WO2023025272A1 - 一种小分子药物缓释递药系统 - Google Patents
一种小分子药物缓释递药系统 Download PDFInfo
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- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- 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
- A61K9/0031—Rectum, anus
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- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the invention belongs to the field of pharmaceutical preparations, and in particular relates to a slow-release drug delivery system for small molecule drugs.
- Injectable sustained-release preparations are one of the current research hotspots of pharmaceutical preparations, which aim to provide a drug reservoir, which can be used for subcutaneous injection, intramuscular injection, intramuscular injection, local injection and other administration methods.
- local injection refers to local administration, such as injection in the spinal cavity, joint cavity, wound, eye, etc., and the drug can exert its effect locally after the drug is slowly released.
- Injectable sustained-release preparations have many advantages, for example: the preparation can be directly injected into the desired administration site for slow drug release, reducing systemic toxicity and increasing therapeutic effect; secondly, the preparation can also reduce the number of administrations and improve patient compliance; In addition, the preparation can significantly reduce the cost of treatment.
- this type of preparation also has some disadvantages, for example: since the drug is released over a long period of time and usually cannot be withdrawn after administration, good preparation stability is required. In addition, it is necessary to pay attention to whether the sustained-release preparation will cause a burst release effect, or produce other adverse effects such as diffusion and toxicity at the injection site.
- sustained-release technology for injectables mainly includes oil sustained-release systems, polymer-based and lipid-based sustained-release systems, etc.
- Patent 201310022657.3 discloses an analgesic sustained-release drug delivery system composed of an analgesic, drug vehicle, and drug sustained-release agent.
- the drug sustained-release agent is liquid oil. Due to the low viscosity of the oil sustained-release system and the diffusion of organic solvents in the body, it may cause a burst release phenomenon, which has potential safety hazards. In addition, its release is relatively fast, which cannot meet the release requirements of some drugs.
- Polymer sustained-release systems are mainly polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA) and polyorthoester (POE).
- Patent document US200303156A1 provides a slow-release microsphere composition and a preparation method thereof.
- the composition includes polymer PLGA, active substance risperidone or 9-hydroxyrisperidone and other excipients.
- the FDA approved a long-acting risperidone microsphere developed by Janssen Pharmaceuticals with PLGA as the sustained-release carrier, and the trade name is RISPERDAL
- the extended release microspheres provide sustained release for 14 days.
- Heron Therapeutics Inc disclosed in the patent document CN106535886A a polyorthoester as a slow-release carrier, a composition containing an amide local anesthetic, an enol non-steroidal anti-inflammatory drug and a polyorthoester and a preparation method thereof.
- a polyorthoester as a slow-release carrier
- a composition containing an amide local anesthetic an enol non-steroidal anti-inflammatory drug and a polyorthoester and a preparation method thereof.
- Lipid-based sustained-release systems are mainly lipoplexes and liposomes.
- PACIRA has developed a long-acting bupivacaine multivesicular liposomal suspension injection with the trade name It is used to treat postoperative pain and nerve block, and the analgesic effect can last for 24 hours.
- the liposome mainly contains two kinds of synthetic phospholipids, dierucoyl phosphatidylcholine (DEPC) and dipalmitoylphosphatidylglycerol (DPPG), and encapsulating bupivacaine in the multivesicular liposome can play a slow-release effect.
- DEPC dierucoyl phosphatidylcholine
- DPPG dipalmitoylphosphatidylglycerol
- encapsulating bupivacaine in the multivesicular liposome can play a slow-release effect.
- the preparation process of multivesicular liposomes is complex and requires high storage conditions.
- the patent CN103705442 discloses an in-situ lipid gel preparation, which is characterized in that the preparation contains phospholipids, a therapeutically effective amount of active substances and a solvent; the phospholipids are preferably one of soybean lecithin, egg yolk lecithin or several, more preferably soybean lecithin; the solvent contains an organic solvent, preferably one or more of absolute ethanol, benzyl alcohol, tert-butanol, glycerin, and water or a physiological aqueous medium.
- Patent CN103705439 discloses a lipid gel preparation, which is characterized in that the preparation comprises PEGylated phospholipids, non-PEGylated phospholipids, therapeutically effective doses of active substances and solvents, in which water or Physiological aqueous medium acts as solvent and does not contain cholesterol.
- CN102933200 discloses a single-phase gel composition, which comprises: 20% to 80% by weight of one or more phospholipids; 0.1% to 70% by weight of water, wherein high shear, high energy or A high pressure homogenizer such that the phospholipids have a particle size of less than 100 nm and the gel composition can be passed through a 25G x 1/2 inch long needle and extruded from a 1 cc syringe at a rate of 2 cc/min with a force not exceeding 12 lbs. and said composition optionally further comprises a pharmacologically active agent.
- Patents CN103705442, CN103705439 and CN102933200 all contain water in different proportions, which may have stability problems such as easy oxidation and low viscosity, so they can only be administered by subcutaneous injection.
- sustained-release systems that have been approved or are currently under research have problems such as complex preparation process, difficult degradation of sustained-release carriers, and safety caused by burst release.
- the lipid-based sustained-release systems under research or on the market all have low viscosity and cannot meet the problem of incisional drug delivery. Therefore, there is an urgent need to develop a sustained-release preparation system suitable for pharmaceutical use, with improved stability, safety, tolerance and/or sustained-release performance, and high viscosity.
- liquid pharmaceutical composition comprising the following components:
- the slow-release carrier is selected from one or more of the compounds of formula I or formula II, and the compound of formula I is Wherein, Rs is selected from H, Each R 1 , R 2 is the same or different, independently selected from saturated or unsaturated aliphatic hydrocarbon groups; each R 3 , R 4 , R 5 is the same or different, independently selected from H or alkyl; L is selected from Alkylene; The compound of formula II is Wherein, R is selected from alkyl;
- At least one pharmaceutically acceptable solvent At least one pharmaceutically acceptable solvent.
- the pharmaceutical composition may further comprise a pharmaceutically acceptable release modifier.
- each R 1 and R 2 are the same or different, and are independently selected from C 10-30 saturated or unsaturated aliphatic hydrocarbon groups, such as C 13-21 alkyl groups; each R 3 , R 4 , and R 5 are the same or different, and are independently selected from H or C 1-10 alkyl groups, such as independently selected from H, methyl, and ethyl; the L is selected from C 1-10 alkyl groups Alkyl, preferably, L is selected from C 1-6 alkylene, such as methylene, ethylene;
- R is selected from C 1-10 alkyl groups, such as C 8-10 alkyl groups.
- the c-component slow-release carrier is selected from HSPC (hydrogenated soybean lecithin), DMPC (dimyristoyl phosphatidylcholine), DPPC (dipalmitoyl phosphatidylcholine), DSPC (di Stearoylphosphatidylcholine), DLPC (dilauroylphosphatidylcholine), SPC soybean phosphatidylcholine (soybean phosphatidylcholine), EPC (egg yolk phospholipid), rapeseed phosphatidylcholine, sunflower phosphatidylcholine, DEPC (dierucoyl egg phosphatidylcholine) Phospholipids), DOPC (Dioleoyl Lecithin), POPC (Palmitoyl Oleoyl Lecithin), Sphingomyelin, Distearoyl Phosphatidic Acid (DSPA), Dioleoy
- the c-component slow-release carrier is SPC soybean phosphatidylcholine (soybean lecithin), EPC (egg yolk phospholipid), DEPC (dierucoyl lecithin), DOPC (dioleacyl lecithin), POPC ( one or more of palmitoyl oleoyl lecithin).
- the pharmaceutically active ingredient is not limited to the type of treatment, and may be anti-inflammatory drugs, local anesthetics, analgesics, antipsychotics, anxiolytics, sedative-hypnotics, antidepressants, antihypertensives Blood pressure drugs, steroid hormones, antiepileptic drugs, bactericides, anticonvulsants, antiparkinsonian drugs, central nervous system stimulants, antipsychotics, antiarrhythmic drugs, antianginal drugs, antithyroid drugs, antidotes, antiemetics Drugs, hypoglycemic drugs, anti-tuberculosis drugs, anti-AIDS drugs, anti-hepatitis B drugs, anti-tumor drugs, anti-rejection drugs and their mixtures.
- suitable pharmaceutically active ingredients may be selected from one or more combinations of the following compounds: aspirin, acetaminophen, benoate, indomethacin, sulindac, diclofenac, Diclofenac potassium, diclofenac sodium, ibuprofen, naproxen, flurbiprofen, flurbiprofen axetil, loxoprofen, nabumetone, ketorolac, phenylbutazone, butadiene hydroxyacid, fenol Profen, Celecoxib, Rofecoxib, Polmacoxib, Nimesulide, Meloxicam, Lornoxicam, Piroxicam, Etodolac, Valdecoxib, Parecoxib, Erecoxib, Lu Micoxib.
- Caffeine Fentanyl, Sufentanil, Remifentanil, Tramadol, Nortramadol, Tapentadol, Dezocine, Pentazocine, Methadone, Pethidine, Ketamine, Diazepam Panam, Chlormetazepam, Lisdexamphetamine, Dextropropoxyphene, Difelikefalin, Oliceridine.
- Chlorpromazine triflupromazine, mesoridazine, pecitazine, thioridazine, chlorprothixene.
- Procainamide isoamyl nitrite, nitroglycerin, propranolol, metoprolol, prazosin, phentolamine, mithiophene, captopril, enalapril.
