CN113292621A - Pharmaceutical crystal form of progesterone and application thereof - Google Patents

Abstract

The invention discloses a pharmaceutical crystal form of progesterone and application thereof, wherein the crystal form is a pharmaceutical eutectic of progesterone and anthracene, and the molecular ratio of the progesterone to the anthracene is 3: 1. The crystal form has higher stability under the conditions of high temperature, high humidity and illumination, and has higher solubility and bioavailability compared with the bulk drug.

Description

Pharmaceutical crystal form of progesterone and application thereof

Technical Field

The invention belongs to the field of medicines, and relates to a pharmaceutical crystal form of progesterone and application thereof.

Background

Progesterone, also known as gestagen, progesterone, and the like, is a natural estrogen produced by the ovary during the luteal phase from the corpus luteum, can also be produced by the adrenal gland and placenta, is involved in the regulation of the hypothalamic-pituitary-ovarian axis along with estrogen, finely intervenes in the ovulatory menstrual cycle, and is a key hormone in maintaining pregnancy. Progesterone has wide clinical applications and can be used for the prevention of spontaneous preterm birth, the treatment of luteal insufficiency, secondary amenorrhea, premenstrual syndrome, and also plays an important role in giving eggs, in vitro fertilization, hormone replacement therapy, etc. (Warren M P, Shantha S.uses of progestin in clinical practice [ J ]. International. J ournal of fertility and hormone's medicine.1998; 44(2): 96-103; Zhang Zheng. determination of progestin and metabolites in plasma and uterus and study of local absorption of progestin membrane [ D ] Sichuan university, 2004.). Progesterone plays a role not only in reproduction through the classical progesterone receptor, but also in the treatment of a wide range of tissues such as the bone, heart and brain (Singh m. proacterins and neuroprotection: are all proteins secreted equivalent [ J ]. Minerva endocrinol.2007.32(2): 95-102.).

In the biopharmaceutical classification system, progesterone belongs to the BCSIV class and is characterized by poor solubility and low permeability. Currently, the formulations on the market are oral capsules, vaginal gels, pessaries and oily injections for injection, such as

And procesterone. However, these dosage forms suffer from several disadvantages to varying degrees. First, progesterone is poorly absorbed by oral capsules and rapidly metabolized in the liver to be inactivated, with liver first pass metabolism of more than 90% (Lipciardi F L, Kwiatkowski A, Noyes N L, et al]Fetiliity and solidity.1999; 71(4) 614 and 618); secondly, intravaginal administration of progesterone, whether as a suppository or gel, requires the patient to remain in a lying position for application, causing difficulties such as inconvenient use and easy leakage for the patient due to the fact thatThe therapeutic effect is not ideal (Damario M A, Goudas V T, Session D R, et al. Crinone 807o variable tropone gel results in lower expression of infection after in vitro transfer-organism [ J]Fetiliity and solidity.1999; 72(5) 830-836); in China, progesterone injection is the first choice of medicine for the fetus protection treatment of pregnant women. However, due to the characteristic of insolubility, the commercially available drugs are oily injection, so that the intramuscular injection has many side effects, such as difficult injection and great irritation, and local allergic reactions such as pain, inflammation, induration, red swelling, bleeding and the like occur at the injection part successively, which influence the drug absorption. Moreover, pregnant women need to get to hospital intramuscular injection of progesterone oily injection every day, which causes running fatigue of patients and is not beneficial to fetus protection. At the same time, absolute bed rest is needed for the patient, the treatment time is long, and the patient is easy to be discontented, which leads to the conflict of nursing (Papaleo E, Quannta L, Molgora M. intramura vs. intrinsic program product in patient experiment under the condition of visual transfer-exercise circulation. A retroactive object under the condition of J-control study]Eur Rev Med Pharmacol sci.2010; 14(2):103-6.). Therefore, the progesterone preparation with high curative effect and small irritation has wide market prospect.

The progesterone has low solubility and bioavailability, liver first-pass effect exists, and the injection prepared from the progesterone has high irritation and poor patient compliance, so that the development and clinical application of a medicinal preparation are limited, and the improvement of the solubility and the bioavailability of the medicament becomes a hotspot of current research.

Disclosure of Invention

In order to make up the defects of the prior art, the invention aims to provide a novel crystal form of progesterone so as to overcome the defects of low solubility and low bioavailability of a progesterone bulk drug.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a pharmaceutical crystal form of progesterone, wherein the crystal form is a pharmaceutical cocrystal of progesterone and anthracene.

