of reducing the cardiovascular risks, such as Atorvastatin for example or Pravastatin.
- Atorvastatin for example or Pravastatin.
- the membership of a molecule in a pharmaco-therapeutic category is made with reference to that attributed to it in its Marketing Authorization.
- transmucosal route means any passive crossing of a lipophilic or amphiphilic molecule through the lingual, sublingual, gingival, palatal, jugal, or any other mucous membranes constituting the oral cavity.
- stable and complete dissolution state is meant a state of dissolution restoring the active ingredient in the molecular state and weakly ionized in its dissolution medium, dissolution state preventing any eventuality of an untimely recrystallization.
- This stable and complete dissolution state can be controlled from the implementation of the formulation according to the invention by evaluation of the visual appearance of the solution obtained (measurement of the degree of clarity) and then at the level of f iltration residues (appearance or not of crystals), and finally in the medium and long term during stability monitoring tests at varying temperatures and degrees of hygrometry.
- hydroalcoholic solution titrating X degrees of alcohol is meant a solution having an alcohol degree of X, corresponding to the ratio between the volume of pure alcohol (100 °) contained in the hydroalcoholic solution and the total volume of this alcoholic solution. solution.
- the degree of alcohol in the hydroalcoholic solution varies depending on the degree of alcohol used to form the solution and the water / alcohol ratio of the solution. For example for an initial alcohol at 100 degrees and a 50/50 water / alcohol ratio, the hydroalcoholic solution titrates 50 degrees alcohol.
- pH corrector agent is meant any acid agent or any basic agent that does not alter the physicochemical characteristics of the active ingredient (s).
- the pH-correcting agent is chosen from sodium carbonates and bicarbonates, monosodium or disodium phosphates, triethanolamine, sodium hydroxide (NaOH) and potassium hydroxide (KOH), but also hydrochloric, sulphuric acid agents.
- Phosphoric, Citric, Malic, Lactic, Succinic and / or Butyric By “antioxidant” is meant an agent that prevents the loss of one or more electrons by a molecule, sometimes accompanied by a loss of protons (H +).
- the antioxidant agent is preferably chosen from vitamins E, C.
- the lipid-lowering and / or cardiovascular protective active ingredient is present in base form or in salt form.
- the formulation according to the invention comprises a pH correcting agent, acid.
- the active ingredient is present in salt form only, for example in the form of succinate, hydrochloride or sulphate, preferably the formulation according to the invention comprises a basic pH corrector agent.
- the active ingredient is present in base form.
- the hypolipidemic molecules in base form in particular the base form Statins, of lower molecular weight than those in the salt form, dissolve and stabilize more easily in the formulation according to the invention and have a better passability for trans- oral mucosa with superior velocity.
- the active ingredient may be chosen in particular from the molecules of the family of Statins, such as Atorvastatin, Pravastatin, Simvastatin, Lovastatin, Fluvastatin or Rosuvastatin.
- the active ingredient is Atorvastatin base, Simvastatin base, Lovastatin base, Mevastatin or Pivastatin base. It may also be fibrates, for example Fenofibrate or Gemf ibrozil, or even Ezetimibe.
- the formulation according to the invention is in the form of a hydroalcoholic solution comprising between 30 and 90% of ethanol by volume and a water content of between 10 and 70%. Even more preferably, the formulation according to the invention is in the form of a hydroalcoholic solution comprising between 40 and 85% of ethanol by volume and a water content of between 15 and 60%.
- the hydroalcoholic solution has a variable degree of alcohol of at least 30 °, preferably between 30 ° and 70 °, still more preferably between 40 ° and 70 °, and ideally between 45 ° and 65 °.
- the hydroalcoholic solution is the only solvent used in the formulation according to the invention.
- the alcohol of the hydroalcoholic solution not only acts as a diluent for water-insoluble molecules, but also as a promoter accelerated trans-mucosal absorption, the rate of which increases with increasing levels of alcohol.
- the degree of alcohol in the formulation should not exceed 70 °, however, since a higher degree would be incompatible with a pharmaceutical product for oral application due to mucosal burn.
- the coefficient of dissolution of a Statin in ethanol makes it possible to obtain a complete dissolution of said active ingredient at a level of 2 mg of Statine for 0.75 ml of ethanol at approximately 50 °. This coefficient can be modulated according to the desired alcohol dosage, the degree of alcohol and the water / ethanol ratio used.
- the pH of the formulation according to the invention is between 5.0 and 9.0, more preferably between 5.5 and 7.5. These pHs are favorable for optimal absorption of the solution.
