CN111789936B - Alarelin composition and preparation method thereof - Google Patents
Alarelin composition and preparation method thereof Download PDFInfo
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- CN111789936B CN111789936B CN201910269552.5A CN201910269552A CN111789936B CN 111789936 B CN111789936 B CN 111789936B CN 201910269552 A CN201910269552 A CN 201910269552A CN 111789936 B CN111789936 B CN 111789936B
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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
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- 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
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- 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
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- 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
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- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- 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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
Abstract
The invention designs a transdermal preparation of an HRT drug and alarelin composition, which consists of drug active ingredients, a transdermal enhancer, a solvent, a high polymer material and a pressure-sensitive adhesive, wherein the drug active ingredients contain alarelin, natural estrogen and natural progestogen. The transdermal preparation reduces the side effects of the alarelin in clinical use, changes the inconvenience of the alarelin in the administration mode, and increases the compliance of patients.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a transdermal preparation of an HRT drug and alarelin composition and a preparation method thereof.
Background
Alarelin, chinese name Alarelin Acetate, alarelin, english name Alarelin Acetate, and polypeptide sequence pGlu-His-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-NHC 2 H 5 Is a synthetic nine peptide analog of gonadotropin releasing hormone (GnRH) which can stimulate the pituitary to release Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) to cause ovaries in the initial period of administrationThe short rise in the sex steroid hormone; repeated administration can inhibit the release of LH and FSH from pituitary gland, and reduce the estradiol level in blood to achieve the effect of removing ovaries, and the inhibition can be used for treating hormone-dependent diseases such as endometriosis and the like. The estrogen level is reduced due to the drug oophorectomy effect of the alarelin, so that menopausal-like symptoms are generated, such as hot flashes, vaginal dryness, unstable emotion, headache, sexual desire and the like, and the life quality of patients is reduced. At the same time, the continuous use of alarelin allows estrogen levels to be reduced to postmenopausal levels. While estrogens have the effects of promoting calcitonin secretion and inhibiting osteoclasts. Low levels of estrogen activate osteoclasts while estrogen also inhibits secretion of parathyroid hormone, which causes a disturbance in vitamin D3 activation, resulting in bone loss. The alarelin is destroyed by digestive enzymes when orally taken, and thus cannot be used for oral administration, and can be used for intramuscular injection, subcutaneous injection, vaginal administration, nasal administration and the like, and is not commonly used because of low bioavailability of vaginal administration and nasal administration. Thus patients have a lower compliance when using existing alarelin formulations.
In order to reduce side effects, small amounts of HRT (hormone replacement therapy) drugs, called "reverse-add therapy", may be added when alarelin is used. The purpose is to make the in vivo estrogen level reach a 'window dose' or 'threshold estrogen level', so that the treatment of endometriosis is not affected, and the side effect caused by low estrogen can be reduced to the maximum extent. The estrogen can directly act on osteoblast receptor to inhibit osteoclast, and change functions of osteoblast and osteoclast, so as to reduce bone loss or increase bone mass. However, in back-addition therapy, the use of an excess of estrogen stimulates focal growth, while the combination of progestogen prevents endometrial hyperplasia and endometrial cancer. However, HTR drugs are mostly administered orally, and alarelin formulations are mainly administered by injection. Due to the different modes of administration, if a combination of alarelin and HTR drugs is required, separate administrations are required, which will affect patient compliance.
The transdermal administration preparation has a plurality of advantages as a dosage form different from the conventional oral preparation or injection preparation: the first pass effect of the liver and the stimulation to the gastrointestinal tract can be avoided, and the drug absorption is not influenced by gastrointestinal tract factors, so that the individual difference of the drug administration is reduced; the release rate of the medicine can be effectively controlled, the stable blood concentration can be maintained for a long time, the peak-valley phenomenon of the blood concentration caused by oral administration is avoided, the blood concentration is kept stable within an effective concentration range, the administration times and the incidence rate of side reactions are obviously reduced, the administration can be timely interrupted when the side reactions occur, and the medication safety of patients is greatly improved.
