CN105535933A - Leuprorelin medicinal composition injection type hypodermic implantation agent - Google Patents

Leuprorelin medicinal composition injection type hypodermic implantation agent Download PDF

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Publication number
CN105535933A
CN105535933A CN201610006182.2A CN201610006182A CN105535933A CN 105535933 A CN105535933 A CN 105535933A CN 201610006182 A CN201610006182 A CN 201610006182A CN 105535933 A CN105535933 A CN 105535933A
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China
Prior art keywords
leuprorelin
injection
pharmaceutical composition
type subcutaneous
plga
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CN201610006182.2A
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Chinese (zh)
Inventor
支钦
李新宇
曹演威
吴丽芬
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SHENZHEN CITY JIANYUAN PHARMACEUTICAL TECHNOLOGY Co Ltd
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SHENZHEN CITY JIANYUAN PHARMACEUTICAL TECHNOLOGY Co Ltd
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Priority to CN201610006182.2A priority Critical patent/CN105535933A/en
Publication of CN105535933A publication Critical patent/CN105535933A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A61K36/8994—Coix (Job's tears)
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Abstract

The invention relates to a leuprorelin medicinal composition injection type hypodermic implantation agent. The leuprorelin medicinal composition injection type hypodermic implantation agent is characterized in that medicine active ingredients are leuprorelin, plant extract and hormone or resistance hormone active medicine cooperating with leuprorelin; in addition, an implantation agent is injected subcutaneously in a liquid mode, under the effect of the body temperature, the solution is changed into gel, and then the effect of controlled release of multiple sex hormone dependent diseases is exerted. Through the implantation agent prepared through the method, on the one hand, the use amount is reduced while the medicine effect is kept, toxic and side effects are reduced, and medicine use safety and compliance are improved; on the other hand, the medicine is slowly released in the body, and the long-acting effect of treating the sex hormone dependent diseases is achieved.

Description

Leuprorelin pharmaceutical composition injection-type subcutaneous implant
Technical field
The present invention relates to field of medicine preparing technology, be specifically related to a kind of leuprorelin pharmaceutical composition injection-type subcutaneous implant and preparation method thereof.
Background technology
Leuprorelin (Leuprorelin/Leuprolideacetate, LA), as a kind of antagonists of gonadotropin-releasing hormone, is polypeptide drug, and it can secrete promoting sexual gland hormone by Stimulation of Pituitary Gland, brings out genitals and generates steroid.Long-term a large amount of use can suppress the generation of pituitary promoting sexual gland hormone and testis or ovary steroid class, can treat or alleviate diversity hormone-dependent diseases as carcinoma of prostate, endometriosis, hysteromyoma, sexual precosity etc.
There is the drug safety hidden danger of drug accumulation and more side effect, as irritated sample symptom, bone pain, gynecomastia, cardiovascular disease, hectic fever, hepato-biliary function decline, bone density reduction etc. in the long-term a large amount of medication of LA.Research finds, some plant extracts, hormones or resistance hormonal activity medicine be determined curative effect in the diversity hormone-dependent diseases treatments such as carcinoma of prostate, endometriosis, hysteromyoma, LA and these are had synergistic medicine and carries out coupling, respective dosage is reduced while maintaining treatment effect, reduce toxic and side effects, improve drug safety and toleration.
Different from LA, the mechanism of action of ginsenoside rh2, lycopene, Semen Coicis oil or Oleum Fructus Bruceae treatment carcinoma of prostate is inducing apoptosis of tumour cell, blocks tumor cells mitosis thus kill and wound cancerous cell, reduce the Hormone refractory of prostate gland cancer cell during both couplings, strengthen therapeutic effect.Other effects of plant extract also can reduce the side effect of LA, and ginsenoside has antiallergic, enhancing human body immunity, activity of resisting tumor metastasis effect; Lycopene has hepatoprotective effect, also affects the function of osteoblast and osteoclast by its anti-oxidation function, thus stops and slow down the generation of osteoporosis.LA belongs to the coupling of LHRH agonist and androgen antagonist medicine with flutamide, bicalutamide coupling, is full hormone ablative best results, the most acceptant endocrine therapy means of patient in carcinoma of prostate.
