Sublingual lozenge of progesterone and analogues thereof as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to sublingual lozenges of progesterone and analogues thereof as well as a preparation method and application of the sublingual lozenges. Specifically, a novel sublingual administration dosage form which is more suitable for being absorbed by a human body is designed according to physicochemical properties of progesterone and analogues thereof. The sublingual lozenge is composed of a main drug, a filler, a disintegrating agent, a mucous membrane promoter, a flavoring agent, a lubricant and the like. The sublingual lozenge is quickly disintegrated under the action of saliva, is quickly absorbed through tongue mucosa, takes effect quickly, avoids the first-pass effect, improves the bioavailability, and is suitable for various clinical scenes needing quick and efficient progestational hormone support.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a sublingual tablet of progesterone and its analogues, its preparation method, and its application. Background Technology

[0002] Progesterone, also known as luteal hormone, is an endogenous steroid hormone mainly secreted by the corpus luteum of the ovary, placenta, and adrenal glands. As a key physiological regulator, it plays a central role in female reproductive health and overall physiological balance, for example: (1) Core role in reproductive endocrine function: In the second half of the menstrual cycle, progesterone promotes the transformation of the proliferative endometrium into the secretory phase, creating a "window period" for implantation of the fertilized egg; after implantation, it provides a "quiet" developmental environment for the embryo by reducing the excitability of the myometrium and inhibiting the production of prostaglandins, which is key to maintaining early pregnancy (pregnancy support). At the same time, it exerts negative feedback inhibition on the hypothalamus-pituitary axis, preventing the appearance of the luteinizing hormone (LH) peak, thereby inhibiting ovulation. (2) Role in the mammary system: On the basis of estrogen promoting the proliferation of mammary ducts, progesterone is responsible for promoting the full development of mammary alveoli, preparing for postpartum lactation. (3) Systemic effects: It affects the central nervous system (such as sedation and sleep), bone metabolism, cardiovascular system, and fluid balance.

[0003] Given its extensive physiological activity, progesterone has a wide range of clinical applications, including: (1) Luteal support in assisted reproductive technology (ART): In in vitro fertilization-embryo transfer (IVF-ET) and other processes, endogenous luteal insufficiency is caused by factors such as controlled ovulation hyperstimulation. Exogenous progesterone and its analogues are the cornerstone for ensuring embryo implantation and maintaining early pregnancy. (2) Hormone replacement therapy (HRT): Used in perimenopausal and postmenopausal women. When used in combination with estrogen, progesterone is responsible for counteracting the continuous proliferative effect of estrogen on the endometrium, significantly reducing the risk of endometrial hyperplasia and even cancer. (3) Treatment of gynecological and obstetric diseases: Used to treat functional uterine bleeding, amenorrhea, menstrual cycle disorders and threatened / habitual abortion caused by luteal insufficiency. (4) Components of oral contraceptives: When combined with estrogen, it exerts a reliable contraceptive effect by inhibiting ovulation.

[0004] Progesterone and its analogues are mainly divided into two categories based on their chemical structure and origin:

[0005] (1) Natural progestin: that is, progesterone itself, usually obtained by semi-synthesis from plant steroids such as diosgenin. Its greatest advantage is that its molecular structure is completely consistent with that of human endogenous progesterone and its analogues. Therefore, it has extremely high receptor selectivity and excellent safety. Adverse reactions (such as androgen-like effects, negative effects on lipid metabolism, etc.) are far lower than those of most synthetic progestins.

[0006] (2) Synthetic progestins: such as norethindrone, levonorgestrel and its analogues, dydrogesterone and its analogues, drospirenone, etc. The chemical structures of progestins and their analogues are modified to improve their oral bioavailability, prolong their half-life, or enhance their progestin activity. They are the main components of modern oral contraceptives.

[0007] Although synthetic progestins dominate the field of contraception, natural progesterone has become the gold standard or first choice in certain medical settings due to its irreplaceable biohomogeneity and safety. Especially in assisted reproductive technology (ART) and perimenopausal human health intervention (HRT), clinical guidelines generally recommend the use of natural progesterone for reasons of embryo safety, optimal endometrial transformation, and more breast-friendly properties.