Disclosure of Invention
In order to reduce the side effects of alarelin in clinical use and simultaneously change the inconvenience of the alarelin in the administration mode and increase the compliance of patients, the invention provides an HRT drug and an alarelin composition transdermal preparation, and the drug active ingredients of the transdermal preparation comprise: alarelin, natural estrogens, and natural progestins.
In particular, in transdermal formulations of such HRT drugs and alarelin compositions, the natural estrogens and natural progestins are included as estradiol and progesterone, respectively. Estradiol and progesterone are natural hormones of human body, and the two natural hormones can avoid side effects of synthetic hormone on human body and improve the safety of the medicine.
Preferably, the proportion of the active ingredients of the medicine in the transdermal preparation is 5-10% of the total mass of the active ingredients of the medicine, 10-20% of estrogen and the balance of progesterone. The metering of the HRT drug is generally selected as the least effective metering, so that the HPT drug does not interfere with the in vivo estrogens and progestogens while reducing the side effects of administration of alarelin.
Specifically, the transdermal preparation consists of active pharmaceutical ingredients, a transdermal enhancer, a solvent, a high polymer material and a pressure-sensitive adhesive.
Preferably, the transdermal preparation is prepared from 0.01% -10% of the total mass of the transdermal preparation, 2-20% of a transdermal enhancer, 5-10% of a solvent, 45-60% of a high polymer material and the balance of a pressure-sensitive adhesive.
Preferably, the transdermal enhancer is a combination of a transdermal peptide and a common transdermal enhancer. Wherein the transdermal peptide is preferably TD1; the common penetration skin enhancer is selected from azone and propylene glycol or a combination of the two. The transdermal peptide TD1 does not need to be connected with polypeptide or protein in a non-covalent way, and can directly carry the alarelin to permeate the skin to play a role; azone and/or propylene glycol can promote estrogen and progestogen to enter blood circulation through skin.
Preferably, the solvent is selected from: ethanol, propylene glycol, water or a combination of the three, and the solvent is mainly used for dissolving the active ingredients of the medicine.
Preferably, the polymer material is selected from: ethylene/vinyl acetate copolymer (EVA), polyvinyl chloride (PVC), polypropylene (PP), cellulose Acetate (CA). Mainly plays a role of bearing medicines
The pressure-sensitive adhesive is selected from the group consisting of: polyisobutylene, acrylic, silicone rubber. The drug delivery system is tightly combined with the skin, has biocompatibility and has certain compatibility with the drug delivery system.
The specific embodiment is as follows:
example 1
Dissolving 0.2g of the active ingredient of the medicine (5% of the alarelin, 10% of the estradiol and 85% of the progesterone) in 20mL of propylene glycol, stirring to enable the active ingredient of the medicine to be fully dissolved in the solvent, continuously adding 1g of TD, 30g of azone and 140mL of propylene glycol, stirring to enable the active ingredient to be fully dispersed and dissolved, then adding 900g of polyvinyl chloride, continuously stirring to enable the active ingredient to be fully dispersed, uniformly stirring, mixing with 899.8g of polyisobutene pressure-sensitive adhesive, stirring, carrying out ultrasonic degassing, uniformly coating on a controlled release film, drying at 50 ℃, cooling, and covering a backing layer to obtain the transdermal preparation of the HRT medicine and the alarelin composition.