In endometriosis treatment in uterus, for reducing the side effect of LA, itself and estrogen, progestogen are carried out coupling by " adding back therapy ", and body inner estrogen level reaches " window dosage ", alleviate estrogen level to greatest extent and reduce the negative effect brought; Use estrogen and proligestone to coordinate LA, extend the treatment time of LA, and can the side effect such as bone loss be alleviated; Li Fumin can alleviate the perimenopausal symptom that LA treatment endometriosis causes; Desogestrel ethinylestradiol can reduce the class menopause syndrome adverse reaction rate such as hectic fever, perspiration, vaginal dryness that LA prolonged application causes; Silymarin effectively can improve the hepatic and renal function reduction phenomenon because long-term taking LA causes.
LA and levonorgestrel, letrozole therapeutic alliance hysteromyoma, can reduce incidence rate that is tired, the untoward reaction such as osteodynia, unregular vaginal bleeding, agitation, distending pain of the breast.
In sum, leuprorelin and ginsenoside rh2, lycopene, Semen Coicis oil, Oleum Fructus Bruceae, flutamide, bicalutamide, estrogen, progestogen, proligestone, Li Fumin, desogestrel ethinylestradiol, silymarin, levonorgestrel or letrozole are carried out coupling, clinical efficacy is good, but be multiple dosage form and separate multiple dosing separately, add drug cost, reduce body compliance, bring inconvenience to patient.For this reason, leuprorelin and its coupling medicine are prepared into injection-type subcutaneous implant by the present invention, to improve the bioavailability of medicine, reduce the toxicity of medicine.
Need do a minimal incision * underwent operative in local when common implant is implanted to implant, but operation can cause larger damage to body, the compliance of patient is poor.
If according to method provided by the invention, leuprorelin pharmaceutical composition is prepared into injection-type subcutaneous implant, and preparation method is simple, easy to operate, only need subcutaneous injection during administration, in vivo slow releasing, realize the long lasting benefits for the treatment of diversity hormone-dependent diseases.Do not need to perform the operation, can not infection risk be caused, the serious psychotic symptoms that long-term intrathecal drug delivery can be avoided to occur and nerve damage.
Summary of the invention
The present invention relates to a kind of pharmaceutical composition injection-type subcutaneous implant containing leuprorelin, the implant prepared by method of the present invention, on the one hand, while maintenance drug effect, reduce consumption, reduce toxic and side effects, improve drug safety and compliance; Medicine slow releasing in vivo on the other hand, realizes the long lasting benefits for the treatment of diversity hormone-dependent diseases.
Particularly; this pharmaceutical composition injection-type subcutaneous implant has synergistic plant extract, hormones or resistance hormonal activity medicine for active component with leuprorelin with leuprorelin; two kinds of medicines be wrapping to by form biodegradable of certain proportion and have in the macromolecular material organic solution of biocompatibility; spraying dry or lyophilization; be prepared into slow-releasing microcapsule; then join in the hydrogel that temperature-responsive polymer polymer makes and mix; add freeze drying protectant; lyophilization, for implantation.
With leuprorelin, there is synergistic plant extract, hormones or resistance hormonal activity medicine, be selected from the one in ginsenoside rh2, lycopene, Semen Coicis oil, Oleum Fructus Bruceae, flutamide, bicalutamide, estrogen, progestogen, proligestone, Li Fumin, desogestrel ethinylestradiol, silymarin, levonorgestrel, letrozole.
Leuprorelin is 1:1 ~ 8:1 with the ratio with synergistic plant extract, hormones or resistance hormonal activity medicine.
Leuprorelin pharmaceutical composition, biodegradable and the mass ratio with the macromolecular material of biocompatibility, temperature-responsive polymer polymer and freeze drying protectant is 4 ~ 30:35 ~ 300:200 ~ 3900:5 ~ 500.
In slow-releasing microcapsule, polymer carrier is selected from polylactide (PLA), PGA (PGA), polylactide-Acetic acid, hydroxy-, bimol. cyclic ester (PLGA), polycaprolactone (PCL), poly hydroxybutyric acid (PHB), valerate (PHBV), poly-capric acid (PDA) one wherein or its mixture, one in preferred polylactide (PLA), PGA (PGA), polylactide-Acetic acid, hydroxy-, bimol. cyclic ester (PLGA), polycaprolactone (PCL) or its mixture, more preferably PLGA, polymer molecular weight is 20000 ~ 50000 dalton.
Organic solvent in slow-releasing microcapsule in macromolecular material organic solution is selected from dichloromethane, ethyl acetate, acetone or oxolane, preferred dichloromethane.