[0008] The clinical application of progesterone has long been severely constrained by its own physicochemical properties and pharmacokinetic defects: (1) Extremely low water solubility: Progesterone belongs to BCS (Biopharmaceutics Classification System) Class II drugs, that is, low solubility and high permeability. Its low solubility in an aqueous environment is the first rate-limiting step in its oral absorption. (2) A startling first-pass effect in the liver: This is the biggest challenge faced by oral administration. After being absorbed by the gastrointestinal tract, progesterone first enters the liver through the portal vein system, where it is extensively and rapidly metabolized by the cytochrome P450 enzyme system (mainly CYP3A4) into inactive metabolites such as pregnenolone and pregnanediol. Studies have shown that its first-pass effect after oral administration is as high as 90% or more, resulting in its absolute bioavailability generally being less than 10%.

[0009] To achieve the required serum progesterone concentrations for treatment, patients often have to take extremely high doses (such as 100mg, 200mg, or even 300mg of micronized progesterone capsules). This not only significantly increases medication costs but also leads to substantial dose-dependent central nervous system side effects due to high blood drug concentration fluctuations, such as severe drowsiness, dizziness, vertigo, and fatigue, severely impacting patients' quality of life, work ability, and medication adherence. Many patients discontinue treatment because they cannot tolerate these side effects. To avoid the first-pass effect, the medical community has developed various non-oral routes, but each has significant drawbacks.

[0010] Injection administration: mainly progesterone oil injection. Although it can 100% avoid the first-pass effect and achieve high-efficiency absorption, its invasiveness, the need for professional medical care, injection site pain, induration formation, and possible allergic reactions make it extremely unsuitable for long-term, home-based chronic disease management, resulting in poor patient compliance.

[0011] Vaginal administration is currently the mainstream route for luteal support in ART. Dosage forms include gels, suppositories, and soft capsules. Its advantage lies in achieving the "first-pass effect" in the uterus, meaning that after drug absorption through the vagina, it can reach a relatively high concentration locally in the uterus. However, this route has drawbacks including inconvenience of use, difficulty in operating the applicator, significantly increased vaginal discharge, local itching / burning sensation, impact on sexual life, and privacy concerns in social and cultural activities. Its applicability is limited for patients with non-reproductive indications (such as HRT) or those requiring stable systemic effects.

[0012] Sublingual mucosal administration is a theoretically very attractive alternative route. Its advantages are: (1) Avoiding the first-pass effect of the liver: the drug is absorbed through the rich capillaries and lymphatic vessels under the tongue and enters the systemic circulation directly, with a bioavailability that can theoretically approach 100%. (2) Rapid onset of action: the mucosa is thin and the blood flow rate is high (jugular venous return), so the drug can take effect within minutes. (3) Convenient and discreet administration: no water is needed, it is non-invasive and painless, and patient compliance is extremely high.

[0013] In the existing technology, although there are some studies that mention mucosal administration of progesterone, none of them have successfully developed a stable sublingual tablet formulation that meets all the above requirements and has clinical practical value. Summary of the Invention

[0014] This invention, through innovative formulation design and process optimization, successfully developed a sublingual delivery system for progesterone and its analogues. The sublingual tablets for progesterone and its analogues fully utilize the advantages of sublingual administration, fundamentally solving the problem of low oral bioavailability of progesterone and achieving rapid onset of action. This invention also provides a method for preparing the aforementioned sublingual tablets, which should be simple, reproducible, easy to scale up for production, and ensure stable and controllable formulation quality.

[0015] To achieve the above objectives, the technical solution adopted by the present invention is: a sublingual tablet containing progesterone and its analogues, comprising, by weight 100% of the total weight of the sublingual tablet, the following components:

[0016] Progesterone and its analogues 2%–5%;

[0017] Filler 40%–70%;

[0018] Disintegrant 5%–15%;

[0019] Mucosal promoter 1%–5%;

[0020] Flavoring agent 1%–3%;

[0021] Lubricant 0.5%–2%.