Further, the molecular ratio of progesterone to anthracene in the drug crystal form is 3: 1.

Further, the experimental formula of the drug crystal form is C₇₇H₁₀₀O₆。

A pharmaceutical crystalline form according to the first aspect of the invention, characterized by an X-ray powder diffraction pattern comprising the following peaks, in terms of 2 Θ: 9.821 +/-0.2 degrees, 19.64 +/-0.2 degrees and Cu-K alpha radiation are detected on a diffractometer.

Further, the X-ray powder diffraction also contained peaks at 13.061 + -0.2 °, 13.539 + -0.2 °, 14.198 + -0.2 °, 14.499 + -0.2 °, 17.76 + -0.2 °, 18.398 + -0.2 °, 21.719 + -0.2 °, 25.459 + -0.2 °, 26.161 + -0.2 °.

Further, the X-ray powder diffraction also contained peaks at 15.859 ± 0.2 °, 16.981 ± 0.2 °, 20.238 ± 0.2 °, 23.759 ± 0.2 °, 25.961 ± 0.2 °, 29.561 ± 0.2 °.

Further, the X-ray powder diffraction pattern is substantially as shown in fig. 5.

The pharmaceutical crystalline form according to the first aspect of the invention, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 128 ℃.

Further, the DSC thermogram is substantially as shown in figure 1.

The pharmaceutical crystalline form according to the first aspect of the invention, characterized by the following unit cell dimensions:

α ═ γ ═ 90.00 °, β ═ 107.425(6) °, Z ═ 2, and the unit cell volume is

In a second aspect, the present invention provides a method for preparing the pharmaceutical crystal form of the first aspect of the present invention,

1) crushing progesterone and anthracene to obtain a white powder sample,

2) and adding a white powder sample into a solvent for dissolving, and volatilizing to obtain colorless blocky crystals.

Further, the solvent is an ester solvent.

Further, the solvent is ethyl acetate.

Further, progesterone and anthracene were pulverized using a ball mill.

In a third aspect, the present invention provides a composition comprising an effective amount of the pharmaceutical crystalline form of the first aspect of the present invention.

Further, the composition also includes a carrier.

Further, the composition is a pharmaceutical composition, a nutraceutical composition, a health food or a medical food.

A fourth aspect of the invention provides a pharmaceutical crystalline form according to the first aspect of the invention or a composition according to the third aspect of the invention for use in the manufacture of a medicament for maintaining pregnancy.

In a fifth aspect, the invention provides a pharmaceutical crystalline form according to the first aspect of the invention or a composition according to the third aspect of the invention for use in the manufacture of a medicament for assisted reproduction.

The sixth aspect of the present invention provides a use of the pharmaceutical crystalline form according to the first aspect of the present invention or the composition according to the third aspect of the present invention in the preparation of a medicament for preventing and/or treating gynecological diseases, cardiovascular and cerebrovascular diseases, and nervous system diseases.

Further, the gynecological diseases include spontaneous premature birth, corpus luteum insufficiency, secondary amenorrhea, premenstrual syndrome.

The seventh aspect of the invention also provides a method of treating a disease, the method comprising administering to the subject an effective amount (e.g., a therapeutically effective amount) of the crystalline form described herein or a composition thereof. The diseases include but are not limited to gynecological diseases, cardiovascular and cerebrovascular diseases and nervous system diseases.

In some embodiments, the methods described herein further comprise administering to the subject an additional agent. In some embodiments, the methods described herein further comprise contacting the biological sample with an additional agent. In some embodiments, the methods described herein further comprise contacting the tissue with an additional agent. In some embodiments, the methods described herein further comprise contacting the cell with an additional agent.

The co-crystals and compositions provided herein can be administered by any route, including enterally (e.g., orally), parenterally, intravenously, intramuscularly, intraarterially, intramedullary, intrathecally, subcutaneously, intraventricularly, transdermally, intradermally, subcutaneously, intradermally, rectally, intravaginally, intraperitoneally, topically (e.g., by powders, ointments, creams, and/or drops). Routes of particular concern are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via the blood and/or lymphatic supply, and/or direct administration to the affected site. Generally, the most suitable route of administration will depend on various factors, including the nature of the agent (e.g., stability in the gastrointestinal environment), and/or the condition of the subject (e.g., whether the subject can tolerate oral administration).