PLGA containing 3% ~ 20% in PLGA organic solution in injection-type subcutaneous implant.
Temperature-responsive polymer polymer is selected from poloxamer188, PLA-PEG-PLA or PLGA-PEG-PLGA, and polymer molecular weight is 3000-5000 dalton.
Freeze drying protectant is selected from polysaccharide or multi-sugar alcohol, is preferably trehalose, mannitol or sorbitol.
In addition, present invention also offers the preparation method of this injection-type implant, its technique is as follows:
The first step, first by biodegradable and the macromolecular material with biocompatibility joins in organic solvent, be mixed with macromolecular material organic solution, leuprorelin pharmaceutical composition be scattered in this organic solution, spraying dry or lyophilization, obtained microcapsule;
Second step, under cryogenic, with water by temperature-responsive polymer dissolution of polymer, makes fully to be swelling to solution state, makes hydrogel solution;
3rd step, join in hydrogel solution by leuprorelin pharmaceutical composition microcapsule powder, mix homogeneously, adds freeze drying protectant, carries out lyophilization, makes leuprorelin pharmaceutical composition injection-type subcutaneous implant.
In the first step, the spray drying condition of microcapsule is preferably 25 DEG C, 0.3 ~ 4MPa.
Cryogenic conditions in second step is preferably 5 ~ 25 DEG C.
Before use, with the sterilized water for injection of 0.2 ~ 2mL, leuprorelin pharmaceutical composition injection-type subcutaneous implant is dissolved, subcutis of reinjecting.
Accompanying drawing explanation
Fig. 1 is the tablets in vitro result figure of leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Fig. 2 is the in vivo release result figure of leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Detailed description of the invention
Below by way of specific embodiment, the present invention will be described in more detail, but scope of the present invention is not limited to following examples.
Embodiment 1:
Get 0.7gPLGA (20000 dalton), join in q. s. methylene chloride, stirring makes it to dissolve completely, make the PLGA organic solution of 2%, 0.08g pharmaceutical composition (leuprorelin: ginsenoside rh2=1:1) is added in this organic solution, 25 DEG C, 0.3MPa spraying dry, obtained microcapsule; Under 5 DEG C of cryogenic conditions, with water, poloxamer188 (30000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add trehalose, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 2:
Get 1gPLA (30000 dalton), join in appropriate ethyl acetate, stirring makes it to dissolve completely, make the PLGA organic solution of 5%, 0.1g pharmaceutical composition (leuprorelin: lycopene=4:1) is added in this organic solution, 25 DEG C, 0.3MPa spraying dry, obtained microcapsule; Under 5 DEG C of cryogenic conditions, with water, PLA-PEG-PLA (30000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add sorbitol, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 3:
Get 4gPLGA (30000 dalton), join in q. s. methylene chloride, stirring makes it to dissolve completely, make the PLGA organic solution of 10%, 0.1g pharmaceutical composition (leuprorelin: Semen Coicis oil=2:1) is added in this organic solution, 25 DEG C, 0.3MPa spraying dry, obtained microcapsule; Under 10 DEG C of cryogenic conditions, with water, poloxamer188 (50000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add trehalose, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 4:
Get 2gPGA (40000 dalton), join in proper amount of acetone, stir and make it to dissolve completely, make the PLGA organic solution of 6%, 0.5g pharmaceutical composition (leuprorelin: Oleum Fructus Bruceae=1:1) is added in this organic solution, lyophilization, obtained microcapsule; Under 10 DEG C of cryogenic conditions, with water, PLA-PEG-PLA (40000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add mannitol, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 5:
Get 3gPCL (50000 dalton), join in appropriate oxolane, stir and make it to dissolve completely, make the PLGA organic solution of 15%, 0.2g pharmaceutical composition (leuprorelin: flutamide=7:1) is added in this organic solution, lyophilization, obtained microcapsule; Under 15 DEG C of cryogenic conditions, with water, PLGA-PEG-PLGA (40000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add sorbitol, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 6:
Get 2.5gPHB (30000 dalton), join in q. s. methylene chloride, stirring makes it to dissolve completely, make the PLGA organic solution of 10%, 0.2g pharmaceutical composition (leuprorelin: bicalutamide=7:1) is added in this organic solution, 25 DEG C, 2MPa spraying dry, obtained microcapsule; Under 18 DEG C of cryogenic conditions, with water, poloxamer188 (30000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add trehalose, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 7:
Get 0.9gPHBV (20000 dalton), join in q. s. methylene chloride, stirring makes it to dissolve completely, make the PLGA organic solution of 16%, 0.6g pharmaceutical composition (leuprorelin: estrogen=5:1) is added in this organic solution, 25 DEG C, 2MPa spraying dry, obtained microcapsule; Under 20 DEG C of cryogenic conditions, with water, poloxamer188 (50000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add mannitol, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 8:
Get 3gPDA (30000 dalton), join in q. s. methylene chloride, stir and make it to dissolve completely, make the PLGA organic solution of 20%, 0.6g pharmaceutical composition (leuprorelin: progestogen=8:1) is added in this organic solution, lyophilization, obtained microcapsule; Under 10 DEG C of cryogenic conditions, with water, poloxamer188 (40000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add trehalose, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 9:
Get 2.5gPLGA (20000 dalton), join in q. s. methylene chloride, stirring makes it to dissolve completely, make the PLGA organic solution of 20%, 0.2g pharmaceutical composition (leuprorelin: proligestone=5:1) is added in this organic solution, 25 DEG C, 0.5MPa spraying dry, obtained microcapsule; Under 15 DEG C of cryogenic conditions, with water, poloxamer188 (30000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add mannitol, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 10:
Get PLGA+PLA (20000 dalton) 4g, join in q. s. methylene chloride, stir and make it to dissolve completely, make the PLGA organic solution of 7%, 0.3g pharmaceutical composition (leuprorelin: Li Fumin=5:1) is added in this organic solution, lyophilization, obtained microcapsule; Under 20 DEG C of cryogenic conditions, with water, PLGA-PEG-PLGA (40000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add sorbitol, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 11:
Get 3.5gPLGA (20000 dalton), join in q. s. methylene chloride, stirring makes it to dissolve completely, make the PLGA organic solution of 5%, 0.4g pharmaceutical composition (leuprorelin: desogestrel ethinylestradiol=8:1) is added in this organic solution, lyophilization, obtained microcapsule; Under 25 DEG C of cryogenic conditions, with water, PLGA-PEG-PLGA (50000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add trehalose, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 12:
Get 5.1gPLGA (20000 dalton), join in q. s. methylene chloride, stirring makes it to dissolve completely, make the PLGA organic solution of 4.6%, 0.2g pharmaceutical composition (leuprorelin: silymarin=8:1) is added in this organic solution, 25 DEG C, 1MPa spraying dry, obtained microcapsule; Under 15 DEG C of cryogenic conditions, with water, poloxamer188 (30000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add trehalose, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 13:
Get 2gPLGA (40000 dalton), join in q. s. methylene chloride, stirring makes it to dissolve completely, make the PLGA organic solution of 10%, 0.2g pharmaceutical composition (leuprorelin: levonorgestrel=3:1) is added in this organic solution, 25 DEG C, 0.5MPa spraying dry, obtained microcapsule; Under 20 DEG C of cryogenic conditions, with water, PLA-PEG-PLA (3000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add mannitol, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
Embodiment 14:
Get 3.5gPLGA (50000 dalton), join in q. s. methylene chloride, stir and make it to dissolve completely, make the PLGA organic solution of 12%, 0.6g pharmaceutical composition (leuprorelin: letrozole=8:1) is added in this organic solution, lyophilization, obtained microcapsule; Under 20 DEG C of cryogenic conditions, with water, PLGA-PEG-PLGA (3000 dalton) is dissolved, make fully to be swelling to solution state, make hydrogel solution; Microcapsule powder is joined in hydrogel solution, mix homogeneously, add sorbitol, lyophilization, obtained leuprorelin pharmaceutical composition injection-type subcutaneous implant.
The release in vitro of embodiment 15 leuprorelin pharmaceutical composition injection-type subcutaneous implant
Sample is by method preparation in embodiment 1,5,7,13.
The mensuration of vitro release is carried out with reference to version Chinese Pharmacopoeia method in 2010,1000mL normal saline is as release medium, temperature (37 ± 0.5) DEG C, rotating speed is 50r/min, with 1mL sterilized water for injection, leuprorelin pharmaceutical composition injection-type subcutaneous implant is dissolved, slowly be expelled in bag filter, preparation is immersed in release medium completely.The design sample time is 0,1 hour, 1,3,5,10,15,20,25,30 day, every sub-sampling 5mL, supplements same volume, synthermal normal saline simultaneously.HPLC measures leuprorelin, calculates accumulative releasing degree.The tablets in vitro of leuprorelin pharmaceutical composition injection-type subcutaneous implant the results are shown in Table 1:
The tablets in vitro result (%) of table 1. leuprorelin pharmaceutical composition injection-type subcutaneous implant
Embodiment 16: release in the body of leuprorelin pharmaceutical composition injection-type subcutaneous implant
Sample is by method preparation in embodiment 1,5,7,13.