- the formulation according to the invention allows the active ingredient passively pass through the oral mucosa within a few seconds after administration.
- This very fast absorption time makes it possible to prevent any stagnation of the solution and of the active principle in the oral atmosphere, as well as their untimely mixing with saliva which can alter them, which would introduce a break in the continuity and stability of dissolution of the active ingredient (s).
- This short delay also makes it possible to prevent any reflex swallowing of the solution and of the active principle that it contains.
- the trans-mucosal passage of the active principle presented in the state of dissolution according to the invention on the side of the external epithelial membrane, consisting of phospholipidic structures which passively absorb, by elective affinity, the lipophilic molecules presented in a stable and complete dissolution state, is based on an osmotic call to the other side of said membrane, in which together participate the concentration of dissolved active ingredient and the degree of the alcoholic solution considered.
- the osmotic appeal is all the more perennial and powerful as the degree of alcohol that serves as an absorption promoter is high.
- a suitable degree of alcohol is between 40 ° and 70 °, preferably between 45 ° and 65 °. This makes it possible simultaneously to obtain and adjust the best coefficient of dissolution and stabilization of the molecules and the promotion of its trans-mucosal passage in a period of 4 to 6 seconds.
- a particularly suitable embodiment corresponds to 1.0 ml of hydroalcoholic solution with a degree of alcohol of about 50 ° or 65 ° for 1 mg or 4 mg of statins.
- the mucous membranes of the mouth possess a very dense, quasi-spongy network of micro-vessels, so that the molecules, both of alcohol solvent and of dissolved active principle, which cross the lipophilic pores of the epithelial membrane, are instantly captured by the sublingual veins and those draining the mucous membranes of the mouth and led to the jugular veins, then to the Superior Cellar vein to the right heart.
- the hypolipidemic molecules are then sent from the left heart into the systemic arterial vascular system which distributes them directly and without delay to the liver cells. The hypolipidemic molecules thus reach the hepatocyte cells by the same nutrient and oxygenating bloodstream essential to their metabolic life.
- the use of the dosage form according to the invention makes it possible passively to administer a dose of lipid-lowering agents, in particular a dose of statins, immediately absorbed as soon as deposited in contact with the mucosa, for immediate distribution by the vascular route. , without any delay for its pharmacological action and without undergoing the prior destructive effects of digestive and hepatic passage.
- the galenic form according to the invention thus allows an immediacy of complete tissue absorption of the lipid-lowering molecules contained in the formulation, then their distribution in the central circulation of the body, generating a rapid pharmacological response of "flash" type.
- a very significant dose can be administered almost instantaneously and passively. of active principle which leads directly arterial to the liver, the very heart of liver cells, where it plays its role as an inhibitor of HM ⁇ 9 CoA reductase.
- This dose of 2 mg is at least equivalent to that obtained and recognized as bioavailable and therefore effective enterally, or between 5 and 20% at best the dose usually administered, depending on the statins considered.
- the bioavailability of the dose administered by the oral transmucosal route is equivalent to or very similar to that obtained orally after loss of digestive absorption and metabolization of high dosages.
- the hydroalcoholic solution according to the invention grading at least 30 degrees of alcohol, also has the advantage of solubilizing the lipid-lowering molecules, in particular of statins, although they are lipophilic or amphiphilic, which allows their spontaneous absorption through lipophilic and selective mouth mucosa, and protect the pharmaceutical formulation against microbiological contamination without having to introduce antimicrobial preservative (s).
- statins although they are lipophilic or amphiphilic, which allows their spontaneous absorption through lipophilic and selective mouth mucosa, and protect the pharmaceutical formulation against microbiological contamination without having to introduce antimicrobial preservative (s).
- the lipid-lowering active ingredient acts as a solvent for the lipid-lowering active ingredient, in particular in the family of the statins, a lipophilic or amphiphilic molecule of low molecular weight, by keeping it stable and in a state of perfect dissolution, it activates the trans-mucosal passage of this dissolved active principle thus presented in the molecular state at the level of the lipophilic oral mucous membrane,
- the degree of alcohol doubly increases the rate of mucosal absorption, by osmotic effect and by causing reflex microvascular vasodilatation, which accelerates the local micro-circulatory flow, and
- the present invention offers a great simplicity of realization and a very good galenic stability: the extremely simplified water / alcohol solution guarantees the solubilization of the active principle and makes it possible to ignore most of the excipients usually used for conventional pharmaceutical preparations, including including conservatives. It thus makes it possible both to reduce manufacturing costs and to reduce the risks of intolerance and the possible interactions between active ingredient and excipients.