The term "co-crystal" refers to a crystal structure comprising at least two different components (e.g., progesterone and a co-form), wherein each component is independently an atom, ion, or molecule. In some embodiments, none of the components are solvents. In some embodiments, at least one component is a solvent. The co-crystal of progesterone and the co-form is different from the salt formed by progesterone and the co-form. In salts, progesterone is complexed with the coformer in such a way that protons are easily transferred from the coformer (e.g., intact proton transfer) to the progesterone at room temperature. However, in this co-crystal, progesterone is complexed with the co-former in such a way that protons are not readily transferred from the co-former to the progesterone at room temperature. In some embodiments, in the co-crystal, no protons are transferred from the conformality to the progestin. In some embodiments, in the co-crystal, a portion of the protons are transferred from the conformality to the progestin. Co-crystals can be used to improve the properties of progesterone (e.g., solubility, stability, ease of formulation, or bioavailability).

The terms "composition" and "formulation" are used interchangeably.

The present invention provides compositions comprising the co-crystals described herein and a carrier. In some embodiments, the carrier is a pharmaceutically acceptable excipient.

In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is a nutraceutical composition. In some embodiments, the composition is a health food.

The health food products described herein may comprise one or more edible carriers that impart one or more of the benefits of the products as described herein. Examples of edible carriers include starch, cyclodextrin, maltodextrin, methyl cellulose, carboxymethoxy cellulose (carbomethoxy cellulose), xanthan gum, and aqueous solutions thereof. Other examples include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, as well as combinations thereof, as known to one of ordinary skill in the art. In some examples, the health food products described herein can further include a neuroprotective food, such as fish oil, linseed oil, and/or benzoate.

In some embodiments, the composition is a medical food. A medical food is a food formulated for enteral consumption or administration. Such foods are typically used for specific dietary management of a target disease (such as those described herein) under the supervision of a physician. In some cases, such medical food compositions are formulated and processed specifically (as opposed to natural foods used in the natural state) for patients in need of treatment (e.g., human patients suffering from a disease or in need of using the product as a primary active agent, to alleviate the disease or condition through specific dietary management). In some examples, the medical food compositions described herein are not one of those compositions recommended by physicians to control symptoms or reduce the risk of a disease or condition as part of an overall diet.

In some embodiments, the co-crystals described herein are provided in an effective amount in a pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacology. Generally, such a preparation method comprises the steps of: the co-crystals (i.e. "active ingredient") described herein are combined with carriers or excipients and/or one or more other auxiliary ingredients and the product is then, if necessary and/or desired, shaped and/or packaged into the desired single-or multi-dose unit.

The pharmaceutical compositions may be prepared, packaged and/or sold in bulk in a single unit dose and/or in multiple single unit doses. A "unit dose" is a discrete amount (discrete amount) of a pharmaceutical composition comprising a predetermined amount of active ingredient. The amount of the active ingredient is typically equal to the dose of the active ingredient administered to the subject and/or a simple fraction of that dose, e.g., one-half or one-third of that dose.

The relative amounts of the active ingredient, pharmaceutically acceptable excipient and/or any additional ingredients in the pharmaceutical compositions of the invention will vary depending on the identity, size and/or condition of the subject being treated and further depending on the route of administration of the composition. The composition may comprise from 0.1% to 100% (w/w) of the active ingredient.

Pharmaceutically acceptable excipients used in preparing the provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents and/or oils. Excipients such as cocoa butter and suppository waxes, colorants, coatings, sweeteners, flavoring agents and flavoring agents may also be present in the composition.

Some examples of substances capable of acting as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycerol, glycerol esters, glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; ethanol, and phosphate buffered solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition according to the judgment of the formulator.

The crystalline forms described herein can be combined with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. In addition, the carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral (e.g., tablets, capsules or soft chewables) or parenteral (including intravenous injections or infusions). In preparing the compositions for oral dosage form, any of the conventional pharmaceutical media may be employed. Conventional pharmaceutical media include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, surfactants, solvents, binders, humectants and the like in the case of oral liquid preparations (such as suspensions, solutions, emulsions and elixirs); an aerosol formulation; or carriers such as starches (e.g., corn starch), sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders (e.g., povidone, solid polyethylene glycol, and the like), disintegrating agents, and the like in the case of oral solid preparations (such as powders, capsules, tablets, and soft chewables).