[0022] The sublingual tablet, by weight (100%), comprises the following essential components:

[0023] Progesterone and its analogues: 2%–5% (w / w). As an active pharmaceutical ingredient, this range ensures that each tablet contains a sufficient dose (e.g., 5 mg–30 mg) while avoiding excessive drug loading that could affect tablet disintegration and dissolution.

[0024] Preferably, the progesterone and its analogues are selected from one or more of progesterone, levonorgestrel, mifepristone, dydrogesterone, and medroxyprogesterone acetate, including but not limited to progesterone, levonorgestrel, mifepristone, dydrogesterone, and medroxyprogesterone acetate.

[0025] Filler: 40%–70% (w / w). Its function is to provide the tablet's structural framework and ensure appropriate tablet weight and volume for easy sublingual administration. It is selected from one or more of mannitol, lactose, microcrystalline cellulose, and pregelatinized starch. A combination of mannitol and microcrystalline cellulose is preferred because mannitol has a cool, sweet taste, and its combination with microcrystalline cellulose improves the compressibility of the powder.

[0026] Disintegrant: 5%–15% (w / w). Its core function is to rapidly absorb water and swell upon contact with saliva, generating a strong swelling force that completely disintegrates the tablet into fine particles within 1–2 minutes, greatly increasing the contact area between the drug and the mucous membrane. It is selected from one or more of croscarmellose sodium (CCNa), croscarmellose (PVPP), carboxymethyl starch sodium (CMS-Na), and low-substituted hydroxypropyl cellulose (L-HPC). Croscarmellose sodium is preferred as a superdisintegrant.

[0027] Mucosal promoters: 1%–5% (w / w). This is a key excipient for achieving high absorption efficiency. Its mechanism of action is to reversibly alter the tight junctions between mucosal epithelial cells or perturb the cellular lipid bilayer, temporarily increasing mucosal permeability, thereby promoting the penetration of the barrier by low-water-soluble progesterone and its analogues. Selected from bile salts (such as sodium cholate, sodium taurocholate), sodium citrate, polyoxyethylene lauryl ethers (such as… One or more of chitosan and its derivatives (including series of chitosans). Sodium citrate is preferred due to its high safety, low irritation, and flavor-correcting properties.

[0028] Flavoring agent: 1%–3% (w / w). Used to mask the inherent bitterness of progesterone and its analogues, greatly improving the patient experience. Selected from one or more of menthol, peppermint flavoring, aspartame, sucralose, and steviol glycosides. A combination of menthol and aspartame is preferred, providing immediate cooling and long-lasting sweetness.

[0029] Lubricant: 0.5%–2% (w / w). Used to reduce friction between the powder and the die wall, ensuring smooth tableting and minimal tablet weight variation. Selected from one or more of magnesium stearate, micronized silica (colloidal silica), and sodium stearate fumarate. Magnesium stearate is preferred.

[0030] Based on the above technical solutions, the present invention may have the following further specific options or optimizations.

[0031] Preferably, the particle size distribution of the progesterone and its analogues is D90 < 30 μm. The unit weight of the sublingual tablet is 50 mg to 150 mg. The hardness of the sublingual tablet is 2 to 4 kg / cm². 2 The disintegration time of the sublingual tablet is less than 2 minutes, preferably less than 1.5 minutes. The in vitro dissolution rate of the sublingual tablet is not less than 85% within 10 minutes.

[0032] Furthermore, the present invention also provides a method for preparing the above-mentioned progesterone and its analogue sublingual tablets, which includes the following steps:

[0033] 1) The progesterone and its analogue raw materials are mixed with fillers, disintegrants, mucosal promoters and flavoring agents in the first mixing to obtain the main mixture;

[0034] 2) Add lubricant to the main mixture obtained in step 1) and mix a second time to obtain the final mixture;

[0035] 3) Compress the final mixture obtained in step 2) into sheets.

