WO2017054151A1 - Timbre pour application externe contenant de l'anastrozole et utilisation de celui-ci - Google Patents

Timbre pour application externe contenant de l'anastrozole et utilisation de celui-ci Download PDF

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Publication number
WO2017054151A1
WO2017054151A1 PCT/CN2015/091164 CN2015091164W WO2017054151A1 WO 2017054151 A1 WO2017054151 A1 WO 2017054151A1 CN 2015091164 W CN2015091164 W CN 2015091164W WO 2017054151 A1 WO2017054151 A1 WO 2017054151A1
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WO
WIPO (PCT)
Prior art keywords
anastrozole
patch
group
transdermal
drug
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PCT/CN2015/091164
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English (en)
Chinese (zh)
Inventor
徐静
张艳红
杨洋
徐光昳
Original Assignee
徐静
哈尔滨健迪医药科技开发有限公司
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Application filed by 徐静, 哈尔滨健迪医药科技开发有限公司 filed Critical 徐静
Priority to PCT/CN2015/091164 priority Critical patent/WO2017054151A1/fr
Publication of WO2017054151A1 publication Critical patent/WO2017054151A1/fr

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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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, in particular to a pharmaceutical external preparation, in particular to an external preparation containing anastrozole and application thereof.
  • Anastrozole is a potent and selective non-steroidal aromatase inhibitor. It can inhibit the conversion of androstenedione produced in the adrenal gland to estrone after postmenopausal, thereby significantly reducing plasma estrogen levels and producing a role in inhibiting the growth of breast tumors. In addition, anastrozole did not significantly affect the production of adrenal corticosteroids or aldosterone.
  • Anastrozole is absorbed orally faster, and about 40% of anastrozole binds to plasma proteins in the body. Most of the metabolism is inactive and excreted by urine. About 10% of anastrozole is excreted from the urine in its original form. According to data reports, after oral administration of 1 mg of this product, the peak time of blood concentration was 1.22 ⁇ 0.46 hours, the peak concentration of blood drug was 9.99 ⁇ 3.24 ng/ml, and the elimination half-life was 35.96 ⁇ 14.17 hours.
  • Anastrozole is indicated for the treatment of advanced breast cancer in postmenopausal women. For patients with estrogen receptor-negative disease, if it is clinically positive for tamoxifen, consider using this product. It is indicated for the adjuvant treatment of early-stage breast cancer with estrogen receptor-positive in postmenopausal women.
  • the anastrozole preparations currently available at home and abroad are oral preparations. Oral medication, there is an unstable blood drug concentration, the individual taking the drug is different, the same dose and the effect is different. The blood concentration reached a peak about 1 hour after oral administration of this product. Moreover, the compliance (admissibility) of oral preparations is poor, especially for special patients, it is difficult to take the medicine on time, which limits the therapeutic application of anastrozole. Therefore, it is urgent to develop alternative drugs for new dosage forms.
  • the anastrozole-containing topical patch of the invention has uniform drug release, mild and long-lasting effect, and the side effect is obviously reduced compared with the oral tablet, and the administration is convenient, thereby significantly improving the compliance of the patient's treatment.
  • the present invention invents a novel new route and method for administration through the skin by using a new dosage form of anastrozole transdermal patch as a drug carrier.
  • the object of the present invention is to overcome the shortcomings of the prior art that anastrozole can not enter the human body at a nearly constant rate over a long period of time in the treatment of breast cancer, and provide a long-acting, skin-absorbing, patient-compliant Good externality, portable and easy to use topical patch containing anastrozole.
  • Another object of the present invention is to provide a method for preparing the external patch.
  • the present invention contains an external patch of anastrozole, the active ingredient is anastrozole, and the present invention is not limited to any specific form of anastrozole and/or a salt thereof, and the drug can be used as a free base or as a pharmaceutically acceptable compound. Salt is used.
  • the transdermal patch of anastrozole prepared by the present invention has been tested by guinea pig in vitro transdermal test, and the transdermal rate can be up to 0.40 mg/10 cm 2 per day, and the maximum daily dose of 1.0 mg of anastrozole is calculated. It is only necessary to apply a patch of 25 cm 2 per day to achieve the continuous maximum daily dose treatment. Different dosages can be easily achieved by adjusting the patch area.