- Clonidine dexmedetomidine, epinephrine, norepinephrine, tizanidine, alpha-methyldopa, glycopyrrolate. cortisone, hydrocortisone, betamethasone, triamcinolone acetonide, dexamethasone, dexamethasone ester, prednisone, prednisolone, methylprednisolone, beclomethasone, clobetasol, progesterone , Testosterone, Testosterone Enanthate, Testosterone Undecanoate, Testosterone Cypionate, Progesterone, Fulvestrant, Pregnenolone, Ganaxolone, Phenytoin, Ethytoin.
- Benzalkonium Chloride Benzethonium Chloride, Sulfamethonium Acetate, Mebenzethonium Chloride, Furacilin, Mercury Nicresol.
- Phenobarbital amobarbital, pentobarbital, secobarbital. carbidopa, levodopa, aniracetam, oxiracetam, piracetam, doxapram, aripiprazole, olanzapine, haloperidol, quetiapine, risperidone , clozapine, paliperidone, atenolol, bisoprolol, metoprolol.
- Atenolol amlodipine, nimodipine, isosorbide mononitrate, epoprostenol, treprostinil, iloprost, beraprost.
- Methimazole propylthiouracil, propranolol, naloxone, lofexidine, flumazenil, amphetamine.
- the pharmaceutically active ingredient is selected from amide local anesthetics, for example, from bupivacaine, ropivacaine, levobupivacaine, mepivacaine, and lidocaine in salt form.
- the salt of the amide local anesthetic may be selected from fatty acid salts and water-soluble salts thereof, and the acids forming the salt include lauric acid, myristic acid, stearic acid, palmitic acid, behenic acid, arachidic acid, methanesulfonic acid, Hydrochloric acid, sulfonic acid, phosphoric acid, acetic acid, citric acid, maleic acid, etc.
- the pharmaceutically active ingredient further includes a second active ingredient in addition to an amide local anesthetic, and the pharmaceutically active ingredient can be selected from COX receptor inhibitors, adrenergic receptor agonists, and sugars.
- COX receptor inhibitors include non-selective COX inhibitors and selective COX-2 inhibitors.
- NSAIDs represented in these classes include, but are not limited to, the following non-selective COX inhibitors: aspirin, acetaminophen, benolate, indomethacin, sulindac, diclofenac, diclofenac potassium, Diclofenac sodium, ibuprofen, naproxen, flurbiprofen, loxoprofen, nabumetone, piroxicam, ketorolac, phenylbutazone, butyrate, fenoprofen; the following optional COX-2 inhibitors: celecoxib, rofecoxib, nimesulide, meloxicam, lornoxicam, etodolac, valdecoxib, parecoxib, erecoxib, lumixide cloth.
- the adrenergic receptor agonists are mainly ⁇ 2-adrenoceptor agonists, including but not limited to clonidine, dexmedetomidine, epinephrine, norepinephrine, tizanidine, ⁇ -methyl doba.
- the glucocorticoid drugs include, but are not limited to cortisone, hydrocortisone, betamethasone, triamcinolone acetonide, dexamethasone, prednisone, prednisolone, methylprednisolone, beclomethasone , Clobetasol.
- the pharmaceutical active ingredient is selected from ropivacaine hydrochloride, ropivacaine mesylate, bupivacaine hydrochloride, levobupivacaine hydrochloride, meloxicam, celecoxib, One or a combination of ketorolac and triamcinolone acetonide.
- the pharmaceutically active ingredient is selected from a combination of an amide local anesthetic and a non-steroidal anti-inflammatory drug, such as a combination of ropivacaine hydrochloride and meloxicam, levobupivacaine hydrochloride and meloxicam Composition, bupivacaine hydrochloride and meloxicam composition, ropivacaine mesylate and meloxicam composition, ropivacaine mesylate and celecoxib composition, ropivacaine hydrochloride and Celecoxib composition, levobupivacaine hydrochloride and celecoxib composition, bupivacaine hydrochloride and celecoxib composition, etc.
- a non-steroidal anti-inflammatory drug such as a combination of ropivacaine hydrochloride and meloxicam, levobupivacaine hydrochloride and meloxicam Composition, bupivacaine hydrochloride and meloxicam composition, ropivacaine mesylate and
- the pharmaceutically acceptable release regulator is selected from one or more of sterols, saturated phospholipids and other surfactants.
- the saturated phospholipid is used to adjust the viscosity of the sustained-release drug delivery system, thereby adjusting the drug diffusion rate, and the sterol and surfactant are used to adjust the hydrophilicity of the sustained-release drug delivery system, so as to achieve the desired drug release rate.
- the sterol comprises cholesterol.
- the saturated phospholipids include hydrogenated soybean phospholipids (HSPC), dilauroyl lecithin (DLPC), dimyristoyl lecithin (DMPC), distearoyl phosphatidylcholine (DSPC), di Palmitoyl lecithin, etc. (DPPC), etc.
- HSPC hydrogenated soybean phospholipids
- DLPC dilauroyl lecithin
- DMPC dimyristoyl lecithin
- DSPC distearoyl phosphatidylcholine
- DPPC di Palmitoyl lecithin
- the surfactant is a nonionic surfactant.
- the surfactant includes polyoxyl 40 stearate, macrogol glyceride caprylate, lauroyl polyoxyethylene glyceride, stearoyl polyoxyethylene glyceride, oleoyl Polyoxyethylene Glycerides, Vitamin E Polyethylene Glycol Succinate, Poloxamer, Polysorbate, Macrogol-12-Hydroxystearate, Propylene Glycol Monocaprylate, Glyceryl Dioleate, Glyceryl monooleate, etc.
- the poloxamer can be selected from, for example, poloxamer 407, poloxamer 188, and the polysorbate can be selected from, for example, polysorbate 80.
- the composition may further comprise one or more antioxidants.
- Antioxidants can be used to prevent or reduce oxidation of phospholipids in the sustained release drug delivery system of the present invention.
- Antioxidants provided by the present invention include but are not limited to vitamin C (ascorbic acid), cysteine hydrochloride, vitamin E (tocopherol), ascorbyl palmitate, glutathione, alpha lipoic acid, thioglycerol.
- the composition may further include other conventional excipients in the field of pharmacy.
- suitable pharmaceutical excipients are in Excipients and their use in injectable products. PDA J Pharm Sci Technol. Volume 51 , July-August 1997, pp. 166-171 and described in Excipient Selection In Parenteral Formulation Development, Pharma Times, Vol. 45, No. 3, March 2013, pp. 65-77, which are cited in their entirety and into the present invention.
- the mass ratio of the glycerol to the slow-release carrier/pharmaceutically acceptable solvent is 1:0.1 to 1:99, such as 1:0.1, 1:0.5, 1:1, 1:5, 1 :10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70 , 1:75, 1:80, 1:85, 1:90, 1:95, 1:99.
- the mass ratio of glycerin to sustained-release carrier/pharmaceutically acceptable solvent is 1:0.3 to 1:35.
- the mass ratio of glycerin to sustained-release carrier/pharmaceutically acceptable solvent is 1:1 to 1:19.
- the mass ratio of the slow-release carrier to the pharmaceutically acceptable solvent is 1:0.1 to 1:10, such as 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5 , 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1 :9, 1:10.
- the mass ratio of the slow-release carrier to the pharmaceutically acceptable solvent is 1:0.3 to 1:8.
- the mass ratio of the slow-release carrier to the pharmaceutically acceptable solvent is 1:0.7 to 1:8.
- the glycerol accounts for about 1% to about 95% (w/w) of the total composition, such as about 1%, 2%, 3%, 4%, 5%, 6%, 7% %, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40% , 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57 %, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%,
- the slow-release carrier accounts for 3% to 90% (w/w) of the total composition, such as 3%, 4%, 5%, 6%, 7%, 8%, 9% , 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26 %, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% , 60%, 61%, 62%, 63%, 64%, 64%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76 %, 77%, 78%
- the pharmaceutically active ingredient accounts for 0.1% to 50.0% (w/w) of the total composition.
- the pharmaceutically active ingredient accounts for 0.1% to 15% (w/w) of the total composition, such as 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0% , 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%.
- the pharmaceutically active ingredient is present in an amount of 3% (w/w) to 10% (w/w).
- each pharmaceutically active ingredient can account for 0.1% to 15% (w/w) of the total composition, such as 0.1%, 0.5%, 1.0%, 1.5% %, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%.
- the total amount of the pharmaceutically acceptable solvent accounts for 5% to 50% (w/w) of the total amount of the composition.
- the total amount of the pharmaceutically acceptable solvent Can account for 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% of the total composition %, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%.
- the total amount of the pharmaceutically acceptable solvent accounts for 10%-50% (w/w) of the total composition, and in some embodiments, the total amount of the pharmaceutically acceptable solvent accounts for From 5% to 30% (w/w) of the total composition.
- the pharmaceutically acceptable solvent is a non-aqueous solvent
- the non-aqueous solvent is selected from ethanol, N-methylpyrrolidone, benzyl alcohol, n-propanol, isopropanol, n-butanol, One or more combinations of isobutanol and tert-butanol.
- the release modifier accounts for 0% to 40% (w/w) of the total composition, preferably 0.1% to 40% (w/w).
- the release modifier can account for 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4% of the total composition , 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, in some embodiments, when the release modifier is selected from saturated phospholipids, the amount of the release modifier is 1 to 30% (w/w); in some embodiments, When the release modifier is selected from surfactants, the release modifier is used in an amount of
- the pharmaceutical composition provided by the present invention is a high-viscosity liquid preparation.