- the pharmacodynamic action time of the galenic form according to the invention is very short, compared to the slowness of absorption.
- existing lipid-lowering drugs that vary between one and two hours after taking oral digestive.
- the quasi-instantaneous vascular delivery provided by the invention is quite suitable for the treatment of hyperlipemias, hypercholesterolemia or the prevention and / or treatment of cardiovascular diseases. It can allow a patient to self-administer a product corresponding to the only fair share actually bioavailable by mouth, equivalent to the effectiveness of an intravenous flash injection into the circulation, without the disadvantages that make this type of administration unacceptable and inconceivable for uninterrupted background treatment for tens of millions of patients.
- the gain in terms of dose / effect ratio is at least 70 to 95%.
- the formulation according to the invention uses at least 70 to 95% less dose for a therapeutic effect obtained without delay.
- the administered lipolipidemic molecules do not encounter any significant obstacle for their instantaneous arterial distribution to hepatic cells, that they gain in a few seconds, the administered basic dose is therefore considerably reduced, comparable to the bioavailable dose required to exercise the liver. pharmacological activity required of lipid-lowering agents. This dose is of course dependent on the desired effect.
- the oral mucosa having a total surface of extremely broad absorption, multiplied by its character of pleated villous tissue, the administration of the formulation according to the invention is devoid of any risk of inadvertent swallowing or false road. Indeed, it allows an extremely rapid peri-mucous passage that limits any salivary mixture or swallowing of the active ingredient administered, with the advantage of not destabilizing the mucous membranes, as / ec elements or various excipients, as is the case certain existing formulations.
- the effects of alcohol are insignificant.
- an aqueous alcohol solution of 0.75 ml ethanol at 50 ° can only produce a circulating blood alcohol content of less than 0.005 g per liter of blood, according to Widmark's official reference formula, ie one hundredth of the legal tolerance in France established at 0.5g per liter of blood.
- the initial passage of the alcoholic solution by the pulmonary route must allow the near-complete elimination of ethanol in the form of vapor extracted by breathing and exhaled, before Ethanol can be distributed in the body.
- the alcoholic vector is eliminated almost completely through the respiratory parenchyma.
- the invention relates to a process for preparing the formulation.
- a method of manufacturing the galenic form according to the invention, particularly adapted comprises the following steps:
- the ethanol used may be absolute ethanol or not. Preferably it will be 95 ° ethanol.
- the method comprises the following steps:
- lipid-lowering agent preferably of the family of the statins, base or salt, - optionally introduce an antioxidant
- the method according to the invention comprises the following steps:
- lipid-lowering active ingredient for example from the family of the statins, in base form
- the method according to the invention comprises the following steps:
- lipid-lowering active ingredient for example from the family of the statins in salt form
- the present invention can be used for the instantaneous reduced-dose and useful transmucosal systemic administration of lipid-lowering and / or cardiovascular protective agents, in particular of Statins, such as Atorvastatin, Pravastatin, Lovastatin or Simvastatin.
- the formulation according to the present invention can be used for the production of a medicament for the treatment of hyperlipemia and / or the prevention and / or treatment of cardiac disorders.
- Such a medicine has a therapeutic activity in a very short time and at doses administered very small compared to traditional doses.
- the invention therefore relates to the use of the formulation for the production of a medicament for the treatment of hyperlipemia by the oral transmucosal route, as well as the use of the formulation for producing a trans-administered medicament oral mucosa for the prevention and / or treatment of cardiovascular conditions.
- the formulation according to the invention corresponding to a very small fluid volume, is very easy to administer. A patient can easily place it in his mouth in direct contact with a specific mucosal area of reduced surface, buccal, para-gingival or sublingual.
- the formulation according to the invention requires a specific industrial packaging, to allow its safe, simple and ergonomic use and prevent any degradation of the active ingredient in contact with the air and the loss of alcohol levels .
- a particular embodiment consists in using a packaging, preferably of small size, plastic or flexible metalloplastic or glass, opaque filled under an inert atmosphere such as nitrogen, for the protection of the stability of the composition and the impermeability to oxygen and radiation.
- a packaging preferably of small size, plastic or flexible metalloplastic or glass, opaque filled under an inert atmosphere such as nitrogen, for the protection of the stability of the composition and the impermeability to oxygen and radiation.
- these packages comprise a cannula allowing the precise deposition of the solution according to the invention in contact with a suitable mucosal area.
- the galenic form according to the invention is packaged in single-dose packages of 0.5 to 2 ml, capable of providing an adequate dose of active ingredient.