SD rat (240 ~ 260g) 42, is divided into 6 groups, and often organize 6, weigh, after etherization, two groups of subcutaneous injection leuprorelin acetate microsphere suspension, as positive control; One group of subcutaneous injection normal saline, as blank group; 4 groups of difference subcutaneous injection leuprorelin pharmaceutical composition injection-type subcutaneous implants, every rat dosage is 0.4g/kg.Respectively at 0,1 after administration hour, 1,3,5,10,15,20,25,30 day, tail venous blood sampling 0.5mL measures wherein leuprorelin content.After blood sample sampling terminates, put to death rat, take out residue implant, after lyophilizing, its Chinese medicine of methanol extraction, HPLC measures leuprorelin content, calculates the remaining dose of implant.
Result: result: leuprorelin pharmaceutical composition injection-type subcutaneous implant discharges stable in vivo, when 25 days, when in body, residual drug is 15.03%, 30 days, residual drug is zero substantially.After implantation, in 1 ~ 2 day, in animal body, testosterone concentration rises rapidly and reaches peak value, drops to lower than normal value, be maintained until 28 ~ 30 days always after 2 days.
Embodiment 17: the external gelling test of leuprorelin pharmaceutical composition injection-type subcutaneous implant
Leuprorelin pharmaceutical composition injection-type subcutaneous implant in Example 1,5,7,13 is in test tube, mixing is dissolved respectively with the sterilized water for injection of 0.5mL, this mixed solution is heated to 37 DEG C, per half a minute takes out and observes gel formation situation, is inverted 30s inner gel does not flow for the mark of gel formation with test tube.
Result: leuprorelin pharmaceutical composition injection-type subcutaneous implant of the present invention forms gel at 37 DEG C, in 1 ~ 5 minute.
Embodiment 18: the tumor-inhibiting action of leuprorelin pharmaceutical composition injection-type subcutaneous implant
Leuprorelin pharmaceutical composition injection-type subcutaneous implant sample is by the method preparation in embodiment 1 ~ 6.
BALB/C strain nude mice (17 ~ 20g) 48, inoculation human prostate tumor (PC-3M) is divided into 8 groups afterwards at random, often organizes 6, weighs, one group of subcutaneous injection leuprorelin acetate microsphere suspension (6), as positive control; One group of subcutaneous injection normal saline (6), as blank group; 6 groups of difference subcutaneous injection leuprorelins pharmaceutical composition injection-type subcutaneous implant (often organizing 6), every rat dosage is 0.75mg/kg.Next day plays administration, and inoculate latter 22 days de-necks and put to death animal, solution takes tumor block, weighs.Result of the test is in table 2.
The tumor-inhibiting action (%) of table 2. leuprorelin pharmaceutical composition injection-type subcutaneous implant
* P<0.01 is compared with blank group
Upper table shows: leuprorelin acetate tumour inhibiting rate is 39.12%, the leuprorelin pharmaceutical composition injection-type subcutaneous implant tumour inhibiting rate that embodiment 1 ~ 6 obtains is 66.87%, 48.14%, 57.17%, 64.16%, 52.81%, 59.72%, can suppress human prostate (PC-3M) preferably.Result of the test shows: have synergistic ginsenoside rh2, lycopene, Semen Coicis oil, Oleum Fructus Bruceae, flutamide or bicalutamide with leuprorelin and merge effect of leuprolide carcinoma of prostate and have potentiation.
Embodiment 19: the endometriosis inhibitory action of leuprorelin pharmaceutical composition injection-type subcutaneous implant
Leuprorelin pharmaceutical composition injection-type subcutaneous implant sample is by the method preparation in embodiment 7 ~ 12.
SD female rats (200-250g) 48, sets up EMT model with reference to Jones method.After 3 weeks, open abdominal cavity, stomach wall plantation place have Ectopic Endometrium grow and have weak yellow liquid content person then model be successfully established.Measure, record the volume (V of Ectopic Endometrium 0).