Example 2
Dissolving 0.4g of the active ingredient (6% of alarelin, 12% of estradiol and 82% of progesterone) in 40mL of propylene glycol, stirring to enable the active ingredient to be fully dissolved in the solvent, continuously adding 1g of TD, 60g of azone and 280mL of propylene glycol, stirring to enable the active ingredient to be fully dispersed and dissolved, then adding 1800g of polyvinyl chloride, continuously stirring to enable the active ingredient to be fully dispersed, uniformly stirring, mixing with 1799.6g of polyisobutene pressure-sensitive adhesive, stirring, performing ultrasonic deaeration, uniformly coating on a controlled release film, drying at 50 ℃, cooling, and covering a backing layer to obtain the transdermal preparation of the HRT drug and alarelin composition.
Example 3
Dissolving 0.25g of the active ingredient (the alarelin accounts for 7%, the estradiol accounts for 12% and the progesterone accounts for 81%) in 25mL of propylene glycol, stirring to enable the active ingredient to be fully dissolved in the solvent, continuously adding 6.25g of TD, 183.75g of azone and 100mL of propylene glycol, stirring to enable the active ingredient to be fully dispersed and dissolved, then adding 687.5g of cellulose acetate, continuously stirring to enable the active ingredient to be fully dispersed, uniformly stirring, mixing with 247.25g of acrylic acid pressure-sensitive adhesive, stirring, performing ultrasonic degassing, uniformly coating on a controlled release film, drying at 50 ℃, cooling, and covering a backing layer to obtain the transdermal preparation of the HRT drug and the alarelin composition.
Example 4
Dissolving 0.5g of the active ingredient of the medicine (6% of the alarelin, 13% of the estradiol and 81% of the progesterone) in 40mL of propylene glycol, stirring to enable the active ingredient of the medicine to be fully dissolved in the solvent, continuously adding 20g of TD 15 g and 80mL of azone, stirring to enable the active ingredient of the medicine to be fully dispersed and dissolved, then adding 450g of polypropylene, continuously stirring to enable the active ingredient of the medicine to be fully dispersed, uniformly stirring, mixing with 404.5g of silicone rubber pressure-sensitive adhesive, stirring, performing ultrasonic degassing, uniformly coating on a controlled release film, drying at 50 ℃, cooling, and covering a backing layer to obtain the transdermal preparation of the HRT medicine and the alarelin composition.
Example 5
Dissolving 0.1g of the active ingredient (8% of alarelin, 12% of estradiol and 80% of progesterone) in 10mL of propylene glycol, stirring to enable the active ingredient to be fully dissolved in the solvent, continuously adding 14g of TD, 16g of azone and 90mL of 95% ethanol, stirring to enable the active ingredient to be fully dispersed and dissolved, then adding 499g of ethylene/vinyl acetate copolymer (EVA), continuously stirring to enable the active ingredient to be fully dispersed, uniformly stirring, mixing with 379.9g of acrylic acid pressure-sensitive adhesive, stirring, performing ultrasonic degassing, uniformly coating on a controlled release film, drying at 50 ℃, cooling, and covering a backing layer to obtain the transdermal preparation of the HRT drug and the alarelin composition.
Example 6
Dissolving 1g of the active ingredient of the medicine (8% of alarelin, 12% of estradiol and 80% of progesterone) in 100mL of propylene glycol, stirring to enable the active ingredient of the medicine to be fully dissolved in the solvent, continuously adding 100g of TD 1g and 400mL of azone, stirring to enable the active ingredient of the medicine to be fully dispersed and dissolved, then adding 2500g of ethylene/vinyl acetate copolymer (EVA), continuously stirring to enable the active ingredient of the medicine to be fully dispersed, uniformly stirring, mixing with 1859g of acrylic acid pressure-sensitive adhesive, stirring, performing ultrasonic degassing, uniformly coating on a controlled release film, drying at 50 ℃, cooling, and covering a backing layer to obtain the transdermal preparation of the HRT medicine and the alarelin composition.