- this packaging is easy to transport and allows easy use of the dosage form at any time of the day.
- Several examples of formulation of Statins according to the invention with a volume of 0.75 ml or 1.00 ml, at about 50 ° of alcohol, are particularly suitable for producing an inhibitory efficiency of cholesterol synthesis or level. liver cells within a few minutes only:
- Formulation 1 Atorvastatin lmq, 1, OmL at 50 ° alcohol
- Atorvastatin base active ingredient: 1.0 mg
- This second example of formulation can be obtained by the implementation of the method described below for a batch of 1000 doses, ie 1.2 L.
- Formulation 3 Lovastatin 2mq, 1.0ml at 50 ° alcohol
- This formulation example can be obtained by carrying out the method described below for a batch of 1000 doses, ie 1 L.
- Formulation 4 Lovastatin 4mq, 1.0ml at 65 ° alcohol - Lovastatin base (active ingredient): 4.0mg
- Formulation 5 Simvastatin 2mq, 1.0ml to 65 ° alcohol
- Vitamin E TPGS (antioxidant): 0.2mg
- This other example of formulation can be obtained by the implementation of the method described by following for a batch of 1000 doses, ie 1, OL. In a stainless steel tank add 0.650 L of 95% V / V ethanol and 0.35 L of purified water. Introduce in the hydroalcoholic solution 2g of Simvastatin base and 0.2g of Vitamin E TPGS.
- This last example of formulation can be obtained by the implementation of the method described in the following for a batch of 1000 doses, ie 1.2L.
- a batch of 1000 doses ie 1.2L.
- Introduce in the hydroalcoholic solution 4g of Simvastatin base and 0.2g of Vitamin E TPGS.
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Abstract
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR0858947A FR2940116B1 (fr) | 2008-12-22 | 2008-12-22 | Formulation pour l'administration d'hypolipemiant par voie trans-muqueuse buccale |
PCT/FR2009/052591 WO2010072950A1 (fr) | 2008-12-22 | 2009-12-17 | Formulation pour l'administration d'hypolipemiants par voie trans-muqueuse buccale |
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EP2379054A1 true EP2379054A1 (fr) | 2011-10-26 |
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EP09805727A Withdrawn EP2379054A1 (fr) | 2008-12-22 | 2009-12-17 | Formulation pour l'administration d'hypolipemiants par voie trans-muqueuse buccale |
Country Status (9)
Country | Link |
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US (1) | US8889663B2 (fr) |
EP (1) | EP2379054A1 (fr) |
JP (1) | JP5529165B2 (fr) |
CN (1) | CN102264346A (fr) |
BR (1) | BRPI0923675A8 (fr) |
FR (1) | FR2940116B1 (fr) |
MX (1) | MX2011006797A (fr) |
RU (1) | RU2528897C2 (fr) |
WO (1) | WO2010072950A1 (fr) |
Families Citing this family (6)
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FR2906140B1 (fr) * | 2006-09-22 | 2008-12-05 | Philippe Perovitch | Forme galenique pour l'administration par voie trans-muqueuse de principes actifs |
GB2497728A (en) * | 2011-12-14 | 2013-06-26 | Londonpharma Ltd | Statin formulations for transmucosal delivery |
FR3000896B1 (fr) * | 2013-01-14 | 2016-08-26 | Philippe Perovitch | Forme galenique pour l'administration de principe(s) actif(s) permettant l'induction acceleree du sommeil et/ou le traitement des troubles du sommeil |
FR3031668A1 (fr) | 2015-01-20 | 2016-07-22 | Philippe Perovitch | Dispositif d'administration d'un principe actif par voie per-muqueuse buccale. |
FR3053244A1 (fr) | 2016-07-01 | 2018-01-05 | Philippe Perovitch | Dispositif d'administration d'au moins un principe actif par voie per-muqueuse buccale. |
WO2023235541A1 (fr) * | 2022-06-03 | 2023-12-07 | Polaryx Therapeutics, Inc. | Formulation de gemfibrozil |
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WO2008035020A2 (fr) * | 2006-09-22 | 2008-03-27 | Philippe Perovitch | Forme galenique pour l'administration par voie trans-muqueuse de principes actifs |
WO2011004117A1 (fr) * | 2009-07-10 | 2011-01-13 | Philippe Perovitch | Procédé et compositions pharmaceutiques pour le traitement de l'hyper glycémie post-prandiale du diabète de type ii par voie trans-muqueuse buccale |