After modeling terminates, be divided into blank group (6), leuprorelin acetate microsphere group (6), leuprorelin pharmaceutical composition injection-type subcutaneous implant group (6 groups, often group 6) at random.Blank group injecting normal saline, 0.1mL/kg, treatment group subcutaneous administrations, 100 μ g/kg.Medication, after 4 weeks, opens abdominal cavity, observes medicine to the effect of Ectopic Endometrium, and the volume (V of surveying record Ectopic Endometrium 1).After calculating medication, medicine is to the suppression ratio I=(1-V of Ectopic Endometrium 1/ V 0) × 100%, the results are shown in Table 3.
Table 3. leuprorelin pharmaceutical composition injection-type subcutaneous implant group is on the impact of rat uterus Ectopic Endometrium
* P<0.05 is compared with blank group
Upper table shows: blank group Ectopic Endometrium slightly increases, and all the other group rat endometrium are all obviously suppressed.Leuprorelin acetate microsphere is 75.8% to the suppression ratio of Ectopic Endometrium, and the suppression ratio of leuprorelin pharmaceutical composition injection-type subcutaneous implant to Ectopic Endometrium that embodiment 7 ~ 12 obtains is respectively 86.2%, 84.1%, 82.7%, 80.7,79.2%, 80.9%.Result of the test shows: have synergistic estrogen, progestogen, proligestone, Li Fumin, desogestrel ethinylestradiol or silymarin with leuprorelin and merge effect of leuprolide endometriosis and have potentiation.
Embodiment 20: the hysteromyoma inhibitory action of leuprorelin pharmaceutical composition injection-type subcutaneous implant
Leuprorelin pharmaceutical composition injection-type subcutaneous implant sample is by the method preparation in embodiment 13 ~ 14.
Female unpregnancy SD rat (200-250g) 30, is divided into hysteromyoma modeling group (24) and blank group (6) two groups at random.Rat Experimental hysteromyoma model is set up with Estrogen and progestin Load Method.Compared with blank group, the uterine smooth muscle hypertrophy of model group rats is obvious, and there were significant differences for both (P < 0.001), and program modeling success is described.
After modeling terminates, be divided into model group (6), leuprorelin acetate microsphere group (6), leuprorelin pharmaceutical composition injection-type subcutaneous implant (2 groups, often group 6) at random.Model group, matched group injecting normal saline, 2mL/100g, treatment group subcutaneous administrations, 0.75mg/kg.Inoculate latter 22 days cervical dislocation put to death each group of rat and get uterus, 10% phosphoric acid buffer formalin is fixed, specimens paraffin embedding slices, and HE dyes, basis of microscopic observation uterine histology metamorphosis.
Comprehensive positive cell proportion and staining power carry out sxemiquantitative judgement.Staining power is by following standard rating: feminine gender is 0 point; Weak but be obviously better than negative control person is 1 point though dye; The medium person of staining power is 2 points; Dyeing powerhouse is 3 points.The positive cell institute accounting evaluation criteria of dyeing is: positive cell number <5% is negative (0 point); 6%-15% is the weak positive (1 point); 16%-30% person is positive (2 points); >31% person is strong positive (3 points).Comprehensive grading: two kinds of scorings are added, and result is divided into 4 grades, 0-1 is divided into (-); 2 are divided into (+); 3-4 is divided into (++); 5-6 is divided into (+++).Section index situation of change is evaluated by the grade of comprehensive grading.
The statistical analysis application SPSS16.0 statistical software of data adds up, measurement data with represent, and check with t; Enumeration data rank test, P<0.05 is that difference has statistical significance.
Each group of rat histopathology appraisal result is in table 4.Blank group, hysteromyoma model group, both pathological proliferation in uterus have pole significant difference (P<0.001), show modeling success.Compared with model group, the pathological proliferation of leuprorelin acetate microsphere group to hysteromyoma rat model has some improvement (P<0.05), the leuprorelin pharmaceutical composition injection-type subcutaneous implant that embodiment 13 ~ 14 obtains significantly can improve the pathological proliferation (P<0.01) of hysteromyoma model rat, and leuprorelin pharmaceutical composition injection-type subcutaneous implant therapeutical effect is better than leuprorelin acetate microsphere.Result of the test shows: have synergistic levonorgestrel or letrozole with leuprorelin and merge effect of leuprolide hysteromyoma and have potentiation.