- the viscosity of the liquid preparation is ⁇ 500 mPa ⁇ s at normal temperature (about 25°C).
- the composition has a viscosity of 500 to 100,000 mPa ⁇ s at 25°C.
- the composition has a viscosity in the range of 500 to 50000 mPa ⁇ s at 25°C.
- the viscosity of the composition is in the range of 500 to 30000 mPa ⁇ s at 25°C.
- the viscosity of the composition is in the range of 500 to 15000 mPa ⁇ s at 25°C.
- the viscosity of the composition is in the range of 500 to 10000 mPa ⁇ s at 25°C.
- the pharmaceutically acceptable solvent and release modifier can act as a viscosity modifier to make the composition suitable for injection.
- the present invention provides a kind of preparation method of described pharmaceutical composition, comprises the steps:
- the mixing of the step (a1) also includes adding at least one pharmaceutically acceptable release regulator, for example, the step (a1) can be slow-release carrier, pharmaceutically acceptable Solvent, glycerol and release modifier are mixed.
- the step (a1) can be slow-release carrier, pharmaceutically acceptable Solvent, glycerol and release modifier are mixed.
- the method includes:
- the present invention provides a sustained release formulation comprising said pharmaceutical composition, said formulation being administered as a depot formulation, in one aspect said formulation being injectable. In another aspect, the formulation can be administered topically.
- the formulation may be administered subcutaneously, perineurally, intramuscularly, or by infusion (direct application into a wound, arterial infusion, rectal infusion).
- the formulation is suitable for topical dermal or mucosal administration.
- the preparation provided by the invention is administered in a single dose, and the amount of the medicine contained therein can achieve the effects of analgesia and nerve block, and can be used for preventing or alleviating local pain.
- the preparation provided by the present invention can form a stable reservoir at the site of administration, which can release the drug slowly and continuously, prolong the release time of the drug, and improve the therapeutic effect.
- the formulation is effective for at least 24 hours after administration. In some embodiments, the formulation is effective for at least 24 to 48 hours after administration. In some embodiments, the formulation is effective for at least 48 to 72 hours after administration. In some embodiments, the formulation is effective for at least 72 hours after administration.
- the preparation further includes a packaging material filled with the preparation, and the packaging material is selected from one or more of the following: vials, prefilled syringes, and cartridges.
- the numerical range is defined as a “number” or may include “integer” or “non-integer”, it should be understood that both endpoints of the range, each integer within the range, and each integer within the range are recited. decimal.
- “the number from 0 to 10” should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers respectively Sum with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
- aliphatic group includes saturated or unsaturated, linear or branched chain-like hydrocarbon group, the type of said aliphatic group can be selected from alkyl (saturated aliphatic group), unsaturated aliphatic group (containing at least one double bond and /or triple bond, such as alkenyl, alkynyl) etc., the number of carbon atoms of the aliphatic hydrocarbon group is preferably 1-40, further preferably 1-30 (such as C1, C2, C3, C4, C5, C6, C6 , C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30), Specifically, it may include but not limited to the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl
- alkyl is a saturated aliphatic hydrocarbon group, which conforms to the relevant definition in the above-mentioned aliphatic hydrocarbon group.
- the number of carbon atoms in the alkyl group is preferably 1-40, more preferably 1-30, or 1-10 (such as C1, C2, C3, C4, C5, C6, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C30, C40, i.e.
- alkyl group when an alkyl group is clearly represented as a linking group, the alkyl group represents a connected alkylene group, therefore, "alkylene "You can also refer to the relevant definition in the above-mentioned aliphatic hydrocarbon group, for example, the number of carbon atoms of the alkylene group can be C1, C2, C3, C4, C5, C6, C6, C7, C8, C9, C10 (that is, the alkylene group Alkyl can be methylene, ethylene, and so on).
- biocompatibility refers to the interaction between the components of a composition and the body.
- active ingredient refers to a drug used in the treatment of a disease. Therefore, active ingredients, drugs can be used alternatively.
- active ingredient or drug as used herein includes, but is not limited to, pharmaceutically active substances of local or systemic action, which may be administered topically or by injection, such as subcutaneous, intradermal, intramuscular and intraarticular injections . At least one active ingredient is present in the sustained release drug delivery system of the present invention.
- amide type used in the present invention refers to amide or caine local anesthetics, such as bupivacaine, levobupivacaine, ropivacaine, mepivacaine, lidocaine and the like.
- Amide local anesthetics are generally composed of a lipophilic part and a hydrophilic part.
- the lipophilic part can be an aromatic hydrocarbon or an aromatic heterocycle, and the benzene ring has the strongest effect.
- the introduction of electron-donating groups such as amino groups on the benzene ring can enhance the activity.
- the hydrophilic part is generally secondary amine, tertiary amine or pyrrolidine, piperidine, morpholine, etc., and tertiary amine is the most common.
- the pKa is generally between 7.5 and 7.9, and it is ionic under physiological conditions.
- SPC soybean phosphatidylcholine (soybean phosphatidylcholine)
- EPC egg yolk phosphatidylcholine (egg yolk phospholipid)
- HSPC hydrogenated soybean phosphatidylcholine
- DLPC dilauroylphosphatidylcholine Choline
- DMPC dimyristoylphosphatidylcholine
- DPPC dipalmitoylphosphatidylcholine
- DSPC distearoylphosphatidylcholine
- DEPC is dierucoylphosphatidylcholine
- DOPC dioleoylphosphatidylcholine Acylcholine (dioleoyl phosphatidylcholine)
- POPC palmitoyl oleoyl phosphatidylcholine
- BA benzyl alcohol
- NMP N-methylpyrrolidone
- DMSO dimethyl methyl phosphatidylcholine
- the present invention provides a sustained-release preparation composition, which is a high-viscosity liquid at normal temperature and can undergo phase transition at the site of administration.
- the selected auxiliary material components in the present invention have good biocompatibility.
- the present invention unexpectedly finds that by controlling the ratio of glycerin, slow-release carrier, and solvent system, the viscosity of the composition preparation can be significantly increased, making the pharmaceutical composition easier to infuse and administer, while staying in the body for a longer time, and improving the drug's sustained release. release effect.
- composition of the present invention is less irritating and has good drug safety and tolerance.
- the sustained-release preparation system provided by the present invention can achieve good release performance of active pharmaceutical ingredients and reduce the possibility of burst release.
- composition of the present invention is especially suitable for the development of pharmaceutical preparations with anesthesia and analgesic activity, and has more advantages compared to other sustained-release analgesic drug systems, such as continuous and stable release of analgesic active ingredients, not only can be injected It is suitable for stable and convenient local administration, with good tolerance of patients and few side effects.
- Figures 1-1 to 1-4 are the rheological results of compositions 3058, 3061, 3062, and 3064, respectively.
- Figures 1-5 are viscosity-shear rate curves for compositions 3058, 3061, 3062, 3064.
- Figure 2-1 shows the status of the administration sites of compositions 3075 and 3076 in rats at 24h, 48h, and 72h.
- Figure 3-1 to Figure 3-2 are the plasma concentration-time curves of ropivacaine and bupivacaine, and the plasma concentration-time curves of meloxicam of compositions 3077 and 3078, respectively.
- Figure 4-1 to Figure 4-2 are respectively the plasma concentration-time curves of ropivacaine and meloxicam of compositions 3079 and 3080.
- Figure 5-1 to Figure 5-2 are respectively the plasma concentration-time curves of ropivacaine and meloxicam of the composition 3082.
- Figure 6-1 to Figure 6-2 are the blood concentration-time curves of ropivacaine and meloxicam blood concentration-time curves of compositions 3079, 3080, and 3081, respectively.
- the present invention unexpectedly finds that adding glycerol to the phospholipid solution can significantly increase the viscosity of the composition, while propylene glycol and polyethylene glycol with different molecular weights do not significantly increase the viscosity of the composition.
- compositions were prepared according to Table 4-1, and rheological studies were carried out.
- Rheometer model TA DHR-1, sample volume: 1mL.
- Measurement mode Oscillation mode: time sweep, fixed Strain 0.5%, frequency 1Hz; Oscillation mode: frequency sweep, fixed Strain 0.5%, frequency sweep range 0.1-100rad/s.
- Figure 1-5 is the viscosity-shear rate curve of the composition in Table 4-1. It can be seen that the viscosity of the composition increases with the increase of the amount of glycerin, and the viscosity of the composition can be adjusted by adding a regulator. In addition, the composition exhibits a phenomenon of shear thinning as the shear rate increases.
- the release of ropivacaine from the composition of Example 5 was determined by adding 100 mg of the pharmaceutical composition from Example 5 to a dialysis bag and placing it in a tube containing 200 mL of phosphate buffer. Shake at 37°C, and take 1 mL of phosphate buffer solution from the tube at 24h, 48h, and 72h respectively.
- the concentrations of ropivacaine mesylate and meloxicam in each sample were determined by HPLC. The results are shown in Table 6-1 below.
- compositions containing different ratios of release modifiers are provided.
- the release of ropivacaine from the composition of Example 7 was determined by adding 100 mg of the pharmaceutical composition from Example 7 into a dialysis bag and placing it in a tube containing 200 mL of phosphate buffer. Shake at 37°C, and take 1 mL of phosphate buffer solution from the tube at 24h, 48h, and 72h respectively.
- the concentrations of ropivacaine mesylate and meloxicam in each sample were determined by HPLC. The results are shown in Table 8-1 below.