  • anastrozole transdermal patch prepared according to the present invention can be passed through the guinea pig in vitro transdermal test, and can be passed through the skin at a release rate of 0.020 to 0.035 mg/cm 2 /day for seven days.
  • the patch of the present invention is extended by two days longer than the patch which has been used for the longest time.
  • the external patch containing anastrozole according to the present invention has an amount of anastrozole of from 0.2 to 2.0 mg per square centimeter, preferably from 0.3 to 1.0 mg, more preferably from 0.3 to 0.5 mg.
  • the external patch containing anastrozole according to the present invention is applied to human skin in a transdermal amount of 0.3 to 2.0 mg, preferably 0.3 to 1.5 mg per day.
  • the external patch containing anastrozole of the present invention may be a matrix type patch or a reservoir type patch.
  • the anastrozole-containing external patch of the present invention further comprises an appropriate amount of a medically acceptable excipient.
  • the anastrozole skeleton type patch of the invention is prepared by mixing anastrozole with a suitable polymer adhesive material or pressure sensitive adhesive, coating the backing material, heating and drying, and then covering the protective layer. Cut and package according to the required size, that is, a skeletal type transdermal patch containing anastrozole. It is characterized in that anastrozole accounts for 4.0% to 25.0% (W/W) of the external patch, and more preferably 5.0% to 20.0% (W/W).
  • the anastrozole skeleton type patch of the present invention wherein the polymer adhesive material or pressure sensitive adhesive may be an acrylic pressure sensitive adhesive, or may be a silicone pressure sensitive adhesive or a polyacrylate pressure sensitive adhesive.
  • the anastrozole reservoir type patch of the invention is prepared by mixing anastrozole with a suitable polymer material or polymer to form a drug depot; and applying the adhesive to the protective layer and heating Drying, coated with controlled release film, made into composite film; adjusting the controlled release film face of the composite film, placing the above drug storage on the controlled release film, covering the backing layer, and sealing the drug storage through heat sealing Between the controlled release film layer and the protective layer, it is cut and packaged according to the required size to form a reservoir-type transdermal patch containing anastrozole. It is characterized in that anastrozole comprises from 0.5% to 30.0% (w/w) of the drug depot, more preferably from 0.5% to 20.0% (w/w).
  • the present invention provides a novel method of administration of anastrozole administered through the skin.
  • the present invention also provides a use of a novel administration method of anastrozole administered through the skin for the treatment of breast cancer.
  • the external patch according to the present invention has a backing layer of a PET film or a non-woven fabric, a protective layer of a PET film after the anti-sticking treatment, a controlled release film of an EVA polymer film, a drug reservoir layer and an adhesive layer.
  • the pressure-sensitive adhesive is a polyacrylate, a polyisobutylene, a silicone rubber or the like; the penetration enhancer is an azone, a propylene glycol, an oleic acid or the like or a mixture of two or more thereof.
  • the patch may be formed into a rectangular, square, circular, elliptical, triangular or a combination of two or more patterns; the preparation process of the patch is a coating molding process or an extrusion molding process; the patch is applied to the body Use on the skin surface.
  • the anastrozole-containing topical patch of the present invention has its unique advantages over conventional oral administration methods.
  • One administration can allow the drug to enter the human body at a nearly constant rate over a long period of time, similar to a long-term intravenous infusion; (2) avoiding the first-pass effect of the liver and the interference and degradation of gastrointestinal factors The effect is to reduce the toxic side effects of the drug on the human body and reduce the individual difference of the drug; (3) maintain the blood concentration close to constant and effective, and avoid the peak and valley phenomenon of blood drug concentration produced by other drug delivery methods; It is easy to use and easy to be accepted by patients, that is, patient compliance is good.
  • the anastrozole-containing topical patch of the present invention has a zero-order rate process in vitro, and the transdermal rate in vitro is close to a constant rate.
  • the process is stable, reproducible and good in adhesion.
  • FIG. 1 Comparison of cumulative transdermal amount of anastrozole-containing topical patch of the present invention on guinea pig and human ex vivo skin
  • the anastrozole used, the raw materials used as the excipients, and the penetration enhancer are all commercially available pharmaceutical grades; the proportions used are percentages by weight.