Wetting agents, emulsifiers, surfactants and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, mold release agents, coating agents, sweeteners, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition. Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, tocopherols, and the like; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Fillers that may be used in oral formulations include, but are not limited to, corn starch, pregelatinized corn starch, soy protein flour, corn cobs, and corn gluten meal, and the like, or combinations thereof. The filler is typically present in the composition at a concentration of about 5% to about 80% (w/w), about 10% to about 70% (w/w), about 10% to about 60%, about 10% to about 50% (w/w), or about 10% to about 40% (w/w). More generally, the filler may be present at a concentration of about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, or about 35% to about 55%.

Binders in which the compositions of the present invention may be used for oral administration include, but are not limited to, polyvinylpyrrolidone (e.g., povidone), cross-linked polyvinylpyrrolidone (crospovidone), various grades of polyethylene glycol including PEG 3350, PEG4000, PEG 6000, PEG 8000 and even PEG 20,000, and the like; copolymers of vinyl pyrrolidone and vinyl acetate (e.g., copovidone) such as the products sold under the trade name BASF, and the like; starches such as potato starch, tapioca starch or corn starch; molasses, corn syrup, honey, maple syrup and sugars of various types; or a combination of two or more binders. The binder is generally present in the composition at a concentration of about 1% to about 30% (w/w). More typically, the composition comprises the binder at a concentration of about 1% to about 20% (w/w), about 1 to about 15% (w/w), about 1% to about 10% (w/w), about 5% to about 15% (w/w), or about 5% to about 10% (w/w).

Humectants that can be used in the composition include, but are not limited to, glycerin (also referred to herein as glycerin), propylene glycol, cetyl alcohol, and glycerol monostearate, and the like. Various grades of polyethylene glycol may also be used as humectants. The humectant may generally be present in the composition at a concentration of about 1% to about 25% (w/w). As an alternative embodiment, the humectant may be present in the composition at a concentration of from 1% to about 20% (w/w), from about 1% to about 15% (w/w) or from about 5% to about 15% (w/w). As a preferred embodiment, the composition contains from about 1% to about 10% (w/w) humectant.

Pharmaceutical compositions include those suitable for oral, sublingual, nasal, rectal, vaginal, topical (e.g., spread or pour-on), buccal and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route will depend on the nature and severity of the condition being treated. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. In certain embodiments, the pharmaceutical composition is formulated for oral administration in the form of a pill, capsule, soft chewable dosage form, lozenge, or tablet. In other embodiments, the pharmaceutical composition is in the form of a suspension.

An "effective amount" of a co-crystal as described herein refers to an amount sufficient to elicit a desired biological response (i.e., to treat and/or reduce the risk of a disorder). As understood by one of ordinary skill in the art, the effective amount of the co-crystals described herein may vary depending on the following factors: biological endpoints, pharmacokinetics of the co-crystal, condition being treated, mode of administration, and age and health of the subject are contemplated. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is prophylactic treatment. In some embodiments, an effective amount is the amount of the co-crystal described herein in a single dose. In some embodiments, an effective amount is a combined amount of the co-crystals described herein in multiple doses.

A "therapeutically effective amount" of a co-crystal as described herein is an amount sufficient to provide a therapeutic benefit in treating a disorder or to delay or minimize one or more symptoms associated with the disorder. A therapeutically effective amount of the co-crystal refers to the amount of the therapeutic agent alone or in combination with other therapies to provide a therapeutic benefit in treating the disorder. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or eliminates the symptoms, signs, or causes of the disorder, and/or enhances the efficacy of another therapeutic agent.

A "prophylactically effective amount" of a co-crystal as described herein is an amount sufficient to prevent the disorder or one or more symptoms associated with the disorder, or to prevent recurrence thereof. A prophylactically effective amount of a co-crystal refers to an amount of a therapeutic agent that alone, or in combination with other drugs, provides a prophylactic benefit in preventing the condition. The term "prophylactically effective amount" can include an amount that increases the overall prophylactic or prophylactic effect of another prophylactic agent.