- compositions containing different active ingredients are provided.
- compositions containing different active ingredients are provided.
- compositions according to Table 13-1 Prepare the composition according to Table 13-1, remove the hair on the outside of the right hind leg of the rat, and administer 0.2 mL of the composition subcutaneously to each rat (the dosage is 100 mg/kg, containing 20 mg according to ROP), at 24h, 48h and Killed by dislocation at 72 hours, opened the administration site, and observed the shape of the preparation at the administration site.
- the results are shown in Figure 2-1.
- Composition 3075 and Composition 3076 were still able to see the reservoir after 72h.
- compositions 3077 and 3078 are shown in Figure 3-1 and Figure 3-2.
- compositions 3079 and 3080 are shown in Figure 4-1 and Figure 4-2.
- composition 3082 The plasma concentration-time curves of composition 3082 are shown in Figure 5-1 and Figure 5-2.
- the pharmacokinetic study in rats is as follows. Animals with a weight of about 180-200 g were randomly grouped and uniquely identified by tail numbers. Inject subcutaneously on the back of the neck of rats, and the administration volume is fixed at 0.2mL/animal. Blood samples were collected 0 h before administration and approximately 0.5, 1, 2, 3, 6, 8, 10, 24, 34, 48, 72 and 96 h after administration into K2EDTA anticoagulant tubes, temporarily stored on ice until centrifuged. Plasma needs to be centrifuged within 60 minutes after blood collection (under the condition of 2-8°C, centrifuge at 8000rpm for 5min). MS detection.
- compositions 3079, 3080, and 3081 are shown in Figure 6-1 and Figure 6-2.
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Abstract
本发明涉及一种药物组合物,包含药学上的活性成分、甘油、缓释载体和药学上可接受的溶剂。所述药物组合物刺激性小,具有良好的缓释性能,用药安全性及耐受性,且在常温下为高粘度液体,特别有利于灌注给药。
Description
本申请要求享有申请人于2021年8月27日向中国国家知识产权局提交的,专利申请号为202110997613.7,发明名称为“一种小分子药物缓释递药系统”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。
本发明属于药物制剂领域,具体涉及一种小分子药物缓释递药系统。
可注射用缓释制剂是目前药物制剂的研究热点之一,其旨在提供一种药物贮库,可用于皮下注射、肌内注射、肌肉注射、局部注射等给药方式。其中,局部注射是指在局部给药,如在脊椎腔、关节腔、伤口、眼内等部位注射,药物缓慢释放后可在局部发挥作用的给药方式。
可注射用缓释制剂具有多种优势,例如:该制剂可以直接注入期望给药部位缓慢释药,降低系统毒性,增加治疗效果;其次,该制剂还可以减少给药次数,提高患者顺应性;此外,该制剂还可显著降低治疗费用。但是,此类制剂同样存在一些缺点,例如:由于药物在较长时间内释放,且用药后通常不能撤回,因此需要具有良好的制剂稳定性。并且,需要关注缓释制剂是否会引起突释效应,或者在注射部位产生弥散、毒性等其他不利影响。
近年来,可注射用缓释技术的研究主要包括油缓释体系、以聚合物和脂质为基质的缓释体系等。
油缓释体系主要以可注射用植物油和有机溶剂为主,专利201310022657.3公开了一种由镇痛剂、药物溶媒、药物缓释剂组成的镇痛缓释递药系统,其中药物缓释剂为液体油。由于油缓释体系粘度较低同时有机溶剂在体内扩散,可能引起突释现象,存在安全性隐患,此外其释放较快,无法满足一些药物的释放需求。
聚合物缓释体系主要为聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)和聚原酸酯(POE)等。专利文献US200303156A1提供了一种缓释微球组合物及其制备方法,所述组合物包含聚合物PLGA、活性物质利培酮或9-羟基利培酮及其他赋形剂。2003年FDA批准了Janssen Pharmaceuticals开发的一种以PLGA为缓释载体的利培酮长效微球,商品名为RISPERDAL
该缓释微球可提供14天持续释放。Heron Therapeutics Inc在专利文献CN106535886A中公开了以聚原酸酯为缓释载体,含有酰胺类局麻药,烯 醇类非甾体抗炎药和聚原酸酯的组合物及其制备方法。目前已获得欧盟批准,商品名为
由于高分子材料在给药部位降解缓慢,因此存在安全性风险。
以脂质为基质的缓释体系主要为脂质复合物和脂质体。PACIRA开发了一种长效布比卡因多囊脂质体混悬注射液,商品名为
用于治疗术后疼痛及神经阻滞,镇痛效果可持续24小时。该脂质体中主要含有二芥酰基卵磷脂(DEPC)和二棕榈酰磷脂酰甘油(DPPG)两种合成磷脂,将布比卡因包裹在多囊脂质体中能起到缓释作用。但是,多囊脂质体制备工艺复杂,且对储藏条件要求高。此外,专利CN103705442公开了一种原位脂质凝胶制剂,其特征在于所述制剂包含磷脂、治疗有效量的活性物质和溶剂;所述磷脂优选为大豆磷脂、蛋黄卵磷脂中的一种或几种,更优选为大豆磷脂;所述的溶剂中含有有机溶剂,优选为无水乙醇、苯甲醇、叔丁醇、甘油中的一种或几种,同时含有水或生理性的水性介质。专利CN103705439公开了一种脂质凝胶制剂,其特征在于所述制剂包含PEG化的磷脂、非PEG化的磷脂、治疗有效量的活性物质和溶剂,这种脂质凝胶制剂中以水或生理性的水性介质作为溶剂,不含有胆固醇。CN102933200公开了单相凝胶组合物,所述组合物包含:20%~80%重量比的一种或多种磷脂;0.1%~70%重量比的水,其中采用高剪切、高能量或高压均质机使所述磷脂的粒径小于100nm以及所述凝胶组合物能通过25GX1/2英寸长的针头并以2cc/min的挤出速率且由不超过12磅的作用力从1cc注射器中挤出,并且所述组合物还任选地包含药理学活性剂。专利CN103705442、CN103705439和CN102933200均含有不同比例水,可能存在易氧化等稳定性问题,同时粘度较低,只能皮下注射给药。
目前已批准或在研的缓释体系存在制备工艺复杂,缓释载体较难降解,突释引起的安全性等问题。此外,在研或上市的以脂质为基质的缓释体系均存在粘度低,无法满足切口给药的问题。因此,亟需开发一种适于药用,稳定性、安全性、耐受性和/或缓释性能得到改善,高粘度的缓释制剂系统。
发明内容
为改善现有技术中存在的问题,本发明提供一种液体药物组合物,包括如下组分:
a.药学活性成分;
b.甘油;
c.缓释载体,所述缓释载体选自式I或式II化合物中的一种或多种,所述式I化合物为
其中,Rs选自H,
每个R
1、R
2相同或不同,彼此独立地选自饱和或不饱和脂肪烃基;每个R
3、R
4、R
5相同或不同,彼此独立地选自H或烷基;L选自亚烷基;所述式II化合物为
其中,R选自烷基;
d.至少一种药学上可接受的溶剂。
根据本发明的实施方案,所述药物组合物可以进一步包含药学上可接受的释放调节剂。