Table 4. is group rat histopathology appraisal result respectively

Claims (17)

1. the pharmaceutical composition injection-type subcutaneous implant containing leuprorelin, it is characterized in that described active constituents of medicine is leuprorelin, and with leuprorelin, there is synergistic plant extract, hormones or resistance hormonal activity medicine, this active constituents of medicine be wrapping to by form biodegradable of certain proportion and have in the macromolecular material organic solution of biocompatibility, spraying dry or lyophilization, be prepared into slow-releasing microcapsule, then join in the hydrogel that temperature-responsive polymer polymer makes and mix, add freeze drying protectant, lyophilization, for implantation.
2. injection-type subcutaneous implant according to claim 1, with leuprorelin, there is synergistic plant extract, hormones or resistance hormonal activity medicine, be selected from the one in ginsenoside rh2, lycopene, Semen Coicis oil, Oleum Fructus Bruceae, flutamide, bicalutamide, estrogen, progestogen, proligestone, Li Fumin, desogestrel ethinylestradiol, silymarin, levonorgestrel, letrozole.
3. injection-type subcutaneous implant according to claim 1, leuprorelin is 1:1 ~ 8:1 with the ratio with synergistic plant extract, hormones or resistance hormonal activity medicine.
4. injection-type subcutaneous implant according to claim 1, pharmaceutical composition, biodegradable and the mass ratio with the macromolecular material of biocompatibility, temperature-responsive polymer polymer and freeze drying protectant is 4 ~ 30:35 ~ 300:200 ~ 3900:5 ~ 500.
5. injection-type subcutaneous implant according to claim 1, the macromolecular material used time prepared by microcapsule is selected from one in polylactide (PLA), PGA (PGA), polylactide-Acetic acid, hydroxy-, bimol. cyclic ester (PLGA), polycaprolactone (PCL), poly hydroxybutyric acid (PHB), valerate (PHBV), poly-capric acid (PDA) or its mixture.
6. macromolecular material according to claim 5, the one in preferred polylactide (PLA), PGA (PGA), polylactide-Acetic acid, hydroxy-, bimol. cyclic ester (PLGA), polycaprolactone (PCL) or its mixture.
7. macromolecular material, more preferably PLGA according to claim 5, polymer molecular weight is 20000 ~ 50000 dalton.
8. injection-type subcutaneous implant according to claim 1, the organic solvent in the macromolecular material organic solution used time prepared by microcapsule is selected from dichloromethane, ethyl acetate, acetone or oxolane.
9. macromolecular material organic solvent according to claim 8, preferred dichloromethane.
10. injection-type subcutaneous implant according to claim 1, containing the PLGA of 3% ~ 20% in PLGA organic solution.
11. injection-type subcutaneous implants according to claim 1, temperature-responsive polymer polymer is selected from poloxamer188, PLA-PEG-PLA or PLGA-PEG-PLGA, and polymer molecular weight is 3000-5000 dalton.
12. injection-type subcutaneous implants according to claim 1, freeze drying protectant is selected from polysaccharide or multi-sugar alcohol.
13. freeze drying protectants according to claim 12, are preferably trehalose, mannitol or sorbitol.
14. injection-type subcutaneous implants according to claim 1, its preparation method is: the first step, first by biodegradable and the macromolecular material with biocompatibility joins in organic solvent, be mixed with macromolecular material organic solution, leuprorelin pharmaceutical composition is scattered in this organic solution, spraying dry or lyophilization, obtained microcapsule; Second step, under cryogenic, with water by temperature-responsive polymer dissolution of polymer, makes fully to be swelling to solution state, makes hydrogel solution; 3rd step, join in hydrogel solution by leuprorelin pharmaceutical composition microcapsule powder, mix homogeneously, adds freeze drying protectant, carries out lyophilization, makes leuprorelin pharmaceutical composition injection-type subcutaneous implant.
15. according to the preparation method described in claim 14, and in the first step, the spray drying condition of microcapsule is 25 DEG C, 0.3 ~ 4MPa.
16. according to the preparation method described in claim 14, and the cryogenic conditions in second step is 5 ~ 25 DEG C.
17. injection-type subcutaneous implants according to claim 1, before use, dissolve leuprorelin pharmaceutical composition injection-type subcutaneous implant with the sterilized water for injection of 0.2 ~ 2mL, subcutis of reinjecting.
CN201610006182.2A 2016-01-04 2016-01-04 Leuprorelin medicinal composition injection type hypodermic implantation agent Pending CN105535933A (en)

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