The term "neurological disease" refers to any disease of the nervous system, including diseases involving the central nervous system (brain, brainstem, spinal cord and cerebellum), the peripheral nervous system (including cranial nerves) and the autonomic nervous system (which is located in part in the central and peripheral nervous systems). Neurodegenerative diseases refer to a disease of the nervous system characterized by loss of nerve cells, including but not limited to: alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), multiple system atrophy, and Huntington's chorea. Examples of neurological diseases include, but are not limited to: headache, numbness and coma, dementia, epilepsy, sleep disorders, trauma, infection, tumor, neuroophthalmology, movement disorders, demyelinating diseases, spinal cord diseases and diseases of the peripheral nerve, muscle and neuromuscular junction. Addiction and psychiatric disorders include, but are not limited to, bipolar disorder and schizophrenia, and are also included in the definition of neurological disorders.

The term "medical food" refers to a food product formulated for enteral consumption or administration, including food products that are typically used for specific dietary management of a disease of interest (such as those described herein) under the supervision of a physician. A "medical food" composition may refer to a composition (as opposed to a natural food used in its natural state) that is specifically formulated and processed for a patient in need of treatment (e.g., a human patient suffering from a disease or in need of using the product as a primary active agent to alleviate a disease or condition through specific dietary management).

The term "characteristic peaks" is a subset of representative peaks to the extent that they are present, and is used to distinguish one crystalline polymorph from another (polymorphs are crystalline forms having the same chemical composition). For example, a characteristic peak is determined by evaluating that a representative peak, if any, present in one crystalline polymorph of a compound is within ± 0.2 ° 2 Θ relative to all other known crystalline polymorphs of the compound.

The term "about" as used herein means about, in. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the upper and lower bounds of the numerical values set forth.

The term "substantially the same" when used to describe a diffractogram, spectrum, or data in a graph means that the diffractogram, spectrum, or data in a graph encompasses all diffractograms, spectra, or data in a graph that vary within acceptable experimental boundaries, as known to those of skill in the art. The experimental boundaries vary depending on the type of diffraction pattern, spectrum, or data in the pattern, but are still known to those skilled in the art.

The new crystalline forms can be identified by powder X-ray diffraction spectroscopy, as described herein. However, those skilled in the art will appreciate that the peak intensity and/or peak condition of powder X-ray diffraction may vary depending on experimental conditions, such as different diffraction test conditions and/or preferential orientation. Meanwhile, the measured 2 theta value has an error of about +/-0.2 degrees 2 theta due to different accuracies of different instruments. However, it is known that the relative intensity values of peaks are more dependent on certain properties of the sample being measured than the location of the peaks, such as the size of crystals in the sample, the orientation of crystals, and the purity of the material being analyzed, and thus it is possible to show peak intensity deviations in the range of about ± 20% or more. However, one skilled in the art can obtain sufficient information from the XRPD data provided herein to identify the crystalline form and various other crystalline forms of the invention, despite experimental error, instrumental error, preferential orientation, and the like.

Pharmaceutical compositions comprising a particular crystalline form can be identified by comparing the X-ray powder diffraction pattern of the composition to the X-ray powder diffraction pattern of the pure particular crystalline form. It will be appreciated that a pharmaceutical composition comprising a particular crystalline form may exhibit an X-ray powder diffraction pattern that is not exactly the same as a pure, particular polymorphic X-ray powder diffraction pattern.

The invention has the advantages and beneficial effects that:

compared with a progesterone bulk drug, the progesterone medicinal crystal form disclosed by the invention has the advantages that the solubility is increased under high-temperature and high-humidity illumination, and the bioavailability is improved.

Drawings

FIG. 1 is a TGA/DSC scan of a progesterone-anthracene co-crystal; wherein panel a is TGA; panel B is DSC;

FIG. 2 is a chart of the infrared absorption spectrum of a progesterone-anthracene cocrystal;

FIG. 3 is a 1H-NMR nuclear magnetic resonance spectrum of a progesterone-anthracene cocrystal;

FIG. 4 is a molecular structure diagram of a progesterone-anthracene cocrystal;

FIG. 5 is an X-powder diffraction pattern of a progesterone-anthracene cocrystal; wherein, the graph A is an X-powder diffraction spectrum of the eutectic crystal and different components thereof; FIG. B is an X-ray powder diffraction pattern of the co-crystal;

fig. 6 is a scanning electron micrograph of the progesterone-anthracene cocrystal at different magnifications; wherein Panel A is 500 ×; panel B is 2000 ×; panel C is 5000 ×;

FIG. 7 is a graph of stability experiments for progesterone-anthracene cocrystals;

fig. 8 is a solubility experimental plot of a progesterone-anthracene co-crystal;

fig. 9 is a bioavailability chart of progesterone-anthracene co-crystals.