  • the preparation method is an ordinary process condition of the industry.
  • Example 1 Preparation of a skeletal type external patch containing anastrozole:
  • Example 2 Preparation of a skeletal type external patch containing anastrozole:
  • Example 3 Preparation of a skeletal type external patch containing anastrozole:
  • Example 5 Preparation of a skeletal type external patch containing anastrozole:
  • Example 7 Preparation of a reservoir-type external patch containing anastrozole:
  • the backing layer is a composite aluminum foil
  • the protective layer is a fluorinated polyethylene film
  • the controlled release film is an EVA polymer film having a thickness of 71 ⁇ m.
  • the total area of the patch was 30 cm 2
  • each tablet contained 15.0 mg of anastrozole in an oval shape of 5.5 cm ⁇ 6 cm.
  • the drug reservoir was quantitatively injected into the controlled release membrane layer of the composite membrane, and the backing layer was vacuum-composited to prepare a reservoir-type patch.
  • Example 8 Preparation of a reservoir-type external patch containing anastrozole:
  • the backing layer is a composite aluminum foil
  • the protective layer is a fluorinated polyethylene film
  • the controlled release film is an EVA polymer film having a thickness of 71 ⁇ m.
  • the total area of the patch was 30 cm 2
  • each tablet contained 9.0 mg of anastrozole and an oval shape of 5.5 cm ⁇ 6 cm.
  • the drug reservoir was quantitatively injected into the controlled release membrane layer of the composite membrane, and the backing layer was vacuum-composited to prepare a reservoir-type patch.
  • the backing layer is a composite aluminum foil
  • the protective layer is a fluorinated polyethylene film
  • the controlled release film is an EVA polymer film having a thickness of 71 ⁇ m.
  • the total area of the patch was 30 cm 2
  • each tablet contained 30.0 mg of anastrozole and an oval shape of 5.5 cm ⁇ 6 cm.
  • Preparation of drug reservoir layer Accurately weigh anastrozole and oleic acid according to the prescription of drug reservoir layer, dissolve it in polyethylene glycol 400 solution, add prescription polyethylene glycol 6000, and heat to 60 °C. Melt, mix well until homogeneous, let cool to room temperature with stirring, mix well and reserve.
  • the drug reservoir was quantitatively injected into the controlled release membrane layer of the composite membrane, and the backing layer was vacuum-composited to prepare a reservoir-type patch.
  • Example 10 In vitro transdermal test of guinea pig isolated skin containing anastrozole-containing external patch of the present invention
  • guinea pig isolated skin 500 grams of guinea pigs were anesthetized with ether, carefully cut off the back and belly hair, and sacrificed The guinea pigs were peeled off from the skin, and the subcutaneous fat was removed. The saline was washed and stored frozen for use.
  • Determination of the transdermal amount of guinea pig skin A sample with an area of 3.305 cm 2 was fixed on the back skin of guinea pigs, and a transdermal test was performed using a Franz transdermal diffusion cell at a water bath temperature of 32 ° C, a stirring speed of 300 rpm, a receiving tank volume of 6 ml, and a receiving liquid. It is a pH 7.3 phosphate buffer solution. All samples were taken at 24, 48, 72, 96, 120, 144, and 168 hours, and the blank receiving liquid of the same volume and the same volume was replaced. The samples were analyzed by high performance liquid chromatography.
  • Example 11 In vitro transdermal test of human isolated skin of anastrozole-containing topical patch of the present invention
  • a sample with an area of 3.305 cm 2 was fixed on the skin of human isolated chest.
  • the transdermal test was carried out using a Franz transdermal diffusion cell at a water bath temperature of 32 ° C, a stirring speed of 300 rpm, a receiving tank volume of 6 ml, and a receiving solution of pH 7.3 phosphate. Buffer solution. All samples were taken at 24, 48, 72, 96, 120, 144, 168 hours (1 to 7 days), and the blank receiving liquid of the same volume and the same volume was replaced. The samples were analyzed by high performance liquid chromatography.
  • the active ingredient anastrozole in the external patch containing anastrozole of the present invention can pass through the skin of guinea pigs and human skin, and the product can always maintain a constant speed in the test for 7 days. Uniform release.