根据本发明的实施方案,所述式I中,每个R
1、R
2相同或不同,彼此独立地选自C
10-30饱和或不饱和脂肪烃基,例如C
13-21烷基;每个R
3、R
4、R
5相同或不同,彼此独立地选自H或C
1-10烷基,例如彼此独立地选自H,甲基,乙基;所述L选自C
1-10亚烷基,优选的,L选自C
1-6亚烷基,例如为亚甲基,亚乙基;
根据本发明的实施方案,式II所示化合物中,R选自C
1-10烷基,例如C
8-10烷基。
根据本发明的实施方案,所述c组分缓释载体选自HSPC(氢化大豆磷脂)、DMPC(二肉豆蔻酰基磷脂酰胆碱)、DPPC(二棕榈酰基磷脂酰胆碱)、DSPC(二硬脂酰基磷脂酰胆碱)、DLPC(二月桂酰磷脂酰胆碱)、SPC大豆磷脂酰胆碱(大豆磷脂),EPC(蛋黄磷脂),油菜籽磷脂,向日葵磷脂,DEPC(二芥酰基卵磷脂),DOPC(二油酸酰基卵磷脂),POPC(棕榈酰基油酰基卵磷脂)、鞘磷脂、二硬脂酰磷脂酸(DSPA)、二油酰磷脂酰乙醇胺(DOPE)、二棕榈酰磷脂酸(DPPA)、肉豆蔻酰溶血磷脂(M-lysoPC)、棕榈酰溶血磷脂(P-lysoPC)、1-硬脂酰-溶血磷脂酰胆碱(S-lysoPC)、二棕榈酰磷脂酰乙醇胺(DPPE)、二硬脂酰磷脂酰乙醇胺(DSPE)、二油酰磷脂酰甘油(DOPG)、二肉豆蔻酰磷脂酰乙醇胺(DMPE)、二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰甘油(DPPG)、1-棕榈酰-2-油酰磷脂酰甘油(POPG)、二硬脂酰酰磷脂酰甘油(DSPG)、二棕榈酰磷酯酰丝氨酸(DPPS)、磷脂酰肌醇(PI)、胆固醇(CHO)中的一种或多种。
优选的,所述c组分缓释载体为SPC大豆磷脂酰胆碱(大豆磷脂),EPC(蛋黄磷脂),DEPC(二芥酰基卵磷脂),DOPC(二油酸酰基卵磷脂),POPC(棕榈酰基油酰基卵磷脂)中的一种或多种。
根据本发明的实施方案,所述药学活性成分不限于治疗类型,并可为抗炎药、局麻药、镇痛药、抗精神失常药、抗焦虑药、镇静催眠药、抗抑郁药、抗高血压药、类固醇激素、抗癫痫药、杀菌剂、抗惊厥药、抗帕金森病药、中枢神经兴奋药、抗精神病药、抗心律失常药、抗心绞痛药、抗甲状腺药、解毒药、止吐药、降糖药、抗结核病药、抗艾滋病药、抗乙肝药、抗肿瘤药、抗排斥药及其混合物。
根据本发明的实施方案,合适的药学活性成分可选自下述化合物中的一种或多种的组合:阿司匹林,对乙酰氨基酚,贝诺酯,吲哚美辛,舒林酸,双氯芬酸,双氯芬酸钾,双氯芬酸钠,布洛芬,萘普生,氟比洛芬,氟比洛芬酯、洛索洛芬,萘丁美酮,酮咯酸,保泰松,丁苯羟酸,非诺洛芬,塞来昔布,罗非昔布,Polmacoxib,尼美舒利,美洛昔康,氯诺昔康,吡罗昔康,依托度酸,伐地考昔,帕瑞昔布,艾瑞昔布,卢米昔布。布比卡因,左旋布比卡因,罗哌卡因,甲哌卡因,利多卡因,普鲁卡因,苯佐卡因,丁卡因,达克罗宁。脑啡肽,强啡肽,β-内啡肽,纳曲酮,丁丙诺啡,吗啡,二甲基吗啡,可待因,双氢可待因,羟考酮、氢可酮、纳布啡,芬太尼,舒芬太尼,瑞芬太尼,曲马多,去甲曲马多,他喷他多,地佐辛,喷他佐辛,美沙酮,哌替啶,氯胺酮,地西泮,氯甲西泮,赖右苯丙胺,右丙氧芬,Difelikefalin,Oliceridine。氯丙嗪,三氟丙嗪,美索哒嗪,哌西他嗪,硫利达嗪,氯普噻吨。地西泮,阿普唑仑,氯硝西泮,奥沙西泮,丙咪嗪,阿密曲替林,多虑平,去甲替林,阿莫沙平,反苯环丙胺,苯乙肼。普鲁卡因胺,亚硝酸异戊酯,硝酸甘油,心得安,美托洛尔,哌唑嗪,酚妥拉明,咪噻吩,卡托普利,依那普利。可乐定,右美托咪定,肾上腺素,去甲肾上腺素,替扎尼定,α-甲基多巴,格隆溴铵。可的松,氢化可的松,倍他米松,曲安奈德,地塞米松,地塞米松酯,泼尼松,泼尼松龙,甲泼尼龙,倍氯米松,氯倍他索,黄体酮,睾酮,庚酸睾酮,十一烷酸睾酮,环戊丙酸睾酮,孕酮,氟维司群,别孕烯醇酮,Ganaxolone,苯妥英,乙妥英。苯扎氯铵,苄索氯铵,醋酸磺胺米隆,甲苄索氯铵,呋喃西林,硝甲酚汞。苯巴比妥、异戊巴比妥、戊巴比妥、司可巴比妥。卡比多巴,左旋多巴,阿尼西坦,奥拉西坦,吡拉西坦,多沙普仑,阿立哌唑,奥氮平,氟哌啶醇,喹硫平,利培酮,氯氮平,帕利哌酮,阿替洛尔,比索洛尔,美托洛尔。阿替洛尔,氨氯地平,尼莫地平,单硝酸异山梨酸酯,依前列醇,曲前列尼尔,伊洛前列素,贝前列素。甲巯咪唑,丙巯氧嘧啶,普萘洛尔,纳洛酮,洛非西定,氟马西尼,苯丙胺。格拉司琼,昂丹司琼,托烷司琼,多拉司琼,帕洛诺司琼,东莨菪碱,多潘立酮,格列吡嗪,格列本脲,格列美脲,优降糖,格列齐特,甲苯磺丁脲,利拉鲁肽,艾塞拉肽,度拉鲁肽,索马鲁肽。达芦那韦,多替拉韦钠,恩曲他滨,拉替拉韦,利托那韦,司他夫定,奈韦拉平,齐多夫定,司他夫定,依曲韦林,阿德福韦酯,恩替卡韦, 替比夫定,拉米夫定,替诺福韦二吡呋酯,磷丙替诺福韦,氨硫脲,吡嗪酰胺,丙硫异烟胺,环磷酰胺,5-氟尿嘧啶,卡莫司汀,洛莫司汀,马法兰,苯丁酸氮芥,甲氨蝶呤,长春新碱,博来霉素,阿霉素,他莫昔芬,环孢素,他克莫司,依维莫司,西罗莫司以及所述化合物的药学可接受的盐,立体异构体,衍生物。
根据本发明的实施方案,所述药学活性成分选自酰胺类局麻药,例如选自布比卡因、罗哌卡因、左旋布比卡因、甲哌卡因、利多卡因的盐形式。所述酰胺类局麻药的盐可以选自其脂肪酸盐和水溶性盐,形成盐的酸包括月桂酸、肉豆蔻酸、硬脂酸、棕榈酸、山嵛酸、花生酸、甲磺酸、盐酸、磺酸、磷酸、醋酸、枸橼酸、马来酸等。
根据本发明的实施方案,所述药学活性成分除了包含酰胺类局麻药,还进一步包含第二种活性成分,所述药学活性成分可选自COX受体抑制药、肾上腺素受体激动药和糖皮质激素类药中的一种。所述COX受体抑制药包括非选择性COX抑制药和选择性COX-2抑制药。这些类别中代表的非甾体抗炎药包括,但不限于,下列非选择性COX抑制药:阿司匹林,对乙酰氨基酚,贝诺酯,吲哚美辛,舒林酸,双氯芬酸,双氯芬酸钾,双氯芬酸钠,布洛芬,萘普生,氟比洛芬,洛索洛芬,萘丁美酮,吡罗昔康,酮咯酸,保泰松,丁苯羟酸,非诺洛芬;下列选择性COX-2抑制药:塞来昔布,罗非昔布,尼美舒利,美洛昔康,氯诺昔康,依托度酸,伐地考昔,帕瑞昔布,艾瑞昔布,卢米昔布。以及所述化合物的药学可接受的盐,立体异构体,衍生物。所述的肾上腺素受体激动药主要是α2-肾上腺素受体激动药,包括但不限于可乐定,右美托咪定,肾上腺素,去甲肾上腺素,替扎尼定,α-甲基多巴。所述的糖皮质激素类药包括,但不限于可的松,氢化可的松,倍他米松,曲安奈德,地塞米松,泼尼松,泼尼松龙,甲泼尼龙,倍氯米松,氯倍他索。
在一些实施方式中,所述药学活性成分选自盐酸罗哌卡因、甲磺酸罗哌卡因、盐酸布比卡因、盐酸左旋布比卡因、美洛昔康、塞来昔布、酮咯酸、曲安奈德中的一种或几种的组合。
在一些实施方式中,所述药学活性成分选自酰胺类局麻药与非甾体抗炎药的组合,例如盐酸罗哌卡因和美洛昔康组合物、盐酸左旋布比卡因和美洛昔康组合物、盐酸布比卡因和美洛昔康组合物、甲磺酸罗哌卡因和美洛昔康组合物、甲磺酸罗哌卡因和塞来昔布组合物、盐酸罗哌卡因和塞来昔布组合物、盐酸左旋布比卡因和塞来昔布组合物、盐酸布比卡因和塞来昔布组合物等。根据本发明的实施方案,所述药学上可接受的释放调节剂选自甾醇、饱和磷脂和其他表面活性剂中的一种或几种。所述饱和磷脂用于调节缓释递药系统的粘度,进而调节药物扩散速度,所述甾醇和表面活性剂用于调节缓释递药系统的亲水性,以便达到期望的药物释放速度。
在一些实施方式中,所述甾醇包括胆固醇。
在一些实施方式中,所述饱和磷脂包括氢化大豆磷脂(HSPC),二月桂酰基卵磷脂(DLPC)、二肉豆蔻酰基卵磷脂(DMPC)、二硬脂酰基磷脂酰胆碱(DSPC)、二棕榈酰基卵磷脂等(DPPC)等。
在一些实施方式中,所述表面活性剂为非离子型表面活性剂。在一些实施方式中,所述表面活性剂包括硬脂酸聚烃氧40酯、辛酸癸酸聚乙二醇甘油酯、月桂酰聚氧乙烯甘油酯、硬脂酰聚氧乙烯甘油酯、油酰聚氧乙烯甘油酯、维生素E聚乙二醇琥珀酸酯、泊洛沙姆,聚山梨酯,聚乙二醇-12-羟基硬脂酸酯、丙二醇单辛酸酯、二油酸甘油酯、单油酸甘油酯等。所述泊洛沙姆可选自例如泊洛沙姆407、泊洛沙姆188,所述聚山梨酯可选自例如聚山梨酯80。
根据本发明的实施方案,所述组合物还可以进一步包括一种或多种抗氧化剂。抗氧化剂可用于防止或减少本发明中所述缓释递药系统中磷脂的氧化。本发明提供的抗氧化剂包括但不限于维生素C(抗坏血酸),半胱氨酸盐酸盐,维生素E(生育酚),抗坏血酸棕榈酸酯,谷胱甘肽,α硫辛酸,硫代甘油。
根据本发明的实施方案,所述组合物还可以进一步包括其他药学领域常规的赋形剂,合适的药物赋形剂的实例在Excipients and their use in injectable products.PDA J Pharm Sci Technol.第51卷,1997年7-8月,第166-171页和Excipient Selection In Parenteral Formulation Development,Pharma Times,第45卷,第3期,2013年3月,第65-77页中描述,他们通过引用整体并入本发明中。