Detailed Description

The present invention will be described in further detail with reference to the accompanying drawings and examples. The following examples are intended to illustrate the invention only and are not intended to limit the scope of the invention. The experimental procedures, in which specific conditions are not specified in the examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.

EXAMPLE 1 preparation of drug Co-crystals

1. Material

Progesterone: zhejiang Xianju pharmaceutical Co Ltd (purity > 99%)

Anthracene: shanghai Mielin Biochemical technology Co., Ltd. (purity > 99%)

Ethyl acetate: beijing chemical plant (analytical pure)

2. Experimental methods

1) Preparation of samples

943.4mg (3.0mmol) of progesterone and 534.7mg (3.0mmol) of anthracene are weighed and added into a ball mill (planetary ball mill, Nanjing Chishun science and technology development Co., Ltd.) to be ball-milled for 40min at 28Hz without solvent, and then a white powder sample is obtained.

2) Cultivation of single crystals

Taking 100mg of the powder sample, adding 15ml of ethyl acetate to dissolve the powder sample, slowly volatilizing the solvent, and obtaining colorless massive crystals after about 1 week.

EXAMPLE 2 TG-DSC analysis of drug cocrystals

1. Conditions of the experiment

The instrument model is as follows: TGA/DSC 3+

The heating rate is as follows: 10 ℃/min

Temperature range: 40-450 deg.C

Gas atmosphere: nitrogen gas

2. Results

The results are shown in fig. 1, where a Differential Scanning Calorimeter (DSC) shows that the eutectic melting point of the samples is 127.96 ℃ over the range of the test temperatures. Thermogravimetric analysis (TGA) shows: decomposition of anthracene and decomposition of progesterone were observed over the temperature range tested.

EXAMPLE 3 Infrared absorption Spectroscopy (IR) of drug cocrystals

1. Experimental Material

The instrument model is as follows: bruker EQUINOX 55 FT-IR

2. Experimental methods

Taking a proper amount of sample, placing the sample in the middle of a probe, and testing

3. Results

As a result, as shown in FIG. 2 and Table 1, the drug cocrystals exhibited infrared absorption peaks at the positions shown in Table 1.

TABLE 1 major infrared absorption peaks of drug cocrystals

EXAMPLE 4 Co-crystals of drugs¹H-NMR nuclear magnetic resonance spectrum

1. Experimental Material

The instrument comprises the following steps: AVANCE III HD 500MHz type nuclear magnetic resonance spectrometer.

Solvent: d⁶-DMSO (TMS internal standard)

2. Results

The results are shown in FIG. 3, where the shift of the NMR spectrum is as follows:¹H-NMR(500MHz,d⁶-DMSO)δ＝8.58(s,1H),8.10(t,2H),7.52(t,2H),5.63(s,1H),2.57-2.55(t,1H),2.42-2.33(m,2H),2.26-2.22(m,2H),2.18-2.14(m,6H),1.80-1.64(d,1H),1.60-1.52(m,5H),1.43-1.35(m,2H),1.20-1.14(m,5H),0.99-0.91(m,2H),0.67(S,3H)。

EXAMPLE 5X-ray Single Crystal diffraction (SXRD) of drug cocrystals

1. Experimental Material

The instrument model is as follows: rigaku AFC-10

2. Method of producing a composite material

Selecting colorless crystals with size of 0.31mm × 0.22mm × 0.18mm, adopting graphite monochromatized Mo-K ray, and radiating with wavelength

Measuring temperature: 173.00(15) K. The structure resolution and refinement are done using the SHELL XT-14 and Olex2 programs. The atomic position is determined by a direct method, then all non-hydrogen atomic coordinates are obtained by a difference function method and a least square method, and the structure is corrected by the least square method.

3. Results

The results are shown in fig. 4 and table 2, where the progesterone to anthracene molecular ratio of the progesterone-anthracene co-crystal was 3: 1.

TABLE 2 Crystal Structure

EXAMPLE 6 powder X-ray diffraction Spectroscopy (PXRD) of drug cocrystals

1. Experimental Material

The instrument model is as follows: x-ray powder apparatus model D8 ADVANCE of Bruker, germany.