[0036] Based on the above technical solutions, the present invention may have the following further specific options or optimizations.

[0037] The above preparation method uses direct compression and specifically includes the following steps:

[0038] a) Raw material pretreatment and weighing: Pulverize progesterone and its analogues raw materials and pass them through a 100-mesh sieve to improve their particle size distribution and solubility. Weigh progesterone and its analogues, fillers, disintegrants, mucosal promoters, and flavoring agents according to the precise prescription amounts.

[0039] b) Main mixing: Place all the powder materials weighed in step a) into a three-dimensional motion mixer or a V-type mixer and mix at a speed of 15-30 rpm for 20-40 minutes until a mixed powder with uniform color and fully dispersed components is obtained.

[0040] c) Adding Lubricant: After passing the lubricant (such as magnesium stearate) through an 80-mesh sieve, add it to the main mixed powder above. Continue mixing at a low speed (10-20 rpm) for 3-8 minutes to ensure uniform distribution of the lubricant and avoid over-mixing, which could lead to excessive lubrication and affect disintegration.

[0041] d) Tableting: The final uniformly mixed powder or granules are directly fed into the hopper of a rotary tablet press. A suitable die (e.g., round or elliptical) is selected, and the press pressure is adjusted to directly compress the powder into tablets. Tablet weight and hardness are monitored online to ensure the finished product meets predetermined standards (weight variation within ±5%, hardness 2-4 kg / cm²). 2 ).

[0042] e) Packaging: The compressed tablets must be immediately packaged in an aluminum-plastic blister pack in a low-humidity environment (relative humidity <30%) to prevent moisture absorption.

[0043] Preferably, the first mixing in step 1) is carried out in a three-dimensional motion mixer or a V-type mixer, and is mixed at a speed of 15-30 rpm for 20-40 minutes until a uniform color and all components are fully dispersed; the lubricant in step 2) is sieved through an 80-mesh sieve before being added, and the second mixing is carried out at a speed of 10-20 rpm for 3-8 minutes until the lubricant is evenly distributed; after being pressed into sheets in step 3), the sheets are packaged at a relative humidity of <30%.

[0044] The present invention also provides the use of the above-mentioned ketones and their analogues sublingual tablets in the preparation of medicaments for exerting progesterone effects via sublingual administration; in the preparation of medicaments for luteal support in assisted reproductive technologies; in the preparation of medicaments for hormone replacement therapy during or after menopause; and in the preparation of medicaments for treating threatened abortion, recurrent miscarriage, or menstrual cycle disorders.

[0045] Compared with existing technologies, the beneficial effects of this invention are: the sublingual tablets containing progesterone and its analogues provided by this invention are absorbed through the sublingual mucosa, allowing the drug to directly reach the systemic circulation, thus achieving 100% avoidance of the first-pass effect of the liver. Animal pharmacokinetic studies have conclusively shown that the relative bioavailability of the sublingual tablets of this invention is as high as 356% (i.e., 3.56 times) of that of commercially available oral micronized progesterone and its analogue capsules. This means that to achieve the same blood drug concentration, the required dose of the sublingual tablets containing progesterone and its analogues provided by this invention can be significantly reduced, thereby laying the foundation for the development of new therapies with low doses, high efficacy, and low side effects.

[0046] Thanks to the abundant blood flow under the tongue and the rapid disintegration design of the prescription, the progesterone and its analogue sublingual tablets provided by this invention can be rapidly released and absorbed within one to two minutes. The time to peak concentration (Tmax) is significantly reduced from approximately 2.0 hours with oral administration to approximately 0.5 hours. This characteristic makes it uniquely valuable in scenarios requiring a rapid progesterone effect, such as certain types of acute luteal insufficiency.

[0047] The progesterone and its analogue sublingual tablets provided by this invention are small in size, requiring no water for administration, eliminating the pain of injection, and avoiding the embarrassment and inconvenience of vaginal administration. The administration process is discreet and clean, greatly respecting patient privacy, and is particularly suitable for HRT patients requiring long-term medication or active young patients, with excellent medication adherence expected.