根据本发明的实施方案,所述甘油与缓释载体/药学上可接受的溶剂质量比例为1:0.1至1:99,例如1:0.1、1:0.5、1:1、1:5、1:10、1:15、1:20、1:25、1:30、1:35、1:40、1:45、1:50、1:55、1:60、1:65、1:70、1:75、1:80、1:85、1:90、1:95、1:99。在一些实施方案中,所述甘油与缓释载体/药学上可接受的溶剂质量比例为1:0.3至1:35。在一些实施方案中,所述甘油与缓释载体/药学上可接受的溶剂质量比例为1:1至1:19。
根据本发明的实施方案,所述缓释载体与药学上可接受的溶剂质量比例为1:0.1至1:10,例如1:0.1、1:0.2、1:0.3、1:0.4、1:0.5、1:0.6、1:0.7、1:0.8、1:0.9、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10。在一些实施方案中,所述缓释载体与药学上可接受的溶剂质量比例为1:0.3至1:8。在一些实施方案中,所述缓释载体与药学上可接受的溶剂质量比例为1:0.7至1:8。
根据本发明的实施方案,所述甘油占组合物总量的约1%至约95%(w/w),例如约1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、 18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%。在一些实施方案中,所述甘油比例约为2%至60%(w/w)。在一些实施方案中,所述甘油比例约为3%至30%(w/w)。
根据本发明的实施方案,所述缓释载体占组合物总量的3%至90%(w/w),例如3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、64%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%。在一些实施方案中,所述缓释载体占组合物总量20%至60%(w/w)。
根据本发明的实施方案,所述药学活性成分占组合物总量的0.1%至50.0%(w/w)。根据一些实施方案,药学活性成分占组合物总量的0.1%至15%(w/w),例如0.1%、0.5%、1.0%、1.5%、2.0%、2.5%、3.0%、3.5%、4.0%、4.5%、5.0%、5.5%、6.0%、6.5%、7.0%、7.5%、8.0%、8.5%、9.0%、9.5%、10.0%、10.5%、11.0%、11.5%、12.0%、12.5%、13.0%、13.5%、14.0%、14.5%、15.0%。根据一些实施方式,药学活性成分以3%(w/w)至10%(w/w)的量存在。根据一些实施方式,当药学活性成分选自两种以上时,每种药学活性成分可以占组合物总量的0.1%至15%(w/w),例如0.1%、0.5%、1.0%、1.5%、2.0%、2.5%、3.0%、3.5%、4.0%、4.5%、5.0%、5.5%、6.0%、6.5%、7.0%、7.5%、8.0%、8.5%、9.0%、9.5%、10.0%、10.5%、11.0%、11.5%、12.0%、12.5%、13.0%、13.5%、14.0%、14.5%、15.0%。
根据本发明的实施方案,所述药学上可接受的溶剂总量占组合物总量的5%至50%(w/w),在一些实施方案中,所述药学上可接受的溶剂总量可以占组合物总量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%。在一些实施方案中,所述药学上可接受的溶剂总量占组合物总量的10%-50%(w/w),在一些实施方 案中,所述药学上可接受的溶剂总量占组合物总量的5%至30%(w/w)。
根据本发明的实施方案,所述药学上可接受的溶剂为非水溶剂,所述非水溶剂选自乙醇、N-甲基吡咯烷酮、苯甲醇、正丙醇,异丙醇,正丁醇,异丁醇、叔丁醇中的一种或多种组合。
根据本发明的实施方案,所述释放调节剂占组合物总量的0%至40%(w/w),优选的,为0.1%至40%(w/w),在一些实施方式中,所述释放调节剂可以占组合物总量的0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%,在一些实施方式中,当所述释放调节剂选自饱和磷脂时,所述释放调节剂用量为1至30%(w/w);在一些实施方式中,当所述释放调节剂选自表面活性剂时,所述释放调节剂用量为0.1%至5%(w/w)。
根据本发明的实施方案,本发明提供的药物组合物为高粘度液体制剂。所述液体制剂粘度为在常温下(25℃左右)≥500mPa·s。在一些实施方式中,在25℃时,所述组合物的粘度500~100000mPa·s。在一些实施方式中,在25℃时所述组合物的粘度在500~50000mPa·s的范围内。在一些实施方式中,在25℃时,所述组合物的粘度在500~30000mPa·s的范围内。在一些实施方式中,在25℃时,所述组合物的粘度在500~15000mPa·s的范围内。在一些实施方式中,在25℃时,所述组合物的粘度在500~10000mPa·s的范围内。
在本发明的药物组合物中,所述药学上可接受的溶剂和释放调节剂可以作为粘度调节剂,使所述组合物适于注射。本发明提供了一种所述药物组合物的制备方法,包括如下步骤:
(a1)将缓释载体、药学上可接受的溶剂混合,在加热条件下搅拌或剪切至澄清均一的混合溶液;
(a2)将至少一种药学上的活性成分添加到所述混合溶液中,在加热条件下搅拌或剪切至形成均一混合物;
(a3)将甘油添加到所述混合溶液中,在加热条件下搅拌或剪切至形成均一溶液。
根据本发明的实施方案,所述步骤(a1)的混合还包括加入至少一种药学上可接受的释放调节剂,例如,所述步骤(a1)可以为将缓释载体、药学上可接受的溶剂、甘油和释放调节剂混合。
在一些实施方式中,所述方法包括:
1.在50~70℃下将缓释载体、药学上可接受的溶剂、药学上可接受的活性成分、甘油混合,直至得到澄清透明溶液。
2.将热溶液过0.22μm滤膜除菌。
3.将所述过滤后的混合溶液冷却至室温。
本发明提供一种包含所述药物组合物的缓释制剂,所述制剂作为储库制剂施用,一方面,所述制剂为可注射的。另一方面,所述制剂可以局部给药。
另一方面,所述制剂可皮下注射,周围神经注射,肌内注射,或灌注给药(向伤口直接施用、动脉灌注、直肠灌注)。
另一方面,所述制剂适合通过皮肤外用或粘膜给药。
本发明提供的制剂以单次剂量施用,所含药量可以达到止痛、神经阻滞的效果,可用于防止或减轻局部疼痛。
根据一些实施方式,本发明提供的制剂可在给药部位形成形态稳定的储库,可缓慢持续地释放药物,延长药物释放时间,提高治疗效果。
在一些实施方式中,所述制剂施用后可持续有效治疗至少24小时。在一些实施方式中,所述制剂施用后可持续有效治疗至少24至48小时。在一些实施方式中,所述制剂施用后可持续有效治疗至少48至72小时。在一些实施方式中,所述制剂施用后可持续有效治疗至少72小时。根据本发明的实施方案,所述制剂进一步包括填充了所述制剂的包材,所述包材选自以下一种或多种:西林瓶、预灌封注射器、卡式瓶。
术语与缩写
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
本申请说明书和权利要求书记载的数值范围,当该数值范围被定义或其仅可为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“0~10的整数”应当理解为记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数。
当该数值范围被定义为“数”或可以包括“整数”或“非整数”时·,应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如,“0~10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数,还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
术语“脂肪烃基”包括饱和或不饱和,直链或具有支链的链状烃基,所述脂肪烃基的类型可选自烷基(饱和脂肪烃基)、不饱和脂肪烃基(含有至少一个双键和/或三键,如烯基,炔基)等,所述脂肪烃基的碳原子数优选为1-40,进一步优先为1-30(例如为C1,C2,C3,C4,C5,C6,C6,C7,C8,C9,C10,C11,C12,C13,C14,C15,C16,C17,C18,C19,C20,C21,C22,C23,C24,C25,C26,C27,C28,C29,C30),具体可包括但不限于如下基团:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、1-己烯基、乙炔基,1-丙炔基,2-丙炔基,1-丁炔基,1-甲基-2-丙炔基,3-丁炔基,1-戊炔基和1-己炔基;其他基团中所含“脂肪烃基”部分同上述解释。