  • the transdermal amount of the preparation of 10 to 40 cm 2 in human skin is about 0.26 mg to 1.04 mg / day, and this concentration has reached an effective therapeutic dose of anastrozole for the treatment of breast cancer. Simply set different drug specifications based on the effective therapeutic dose.
  • the daily transdermal amount of the anastrozole-containing external patch of the present invention on guinea pig and human skin is shown in Fig. 1.
  • Example 12 Antitumor test study of the external patch containing anastrozole of the present invention
  • mice Take 40 healthy BALB/c mice, female, 6-8 weeks old, weighing 15-18.5 g, and inoculate 1.0 ⁇ 10 6 (0.1 ml) 4T1 breast cancer cells into the right chest of each mouse, 5- All mice in 7 days could reach the subcutaneous nodules. When the tumor grew to more than 200 mm 3 in about 2 weeks, the model was considered successful and the tumor inhibition experiment was started.
  • mice were randomly grouped and the tumor inhibition experiment began.
  • group A was the control group (pH 7.3 phosphate buffer)
  • group B was the low dose group of anastrozole patch (specification: 0.1 cm 2 / sticker , 0.3mg/cm 2 )
  • group C is the anastrozole patch medium dose group (specification: 0.1cm 2 / paste, 1.0mg/cm 2 )
  • group D is anastrozole patch high dose group (specification: 0.1 Cm 2 / sticker, 2.0 mg/cm 2 )
  • group E is the anastrozole oral group.
  • the environment is normally illuminated (8:00 am to 8:00 pm), the animals are free to eat and enter the water at room temperature of 22 ⁇ 2 ° C, suitable humidity.
  • mice began to give drug intervention, and the reference group was administered with a dose, and group A was administered with 0.1 ml of PH7.3 phosphate buffer for intragastric administration/day.
  • Group B was given a small dose of anastrozole patch, which was changed every 7 days;
  • group C was given a medium dose of anastrozole patch, which was replaced every 7 days;
  • group D was given a large dose of anastrozole patch.
  • the test was changed every 7 days; the group E was given anastrozole powder 0.155 mg/kg/day, and the anastrozole powder was dissolved in 0.1 ml of PH7.3 phosphate buffer solution; all the groups were continuously administered for 3 weeks.
  • patch administration method After the animal's back is sheared, sodium sulfide is depilated to expose a round skin with a diameter of 1 cm, washed with warm water and then dried.
  • the anastrozole-containing external patch of the present invention is applied the next day, and the patch is covered with a sterile dressing to prevent the patch from falling off.
  • the data results were processed by SPSS 13.0 for windows statistical software.
  • the normal distribution data of measurement data were average ⁇ standard deviation. Representation, one-way analysis of variance, LSD test or SNK test for comparison between groups; non-normal distribution data expressed as median (M), nonparametric test, Kruskal-Wallis H test and Mann-Whitney U test, The test results were statistically significant at P ⁇ 0.05.
  • mice can reach subcutaneous tumor nodules 7 days after inoculation of 4T1 breast cancer cell lines, and the tumor formation rate is 100%. At the beginning, the mice have good spirits and no significant changes in activity status. When the tumors were mostly round or elliptical, the size was uniform. After the drug intervention, the implanted tumors began to gradually become irregular and of different sizes. There was no significant difference in body weight and implant tumor volume between the 5 groups (P>0.05). After 3 weeks, the tumor-bearing mice began to have rough skin on the back of the neck. The hair color was dark, sparse, slow-moving, and wasted.
  • mice in groups B, C, D, and E had less active feeding than group A, which was considered to be caused by chemotherapy side effects. There was no significant difference in the general condition of the mice in the 5 groups before sacrifice. At the time of sacrifice, the mice in each group received a normal distribution of body weight, and the body weight of each group was expressed as mean ⁇ standard deviation. The results are as follows:
  • the tanne was 800 nm, the whole body emitted green fluorescence and the whole body fluorescence was evenly distributed; After 24 hours, the imaging was performed under the same method and conditions again. The fluorescence was strong at the site of the implanted tumor, the kidney and the bladder, and the fluorescence of other parts was weak. After 48 hours, imaging was performed under the same method and conditions again, and the fluorescence distribution of the mouse was mostly concentrated.