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US5582838A (en) * | 1994-12-22 | 1996-12-10 | Merck & Co., Inc. | Controlled release drug suspension delivery device |
US20030095925A1 (en) * | 1997-10-01 | 2003-05-22 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating metabolic disorders |
US20030077229A1 (en) * | 1997-10-01 | 2003-04-24 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing cardiovascular or renal drugs |
DE19929197A1 (de) * | 1999-06-25 | 2000-12-28 | Novosis Pharma Ag | Transdermalsysteme zur Abgabe von 5-HT3-Rezeptor-Antagonisten und ihre Verwendung zur antiemitischen Behandlung |
US20070225379A1 (en) * | 2001-08-03 | 2007-09-27 | Carrara Dario Norberto R | Transdermal delivery of systemically active central nervous system drugs |
US7033612B2 (en) * | 2003-01-03 | 2006-04-25 | Kang David S | Composition and method for treating age-related disorders |
JP2004231603A (ja) * | 2003-01-31 | 2004-08-19 | Hideji Watanabe | コエンザイムq10を主成分とする口腔内塗布剤及びその製造方法 |
US20050281868A1 (en) * | 2004-06-21 | 2005-12-22 | Fairfield Clinical Trials, Llc | Transdermal delivery system for statin combination therapy |
BRPI0501708A (pt) * | 2005-05-10 | 2007-05-02 | Jean Marc Millet | dispositivo de liberação lenta por processo transdérmico de um medicamento contra o excesso de colesterol e método de produção de um dispositivo transdérmico |
CN1778296B (zh) * | 2005-07-19 | 2010-04-14 | 淮北辉克药业有限公司 | 他汀类药物的长效制剂 |
US20080249120A1 (en) * | 2006-11-22 | 2008-10-09 | Glenmark Pharmaceuticals Limited | Pharmaceutical compositions |
FR2910317B1 (fr) * | 2006-12-21 | 2009-02-13 | Philippe Perovitch | Forme galenique pour l'administration par voie transmuqueuse de paracetamol |
WO2008079295A1 (fr) * | 2006-12-22 | 2008-07-03 | Novadel Pharma Inc. | Préparations antinauséeuses à pulvériser, à usage oral, stables, et méthodes associées |
WO2008132710A2 (fr) * | 2007-05-01 | 2008-11-06 | Sigmoid Pharma Limited | Compositions pharmaceutiques à base de nimodipine |
-
2008
- 2008-12-22 FR FR0858947A patent/FR2940116B1/fr not_active Expired - Fee Related
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2009
- 2009-12-17 US US13/141,597 patent/US8889663B2/en not_active Expired - Fee Related
- 2009-12-17 JP JP2011542870A patent/JP5529165B2/ja not_active Expired - Fee Related
- 2009-12-17 RU RU2011130508/15A patent/RU2528897C2/ru not_active IP Right Cessation
- 2009-12-17 CN CN200980152796XA patent/CN102264346A/zh active Pending
- 2009-12-17 BR BRPI0923675A patent/BRPI0923675A8/pt not_active Application Discontinuation
- 2009-12-17 EP EP09805727A patent/EP2379054A1/fr not_active Withdrawn
- 2009-12-17 MX MX2011006797A patent/MX2011006797A/es active IP Right Grant
- 2009-12-17 WO PCT/FR2009/052591 patent/WO2010072950A1/fr active Application Filing
Patent Citations (2)
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WO2008035020A2 (fr) * | 2006-09-22 | 2008-03-27 | Philippe Perovitch | Forme galenique pour l'administration par voie trans-muqueuse de principes actifs |
WO2011004117A1 (fr) * | 2009-07-10 | 2011-01-13 | Philippe Perovitch | Procédé et compositions pharmaceutiques pour le traitement de l'hyper glycémie post-prandiale du diabète de type ii par voie trans-muqueuse buccale |
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Also Published As
Publication number | Publication date |
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MX2011006797A (es) | 2011-09-06 |
FR2940116B1 (fr) | 2012-07-06 |
CN102264346A (zh) | 2011-11-30 |
BRPI0923675A2 (pt) | 2016-01-19 |
JP2012513454A (ja) | 2012-06-14 |
BRPI0923675A8 (pt) | 2018-05-29 |
RU2528897C2 (ru) | 2014-09-20 |
US20110257149A1 (en) | 2011-10-20 |
WO2010072950A1 (fr) | 2010-07-01 |
RU2011130508A (ru) | 2013-01-27 |
US8889663B2 (en) | 2014-11-18 |
FR2940116A1 (fr) | 2010-06-25 |
JP5529165B2 (ja) | 2014-06-25 |
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