术语“烷基”为饱和脂肪烃基,符合上述脂肪烃基中的相关定义,例如所述烷基的碳原子数优选为1-40,进一步优选为1-30,或1-10(例如为C1,C2,C3,C4,C5,C6,C6,C7,C8,C9,C10,C11,C12,C13,C14,C15,C16,C17,C18,C19,C20,C21,C22,C23,C24,C25,C26,C27,C28,C29,C30,C31,C32,C33,C34,C35,C36,C37,C38,C30,C40,即甲基,乙基,丙基,如此类推)。且本领域技术人员可以理解,在一些具体的结构中,当烷基基团清楚地表示为连接基团时,则该烷基基团代表连接的亚烷基基团,因此,“亚烷基”亦可参照上述脂肪烃基中的相关定义,例如所述亚烷基的碳原子数可以为C1,C2,C3,C4,C5,C6,C6,C7,C8,C9,C10(即所述亚烷基可以为亚甲基,亚乙基,如此类推)。
术语“生物相容性”是指组合物成分与机体之间的相互作用。
术语“活性成分”是指用于治疗疾病的药物。因此,活性成分、药物可替换使用。此处使用的术语“活性成分”或“药物”包括但不限于局部或全身作用的药物活性物质,其可以通过局部给药或通过注射,如皮下、皮内、肌内及关节内注射进行施用。至少一种活性成分存在于本发明的缓释递药系统中。
本发明所用的术语“酰胺型”是指酰胺或卡因类局部麻醉剂,如布比卡因,左旋布比卡因,罗哌卡因,甲哌卡因,利多卡因等。酰胺类局麻药一般由亲脂部分和亲水部分组成,亲脂性部分,可为芳烃或芳杂环,而以苯环作用最强。苯环上引入给电子基团例如氨基等可使活性增强。亲水部分一般为仲胺、叔胺或吡咯烷、哌啶、吗啉等,以叔胺最为常见。pKa一般在7.5~7.9之间,生理条件下为离子型。
本发明使用的缩写词具有如下定义:SPC为大豆磷脂酰胆碱(大豆磷脂),EPC为蛋黄 磷脂酰胆碱(蛋黄磷脂),HSPC为氢化大豆磷脂酰胆碱,DLPC为二月桂酰磷脂酰胆碱,DMPC为二肉豆蔻酰基磷脂酰胆碱,DPPC为二棕榈酰基磷脂酰胆碱,DSPC为二硬脂酰基磷脂酰胆碱,DEPC为二芥酰基卵磷脂,DOPC为二油酸酰基磷脂酰胆碱(二油酸酰基卵磷脂),POPC为棕榈酰基油酰基卵磷脂,BA代表苯甲醇,NMP代表N-甲基吡咯烷酮,DMSO代表二甲基亚砜,BUP代表布比卡因,ROP代表罗哌卡因,MLX代表美洛昔康、CHO代表胆固醇、PRX代表吡罗昔康、LBUP代表左旋布比卡因、TAC代表曲安奈德、KTL代表酮咯酸、CLD代表可乐定,EtOH代表无水乙醇,BA代表苯甲醇,PEG200代表聚乙二醇200,PEG400代表聚乙二醇400,PEG600代表聚乙二醇600。
1)本发明提供了一种缓释制剂组合物,该组合物制剂在常温下为高粘度液体,在给药部位可发生相变。本发明所选用的辅料成分具有良好的生物相容性。本发明意外地发现,通过控制甘油、缓释载体、溶剂体系的比例,可以显著提高组合物制剂的粘度,使药物组合物更易于灌注给药,同时在体内滞留更长时间,改善药物的缓释效果。
2)本发明还进一步发现,在制剂体系中加入合适的释放调节剂,可以进一步改善体系粘度,以及改良活性成分的释放性能等;
3)本发明组合物刺激性小,具有良好的用药安全性及耐受性。
4)本发明提供的缓释制剂系统,能够使得活性药物成分实现良好的释放性能,降低突释的可能性。
5)本发明的组合物尤其适用于具有麻醉、镇痛活性的药物制剂开发,相对于其他缓释镇痛药体系具有更多的优势,例如对于镇痛活性成分的释放持续稳定,不仅可以注射给药,而且适用于稳定便捷的局部给药,患者耐受性好,副作用少。
图1-1至图1-4分别为组合物3058、3061、3062、3064的流变学结果。
图1-5为组合物3058、3061、3062、3064粘度-剪切速率曲线。
图2-1为组合物3075和3076的大鼠体内24h、48h、72h给药部位状态。
图3-1至图3-2分别为组合物3077和3078的罗哌卡因及布比卡因血药浓度-时间曲线、美洛昔康血药浓度-时间曲线。
图4-1至图4-2分别为组合物3079和3080的罗哌卡因血药浓度-时间曲线、美洛昔康血药浓度-时间曲线。
图5-1至图5-2分别为组合物3082的罗哌卡因血药浓度-时间曲线、美洛昔康血药浓度-时间曲线。
图6-1至图6-2分别为组合物3079、3080、3081的罗哌卡因血药浓度-时间曲线、美洛昔康血药浓度-时间曲线。
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实验动物来源:
实施例1
不同种类醇对组合物粘度的研究
按表1-1配制组合物,在加热状态下将SPC溶于BA中,分别加入甘油、丙二醇、PEG200、PEG400、PEG600,加热搅拌至形成均一溶液,室温放置,考察不同种类醇对体系粘度的影响。采用14号转子,50rpm转速检测组合物粘度,结果见表1-2。
表1-1组合物活性成分
表1-2组合物溶液状态及粘度
本发明出乎意料的发现,在磷脂溶液中加入甘油,可显著增加组合物的粘度,而丙二醇及不同分子量聚乙二醇对组合物粘度增加不明显。
实施例2
甘油/有机溶剂/缓释载体比例对组合物粘度的研究
按表2-1和2-2配制组合物,在加热状态下将SPC溶于不同种类及比例溶剂中,加入甘油,加热搅拌至形成均一溶液,室温放置后,考察组合物辅料比例对体系粘度的影响。
表2-1含有不同溶剂的组合物粘度检测结果
表2-2含有不同溶剂的组合物粘度检测结果
实施例3
组合物均一性研究
取表2-1和2-2中的不同粘度的组合物于PE管中,于9000rpm离心15min,观察离心后的溶液状态。结果见表3-1和表3-2。
表3-1不同溶剂(苯甲醇)的组合物均一性结果
表3-2不同溶剂(无水乙醇)的组合物均一性结果
由结果可知,不同粘度下的样品高速离心后状态无分层,呈均一状态,说明物理稳定性良好。
实施例4
流变学研究
按表4-1制备组合物,进行流变学研究。流变仪型号:TA DHR-1,样品量:1mL。测定模式:振荡模式:时间扫描,固定Strain 0.5%,频率1Hz;振荡模式:频率扫描,固定Strain 0.5%,频率扫描范围为0.1-100rad/s。
表4-1组合物成分
流变学中当储能模量(G’)大于损耗模量(G”)时,样品呈现凝胶特性,当储能模量(G’)小于损耗模量(G”)时,样品呈现溶液特性。根据图1-1至1-4所示,本发明中的组合物均呈现溶液特性。
图1-5为表4-1中组合物粘度-剪切速率曲线,可知组合物粘度随甘油用量的增加而增加,并且可以通过加入调节剂的方式调整组合物的粘度。此外,随着剪切速率的增加,组合物呈现剪切稀化的现象。
实施例5
含有不同甘油比例的药物组合物
按表5-1配制组合物,在加热状态下将SPC和活性成分溶于有机溶剂中,加入不同比例甘油,加热搅拌,均可形成均一溶液。
表5-1组合物成分
实施例6
药物从不同甘油比例药物组合物中的释放
将100mg来自实施例5的药物组合物加入透析袋中,置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例5组合物中的释放。在37℃下振摇,分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中甲磺酸罗哌卡因和美洛昔康的浓度。结果显示于下表6-1中。
表6-1甲磺酸罗哌卡因和美洛昔康从组合物中的释放
实施例7
含有不同释放调节剂比例的药物组合物
按表7-1配制组合物,在加热状态下将SPC、DPPC和活性成分溶于有机溶剂中,加入甘油,加热搅拌,均可形成均一溶液。
表7-1组合物成分
实施例8
药物从不同释放调节剂比例的药物组合物中的释放
将100mg来自实施例7的药物组合物加入透析袋中,置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例7组合物中的释放。在37℃下振摇,分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中甲磺酸罗哌卡因和美洛昔康的浓度。结果显示于下表8-1中。
表8-1甲磺酸罗哌卡因和美洛昔康从组合物中的释放
实施例9
含有不同活性成分的药物组合物
按表9-1配制组合物,在加热状态下将SPC和活性成分溶于有机溶剂中,加入甘油,加热搅拌,均可形成均一溶液。
表9-1组合物成分
编号 | 甘油 | SPC | BA | 盐酸ROP | 甲磺酸ROP | 盐酸BUP | MLX | PRX | NMP |
wt% | wt% | wt% | wt% | wt% | wt% | wt% | wt% | wt% | |
3066 | 8 | 67.6 | 16.9 | 6 | 0 | 0 | 0.15 | 0 | 1.35 |
3067 | 8 | 67 | 16.75 | 0 | 6.75 | 0 | 0.15 | 0 | 1.35 |
3068 | 8 | 67.6 | 16.9 | 0 | 0 | 6 | 0.15 | 0 | 1.35 |
3069 | 8 | 67.6 | 16.9 | 0 | 6 | 0 | 0 | 0.15 | 1.35 |
实施例10
含有不同活性成分的药物组合物
按表10-1配制组合物,在加热状态下将SPC和活性成分溶于有机溶剂中,加入甘油,加热搅拌,均可形成均一溶液。
表10-1组合物成分
实施例11
含有不同抗氧化剂的药物组合物
按表11-1配制组合物,在加热状态下将SPC和活性成分溶于有机溶剂中,加入甘油,加热搅拌,均可形成均一溶液。
表11-1含有不同抗氧化剂的组合物
实施例12
药物组合物的稳定性
按表12-1配制组合物,在加热状态下将SPC和活性成分溶于有机溶剂中,加入甘油,加热搅拌,均可形成均一溶液。将样品于60℃和40℃放置,考察有关物质的变化,结果见表12-2。