  • mice After 3 weeks of treatment, all the mice were sacrificed by cervical dislocation. The tumor was completely exfoliated, and some tumors were fixed in neutral formalin (10%) for HE staining. The other part was fixed in 70% alcohol to prepare a single. Cell suspension was used for flow cytometry analysis of apoptosis rate;
  • mice The fresh lungs of the removed mice were washed with physiological saline, and the number of metastatic lesions on both lungs was counted under a stereo microscope. Under the microscope, all the specimens showed metastatic nodules. There were more group A, nodules were white, round or elliptical. After counting the number of metastases, the lungs were fixed in neutral formalin. 10%) to be HE stained for use.
  • HE staining of all tumor specimens and lung nodules All tumor specimens and lungs were embedded in paraffin, 4-6um sections, HE staining, microscopically confirmed tumor as breast invasive carcinoma, double lung knot Section confirmed as breast cancer metastasis.
  • the present invention studies the antitumor effect of anastrozole external preparations and advanced animal models of breast cancer, and has rarely been reported at home and abroad.
  • BALB/C mice were inoculated with mouse 4T1 high-invasive cell line to construct a model of advanced metastatic breast cancer.
  • the tumor growth rate was consistent when the drug was not used for intervention, and the individual differences were small, which was easy to observe.
  • the tumor volume and the Pearl imager imaging system were used to detect the tumor fluorescence density value to simultaneously evaluate the anti-tumor effect of the drug: the results were consistent and the reliability was high.
  • This experiment yielded consistent results regardless of the size of the implanted tumor or the evaluation of the fluorescence density of the implanted tumor in situ: oral administration of anastrozole and the three dose groups of anastrozole of the present invention (0.3 mg/cm) 2 , 1.0mg/cm 2 , 2.0mg/cm 2 ) patches have better anti-tumor effects.
  • mice in group D and group E were lighter than before, and the weight of the remaining three groups was slightly higher than before.
  • mice in group D and group E actively took less food during the treatment period, and passed statistics.
  • group B group E ⁇ group C
  • the ⁇ D group is directly proportional, and the side effects of the anastrozole external preparation of the present invention are lighter than those of the oral administration under the same dosage conditions.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un timbre pour application externe d'l'anastrozole et un procédé de préparation de celui-ci, le timbre pour application externe étant un type à squelette ou un timbre de type à réservoir, dans lequel la teneur en anastrozole est de 0,2 à 2,0 mg/cm2, de préférence de 0,3 à 1,0 mg, plus de préférence de 0,3 à 0,5 mg ; le taux de pénétration percutanée in vitro est proche d'une vitesse constante ; et le timbre a peu d'effets secondaires, une bonne observance du patient, et est facile à transporter lorsqu'il est utilisé pour le traitement du cancer du sein.
PCT/CN2015/091164 2015-09-30 2015-09-30 Timbre pour application externe contenant de l'anastrozole et utilisation de celui-ci WO2017054151A1 (fr)

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PCT/CN2015/091164 WO2017054151A1 (fr) 2015-09-30 2015-09-30 Timbre pour application externe contenant de l'anastrozole et utilisation de celui-ci

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PCT/CN2015/091164 WO2017054151A1 (fr) 2015-09-30 2015-09-30 Timbre pour application externe contenant de l'anastrozole et utilisation de celui-ci

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009007334A2 (fr) * 2007-07-10 2009-01-15 Braetter Christian Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol
CN101513397A (zh) * 2009-03-24 2009-08-26 沈阳药科大学 阿那曲唑控释贴剂及其制备方法
CN105055379A (zh) * 2015-09-19 2015-11-18 徐静 一种含有阿那曲唑的外用贴剂及其应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009007334A2 (fr) * 2007-07-10 2009-01-15 Braetter Christian Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol
CN101513397A (zh) * 2009-03-24 2009-08-26 沈阳药科大学 阿那曲唑控释贴剂及其制备方法
CN105055379A (zh) * 2015-09-19 2015-11-18 徐静 一种含有阿那曲唑的外用贴剂及其应用

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