2. Conditions of the experiment

Copper target, 40KV/40mA, initial angle 5 degree, end angle 60 degree, step width 0.02, scanning speed 17.7 second/step wavelength

Graphite monochromators.

3. Results

The experimental results are shown in fig. 5 and table 3, and the X-ray powder diffraction pattern of progesterone-anthracene has characteristic diffraction peaks corresponding to the corresponding positions of the 2 theta values.

TABLE 3 drug Co-crystal progesterone-anthracene sample X-powder diffraction Spectroscopy absorption peaks

EXAMPLE 7 scanning Electron microscopy of drug cocrystals

Drug cocrystal samples were scanned using a Jeol JSM-6100 instrument.

The test results are shown in FIG. 6, where A is a magnification of 500; b is a magnification of 2000; c is a magnification of 5000; as can be seen from a scanning electron microscope image, the size of the eutectic crystal particles is small, and the water solubility is favorably improved; the eutectic particles are uniform, which shows that the preparation process is good and is very beneficial to industrial production and preparation.

EXAMPLE 8 stability study of drug Co-Crystal progesterone-Anthracene

1. Experimental Material

Comprehensive medicine stability test box (Shanghai-Hengscientific instruments Co., Ltd.)

2. Experimental methods

The stability experiment examines the stability and the transformation rule of the sample under the conditions of high temperature, high humidity and illumination. 100mg of test sample powder is filled into a weighing bottle, the opening of the sample is respectively placed under the conditions of high temperature (60 +/-2 ℃), high humidity (90% +/-5%) and illumination (4500 +/-500 lx) for 10 days, and samples are respectively taken on the 0 th day, the 5 th day and the 10 th day for powder X-ray diffraction analysis.

2. Results

The experimental result is shown in fig. 7, the powder X-ray diffraction of the progesterone-anthracene eutectic does not change significantly under the conditions of high temperature, high humidity and illumination, which indicates that the eutectic is stable.

Example 9 solubility study of drug Co-crystals progesterone-anthracene

1. Experimental Material

Tiandatianfa RC806D dissolution tester

2. Experimental methods

Sieving the sample with a 100-mesh sieve, weighing 2g of the sample, respectively adding into 1000mL of deionized water, stirring at 37 ℃ and 100rpm by a slurry method, respectively sampling 2mL at 5min, 15min, 30min, 45min, 60min, 90min, 120min, 180min, 240min, 300min and 360min, filtering with a filter membrane, taking the filtrate as the sample, injecting 2 needles, and detecting by HPLC.

Liquid phase conditions: high performance liquid chromatograph: waters; chromatographic column of Waters Xbridge C184.6 × 150mm, 3.5 μm chromatographic column; mobile phase: acetonitrile and water 45: 55; the detection wavelength is 280 nm; flow rate: 0.8 mL/min; column temperature: 40 ℃; sample introduction amount: 20 mu L of the solution; operating time: and 15 min.

3. Results of the experiment

The experimental result is shown in fig. 8, and the water solubility of the pharmaceutical co-crystal progesterone-anthracene co-crystal is remarkably increased.

EXAMPLE 10 pharmacokinetic Studies of drug Co-Crystal progesterone-Anthracene

1. Animal(s) production

Healthy female SD rats (7-9 weeks old, weight 220 + -30 g, 5 per group) were purchased from Peking Wintolite laboratory animals technology, Inc.

2. Animal administration method

All animals were kept on a 12 hr/12 hr light/dark cycle, 5 animals per cage, with free diet. The progesterone eutectic is prepared into a solution with PBS (phosphate buffered saline, containing 0.1% DMSO), the dosage of the progesterone eutectic is 5.0mg/kg, and the progesterone eutectic is administered through intramuscular injection.

3. Method for preparing biological sample

Samples of 50 μ L jugular venous blood were collected in batches at defined times (15, 30min and 1, 1.5, 2, 3, 5, 7, 12, 24, 48h) into heparinized tubes. The blood was then centrifuged for 15 min. Plasma samples were stored at-20 ℃. mu.L rat plasma, 5. mu.L methanol and 200. mu.L internal standard solution (buspirone, 5ng/mL) were added to 1mL methanol: acetonitrile (1:1, v/v). The plasma samples were vortexed for 1min, centrifuged at 4000rpm for 15min, and the plasma samples were vortexed with methanol: the supernatant was diluted 20 times with water (1:1, v/v, 0.1% trifluoroacetic acid) and injected.