表12-1含有不同抗氧化剂的组合物
表12-2组合物稳定性
由表12-2结果可知,药物组合物在60℃及40℃条件下,有关物质无明显增长,化学稳定性良好。
实施例13
药物组合物的体内施用
按表13-1配制组合物,将大鼠右后腿外侧毛发剔除,每只皮下给予制剂0.2mL组合物(给药剂量为100mg/kg,按ROP算含药20mg),于24h、48h和72h脱臼处死打开给药部位,观察给药部位制剂形态。结果见图2-1。组合物3075和组合物3076在72h后仍可看到储库。
表13-1组合物成分
实施例14
药物组合物的体内施用
犬体内药代动力学研究如下。重量约10kg的比格犬实验前禁食12小时(取下喂食的食盒)以上,自由饮水,给药后4小时给食。各组按皮下注射进行给药,样品信息见表14-1。每只比格犬分两次接受注射,每次50mg,各组动物于给药前取0小时、于给药后0.5、1、2、3、6、8、12、24、36、48、60、72和96小时各采集血样约0.5mL至EDTA-2K+抗凝的采血管中,全血经8000rpm离心5min后收集血浆,随后通过LC-MS/MS检测血浆样品中的药物浓度。
表14-1组合物成分
组合物3077、3078的血药浓度-时间曲线见图3-1和图3-2。
实施例15
药物组合物的体内施用
犬体内药代动力学研究如下。重量约10kg的比格犬实验前禁食12小时(取下喂食的食盒)以上,自由饮水,给药后4小时给食。各组按皮下注射进行给药,样品信息见表15-1。每只比格犬分两次接受注射,每次50mg,各组动物于给药前取0小时、于给药后0.5、1、2、3、6、8、12、24、36、48、60、72和96小时各采集血样约0.5mL至EDTA-2K+抗凝的采血管中,全血经8000rpm离心5min后收集血浆,随后通过LC-MS/MS检测血浆样品中的药物浓度。
表15-1组合物成分
组合物3079、3080的血药浓度-时间曲线见图4-1和图4-2。
实施例16
药物组合物的体内施用
犬体内药代动力学研究如下。重量约10kg的比格犬实验前禁食12小时(取下喂食的食盒)以上,自由饮水,给药后4小时给食。各组按皮下注射进行给药,样品信息见表16-1。每只比格犬分两次接受注射,每次50mg,各组动物于给药前取0小时、于给药后0.5、1、2、3、6、8、12、24、36、48、60、72和96小时各采集血样约0.5mL至EDTA-2K+抗凝的采血管中,全血经8000rpm离心5min后收集血浆,随后通过LC-MS/MS检测血浆样品中的药物浓度。
表16-1组合物成分
组合物3082的血药浓度-时间曲线见图5-1和图5-2。
实施例17
药物组合物的体内施用
大鼠体内药代动力学研究如下。重量约180~200g动物随机分组后,采用尾部编号进行唯一标识。于大鼠颈背部皮下注射给药,给药体积固定为0.2mL/只动物。给药前0h, 给药后大约0.5、1、2、3、6、8、10、24、34、48、72和96h各采集血样至K2EDTA抗凝管中,于冰上暂存至离心。采血后60min内需离心出血浆(2-8℃条件下,以8000rpm离心5min),离心后将血浆转移至96孔板或离心管中,湿冰冰盒转运,≤-15℃保存至LC-MS/MS检测。
表17-1组合物成分
组合物3079、3080、3081的血药浓度-时间曲线见图6-1和图6-2。
以上,对本发明示例性的实施方式进行了说明。但是,本发明的保护范围不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
- 根据权利要求1的药物组合物,其特征在于,所述式I中,每个R 1、R 2相同或不同,彼此独立地选自C 10-30饱和或不饱和脂肪烃基,例如C 13-21烷基;每个R 3、R 4、R 5相同或不同,彼此独立地选自H或C 1-10烷基,例如彼此独立地选自H,甲基,乙基;所述L选自C 1-10亚烷基,优选的,L选自C 1-6亚烷基,例如为亚甲基,亚乙基;所述式II所示化合物中,R选自C 1-10烷基,例如C 8-10烷基。
- 根据权利要求1或2的药物组合物,其特征在于,所述c组分缓释载体选自HSPC(氢化大豆磷脂)、DMPC(二肉豆蔻酰基磷脂酰胆碱)、DPPC(二棕榈酰基磷脂酰胆碱)、DSPC(二硬脂酰基磷脂酰胆碱)、DLPC(二月桂酰磷脂酰胆碱)、SPC大豆磷脂酰胆碱(大豆磷脂),EPC(蛋黄磷脂),油菜籽磷脂,向日葵磷脂,DEPC(二芥酰基卵磷脂),DOPC(二油酸酰基卵磷脂),POPC(棕榈酰基油酰基卵磷脂)、鞘磷脂、二硬脂酰磷脂酸(DSPA)、二油酰磷脂酰乙醇胺(DOPE)、二棕榈酰磷脂酸(DPPA)、肉豆蔻酰溶血磷脂(M-lysoPC)、棕榈酰溶血磷脂(P-lysoPC)、1-硬脂酰-溶血磷脂酰胆碱(S-lysoPC)、二棕榈酰磷脂酰乙醇胺(DPPE)、二硬脂酰磷脂酰乙醇胺(DSPE)、二油酰磷脂酰甘油(DOPG)、二肉豆蔻酰磷脂酰乙醇胺(DMPE)、二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰甘油(DPPG)、1-棕榈酰-2-油酰磷脂酰甘油(POPG)、二硬脂酰酰磷脂酰甘油(DSPG)、二棕榈酰磷酯酰丝氨酸(DPPS)、磷脂酰肌醇(PI)、胆固醇(CHO)中的一种或多种。
- 根据权利要求1-3任一项所述的药物组合物,其特征在于,所述药物组合物还包含药学上可接受的释放调节剂;和/或所述药物组合物可以进一步包含一种或多种抗氧化剂;
- 根据权利要求1-4任一项所述的药物组合物,其特征在于,所述溶剂为非水溶剂。
- 根据权利要求4所述的药物组合物,其特征在于,所述药学上可接受的释放调节剂选自甾醇、饱和磷脂和其他表面活性剂中的一种或几种;优选的,所述甾醇为胆固醇;所述饱和磷脂选自氢化大豆磷脂(HSPC),二月桂酰基卵磷脂(DLPC)、二肉豆蔻酰基卵磷脂(DMPC)、二硬脂酰基磷脂酰胆碱(DSPC)、二棕榈酰基卵磷脂等(DPPC);所述表面活性剂选自硬脂酸聚烃氧40酯、辛酸癸酸聚乙二醇甘油酯、月桂酰聚氧乙烯甘油酯、硬脂酰聚氧乙烯甘油酯、油酰聚氧乙烯甘油酯、维生素E聚乙二醇琥珀酸酯、泊洛沙姆,聚山梨酯,聚乙二醇-12-羟基硬脂酸酯、丙二醇单辛酸酯、二油酸甘油酯、单油酸甘油酯;所述抗氧化剂选自维生素C(抗坏血酸),半胱氨酸盐酸盐,维生素E(生育酚),抗坏血酸棕榈酸酯,谷胱甘肽,α硫辛酸,硫代甘油。
- 根据权利要求1-6任一项所述的药物组合物,其特征在于,所述甘油与缓释载体/药学上可接受的溶剂质量比例为1:0.1至1:99;所述缓释载体与药学上可接受的溶剂质量比例为1:0.1至1:10;所述甘油占组合物总量的约1%至约95%(w/w);所述缓释载体占组合物总量 的3%至90%(w/w);所述药学活性成分占组合物总量的0.1%至50.0%(w/w);所述溶剂总量占组合物总量的5%至50%(w/w)。
- 根据权利要求1-7任一项所述的药物组合物的制备方法,其特征在于,包括如下步骤:(a1)将缓释载体、药学上可接受的溶剂混合,在加热条件下搅拌或剪切至澄清均一的混合溶液;(a2)将至少一种药学上的活性成分添加到所述混合溶液中,在加热条件下搅拌或剪切至形成均一混合物;(a3)将甘油添加到所述混合溶液中,在加热条件下搅拌或剪切至形成均一溶液;优选的,所述步骤(a1)的混合还包括加入至少一种药学上可接受的释放调节剂,例如,所述步骤(a1)可以为将缓释载体、药学上可接受的溶剂、甘油和释放调节剂混合。
- 一种包含权利要求1-7任一项所述的药物组合物的缓释制剂,其特征在于,所述制剂作为储库制剂施用,优选的,所述制剂为可注射的或所述制剂可以局部给药;更优选的,所述制剂可皮下注射,周围神经注射,肌内注射,灌注给药(向伤口直接施用、动脉灌注、直肠灌注),还可以通过皮肤外用或粘膜给药。
- 根据权利要求9所述的制剂,其特征在于,所述制剂进一步包括填充了所述制剂的包材,所述包材选自以下一种或多种:西林瓶、预灌封注射器、卡式瓶。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102688482A (zh) * | 2011-03-22 | 2012-09-26 | 扬州永济医药新技术有限公司 | 注射用糖尿病多肽药物的缓释制剂及其生产方法 |
CN113018248A (zh) * | 2019-12-23 | 2021-06-25 | 南京清普生物科技有限公司 | 一种缓释递药系统 |
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Non-Patent Citations (1)
Title |
---|
"Pharmaceutics", 30 November 2013, LIAONING UNIVERSITY PRESS, Shenyang, CN, ISBN: 7-5610-7514-6, article ZHANG CHAOYUN, QIN YADONG: "Glycerol", pages: 209 - 210, XP009544039 * |
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