Example 7
Taking 3g of the active ingredient of the medicine (8% of alarelin, 12% of estradiol and 80% of progesterone) and dissolving in 300mL of propylene glycol, stirring to enable the active ingredient of the medicine to be fully dissolved in the solvent, continuously adding 1g of TD, 90g of azone and 420mL of propylene glycol, stirring to enable the active ingredient of the medicine to be fully dispersed and dissolved, then adding 2700g of ethylene/vinyl acetate copolymer (EVA), continuously stirring to enable the active ingredient of the medicine to be fully dispersed, uniformly stirring, mixing with 2458.8g of acrylic acid pressure-sensitive adhesive, stirring, performing ultrasonic degassing, uniformly coating on a controlled release film, drying at 50 ℃, cooling, and covering a backing layer to obtain the transdermal preparation of the HRT medicine and the alarelin composition.
Example 8
5g of the active ingredient (8% of alarelin, 12% of estradiol and 80% of progesterone) of the medicine is taken and dissolved in 500mL of propylene glycol, the active ingredient of the medicine is fully dissolved in the solvent by stirring, 1g of TD, 190g of azone and 700mL of propylene glycol are continuously added, the active ingredient of the medicine is fully dispersed and dissolved, 5000g of ethylene/vinyl acetate copolymer (EVA) is then added, the active ingredient of the medicine is continuously stirred and fully dispersed, after being uniformly stirred, the active ingredient of the medicine is mixed with 3550g of acrylic acid pressure-sensitive adhesive, the active ingredient of the medicine is subjected to ultrasonic deaeration after being stirred, and then is uniformly coated on a controlled release film, dried and cooled at 50 ℃, and a backing layer is covered, so that the transdermal preparation of the HRT medicine and the alarelin composition can be obtained.
EXAMPLE 9 Effect of HRT drug and Alarerelin composition transdermal formulation on endometriosis
60 healthy female non-pregnant rats, which have a weight of 200-250g, are anesthetized by intraperitoneal injection of pentobarbital sodium horn, and the rats are fixed on an operation plate, the abdomen is sheared, the skin is conventionally disinfected, and the skin is cut from the middle of the position about the upper end of the urethra. Ligating the uterine blood vessels, cutting the left uterine horn approximately long, and performing end-to-end anastomosis. In the Luo type nutrient solution, the picked uterine horn is longitudinally cut, the endometrium is separated from the myometrium, and the cut endometrium tissue segment is made to have the surface epithelium facing the abdominal wall and sewed on the right side abdominal wall in the abdominal cavity, and the suture line is a non-invasive No. 1 cotton fiber monofilament line. The remaining endometrium tissue was histologically examined to confirm that the implant was endometrial and the abdomen closed after penicillin was placed in the abdominal cavity. Penicillin is continuously injected after operation for normal feeding. After modeling for 4 weeks, the growth condition of the ectopic endometrium is checked by a second laparotomy, the volume of the transplanting range is increased, the transplanting range is transparent nodular and saccular, the yellowish transparent saccular liquid is accumulated in the transplanting range as the modeling success, and the volume V of the ectopic endometrium is measured and recorded 0 . The treatment is started the next day after operation, rats with failed modeling are removed and then are grouped for administration, and the model group is not administered; the alarelin acetate injection group is subcutaneously injected once a day; the abdomen of the rat of the example is shaved at the site where the operation is not performed, and after the site is cleaned, the HRT medicine and the alarelin composition transdermal preparation are stuck to the site, and once daily, the hair removal is performed at regular time, so that the transdermal preparation can be firmly stuck to the skin of the rat. After 4 weeks of treatment, the effect of the drug on ectopic intima was observed and the volume V of the ectopic intima was measured and recorded 1 The results are shown in Table 1.
TABLE 1 ectopic intimal volume (mm) before and after treatment for each group of EMs rats 3 )
P < 0.05 compared to model group.
From table 1, except for slightly increasing ectopic endometrium of the model group, the ectopic endometrium of the rats of the other groups is obviously smaller than the volume before administration, and the example group has no obvious difference from the alarelin acetate injection, which proves that the HRT medicament and the alarelin composition transdermal preparation have curative effect on endometriosis.