4. Biological sample analysis method

LC-MS/MS instrument model: AB Sciex 5500; LC-MS/MS quantitative analysis software: 1.6.3; an ionization mode: electrospray positive ions; the scanning mode is as follows: multiple Reaction Monitoring (MRM); analyte MRM: EE-DNS, 530.4/171.0; internal standard MRM: buspirone, 386.2/122.2;

liquid phase conditions: shimadzu LC-30AD, ACE Excel 5C 4(50mm × 2.1mm), sample size 10 μ L; mobile phase: a5 mM ammonium acetate (0.05% trifluoroacetic acid) and B acetonitrile (0.1% trifluoroacetic acid) at a flow rate of 0.8mL/min, and the gradients of mobile phases A and B are shown in the following table.

TABLE 4 gradient of mobile phases A and B

Time (min)	A(％)	B(％)
			0.4-1.8	80	20
1.8-2.7	5	95
			2.7-3.5	80	20

5. Results

The test result is shown in fig. 9, the peak reaching time of the progesterone is 1h, the eutectic peak reaching time is 1.5h, and the eutectic Cmax is 1.2 times of the progesterone, so that the bioavailability is better.

The above description of the embodiments is only intended to illustrate the method of the invention and its core idea. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications will also fall into the protection scope of the claims of the present invention.

Claims (10)

1. A pharmaceutical crystal form of progesterone, wherein the crystal form is a pharmaceutical co-crystal of progesterone and anthracene;

preferably, the molecular ratio of progesterone to anthracene in the pharmaceutical crystalline form is 3: 1.

2. The pharmaceutical crystalline form according to claim 1, characterized in that it is characterized by an X-ray powder diffraction pattern comprising the following peaks, in terms of 2 Θ: 9.821 +/-0.2 degrees and 19.64 +/-0.2 degrees;

preferably, the X-ray powder diffraction further comprises peaks at 13.061 ± 0.2 °, 13.539 ± 0.2 °, 14.198 ± 0.2 °, 14.499 ± 0.2 °, 17.76 ± 0.2 °, 18.398 ± 0.2 °, 21.719 ± 0.2 °, 25.459 ± 0.2 °, 26.161 ± 0.2 °;

preferably, the X-ray powder diffraction further comprises peaks at 15.859 ± 0.2 °, 16.981 ± 0.2 °, 20.238 ± 0.2 °, 23.759 ± 0.2 °, 25.961 ± 0.2 °, 29.561 ± 0.2 °;

preferably, the X-ray powder diffraction pattern is substantially as shown in figure 5.

3. The pharmaceutical crystalline form of claim 1, characterized in that it is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 128 ℃;

preferably, the DSC thermogram is substantially as shown in figure 1.

4. The pharmaceutical crystalline form according to claim 1, characterized in thatIt is then characterized by the following unit cell dimensions:

α ═ γ ═ 90.00 °, β ═ 107.425(6) °, Z ═ 2, and the unit cell volume is

5. A process for preparing a pharmaceutical crystalline form according to any one of claims 1 to 4,

1) crushing progesterone and anthracene to obtain a white powder sample,

2) adding a white powder sample into a solvent for dissolving, and volatilizing to obtain a colorless massive crystal;

preferably, the solvent is an ester solvent;

preferably, the solvent is ethyl acetate;

preferably, the progesterone and anthracene are pulverized using a ball mill.

6. A composition comprising an effective amount of the pharmaceutical crystalline form of any one of claims 1-4;

preferably, the composition further comprises a carrier;

preferably, the composition is a pharmaceutical composition, nutraceutical composition, health food or medical food.

7. Use of a pharmaceutical crystalline form according to any one of claims 1 to 4 or a composition according to claim 6 for the manufacture of a medicament for maintaining pregnancy.

8. Use of a pharmaceutical crystalline form according to any one of claims 1 to 4 or a composition according to claim 6 for the manufacture of a medicament for assisted reproduction.

9. Use of the co-crystal according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 6 for the preparation of a medicament for the prevention and/or treatment of gynaecological disorders, cardiovascular and cerebrovascular disorders, neurological disorders.

10. Use according to claim 9, characterized in that the gynaecological disorders comprise spontaneous preterm birth, luteal insufficiency, secondary amenorrhea, premenstrual syndrome.

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