EXAMPLE 10 influence of transdermal formulations of HRT drug and Alarerelin composition on in vivo estradiol and progesterone levels
The rats of each group of example 9 were subjected to 4 weeks of administration, 5mL of blood was collected from the abdominal aorta before laparotomy, the blood sample was allowed to stand at room temperature for 1 hour, centrifuged (3200 rpm,15 min) at 4℃and the supernatant was aspirated into a tube, and estradiol in serum of the model rats was detected by enzyme-linked immunosorbent assay (ELISA) (E 2 ) Progesterone (P) content, 9 healthy, non-pregnant female rats that had not been treated at the same time were removed from the abdominal aorta and 5mL of blood was collected, and the blood samples were treated in the same manner, and the results are shown in table 2.
TABLE 2E 2 and P levels in serum after treatment of EMs rats in each group
As shown in table 2, the levels of estradiol and progesterone after administration of the alarelin acetate injection were lower than those of the blank control group and the model group, and the results of example 9 show that the alarelin acetate injection can effectively treat endometriosis, but can cause menopausal-like side effects. The results of the examples, which show that the levels of estradiol and progesterone after administration are slightly higher than that of the blank control group, but significantly lower than that of the model group, show that the transdermal formulations of the HRT drug and the alarelin composition of the invention are effective in treating endometriosis and simultaneously reduce menopausal-like side effects caused by alarelin.
Claims (4)
1. The transdermal preparation of the HRT medicine and the alarelin composition is characterized by comprising medicine active ingredients, a transdermal enhancer, a solvent, a high polymer material and a pressure-sensitive adhesive;
wherein the prescription of the transdermal preparation comprises 0.01% -10% of the total mass of the transdermal preparation, 2-20% of a transdermal enhancer, 5-10% of a solvent, 45-60% of a high polymer material and the balance of a pressure-sensitive adhesive;
wherein the effective components of the medicine comprise: alarelin, estradiol, and progesterone;
wherein, the proportion of the active ingredients of the medicine is as follows: the alarelin accounts for 5-10% of the total mass of the active ingredients of the medicine, the estradiol accounts for 10-20%, and the rest is progesterone;
wherein the transdermal enhancer is a combination of transdermal peptide and common transdermal enhancer;
wherein the transdermal peptide is TD; the common transdermal enhancer is selected from azone, propylene glycol or a combination of the two.
2. The transdermal formulation of claim 1, wherein the solvent is selected from the group consisting of: ethanol, propylene glycol, water, or a combination of the three.
3. The transdermal formulation of claim 1, wherein the polymeric material is selected from the group consisting of: ethylene/vinyl acetate copolymer (EVA), polyvinyl chloride (PVC), polypropylene (PP), cellulose Acetate (CA).
4. The transdermal formulation of claim 1, wherein the pressure sensitive adhesive is selected from the group consisting of: polyisobutylene, acrylic, silicone rubber.
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| CN104829695A (en) * | 2015-05-04 | 2015-08-12 | 吉尔生化（上海）有限公司 | Purifying method for alarelin |
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| CN104829695A (en) * | 2015-05-04 | 2015-08-12 | 吉尔生化（上海）有限公司 | Purifying method for alarelin |
Non-Patent Citations (3)
| Title |
|---|
| Kamran S. Moghissi 等.Goserelin acetate (Zoladex)* with or without hormone replacement.therapy for the treatment of endometrosts.《FERTILITY AND STERILITY》.1998,第69卷(第6期),第1056-1062页. * |
| 崔福德 等.《药剂学》.人民卫生出版社,2021,(第7版),第452-467页. * |
| 郭悦慈.腹腔镜术后短期应用GnRH-a治疗内异症伴不孕的临床分析.中国优秀硕士学位论文全文数据库医药卫生科技辑》.2008,(第03期),第28-29页. * |
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