[0048] The sublingual tablets containing progesterone and its analogues provided by this invention significantly improve bioavailability, thereby reducing the absolute dosage required to achieve the same therapeutic effect. This directly means that the incidence and intensity of central nervous system side effects (such as severe drowsiness and dizziness) caused by high peak blood drug concentrations are expected to decrease significantly, thus improving patients' quality of life. Attached Figure Description

[0049] Figure 1 This is a comparison of the average blood concentration-time curves of the progesterone sublingual tablets prepared in Example 1 of this invention and commercially available oral progesterone and its analogues in beagle dogs. Detailed Implementation

[0050] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. However, the implementation of this invention is not limited thereto. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or according to the conditions recommended by the manufacturer.

[0051] Example 1: Formulation screening and preparation of sublingual tablets containing progesterone and its analogues

[0052] This invention designs and compares multiple formulations to ultimately determine the optimal formulation (formulation number: SL-03). The preparation process is illustrated below using the optimal formulation as an example.

[0053] Prescription (dosage per 1000 tablets):

[0054] Progesterone (passed through a 100-mesh sieve): 10.0g

[0055] Mannitol ( 200SD): 50.0g

[0056] Microcrystalline cellulose ( PH102): 15.0g

[0057] Cross-linked carboxymethyl cellulose sodium 10.0g

[0058] Sodium citrate: 3.0g

[0059] Menthol: 1.0g

[0060] Aspartame: 0.5g

[0061] Magnesium stearate: 0.5g

[0062] Total weight: 90.0g (each tablet weighs 90mg and contains 10mg of progesterone)

[0063] Preparation process:

[0064] 1. Pretreatment: Progesterone and its analogue raw materials are processed by air jet mill to ensure that more than 90% of the particles have a particle size D90 < 30 μm.

[0065] 2. Main Mixing: Add progesterone and its analogues, mannitol, microcrystalline cellulose, croscarmellose sodium, sodium citrate, menthol, and aspartame sequentially to a 60L three-dimensional motion mixer. Set the mixer speed to 20 rpm and the mixing time to 30 minutes.

[0066] 3. Add lubricant: After mixing, stop the machine. Evenly sprinkle the magnesium stearate (which has passed through an 80-mesh sieve) onto the powder surface. Restart the mixer, set the speed to 15 rpm, and mix for 5 minutes.

[0067] 4. Tableting: Transfer the well-mixed final powder to a 32-punch rotary tablet press equipped with a forced feeder. Use a standard circular concave die with a diameter of 6mm. Set the main pressure of the tablet press to 8kN, control the tablet weight to 90mg ± 2.7mg (3%), and the average hardness to 3.2kg / cm². 2 .

[0068] 5. Packaging and storage: The compressed tablets should be packaged immediately using an aluminum-aluminum blister packaging machine at a temperature of 25±2℃ and a relative humidity of <30%.

[0069] Example 2: Pharmacokinetic Study

[0070] To objectively evaluate the in vivo performance of the formulation of this invention, we conducted rigorous animal pharmacokinetic studies. The experimental animals were healthy adult male beagle dogs, weighing 15±2 kg, SPF grade, fasted for 12 hours before the experiment, and allowed free access to water. The dogs were randomly divided into two groups of three. The experimental group (T) was given sublingual tablets of progesterone and its analogues prepared in Example 1 of this invention. The tablets were precisely placed under the dog's tongue to ensure natural absorption. The control group (R) was given commercially available progesterone micronized oral capsules (… The contents of 100 mg / capsule were administered orally by gavage. Both groups were given an equivalent dose of progesterone 1.0 mg / kg.

[0071] Blood sample collection: Approximately 3 mL of blood was collected venously before drug administration (0 h) and at 0.15 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, and 48 h after drug administration. Blood samples were anticoagulated with heparin, immediately centrifuged (4℃, 4000 rpm, 10 min) to separate plasma, and frozen at -80℃ for analysis. The concentration of progesterone in Beagle dog plasma was determined using a well-validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) method. This method exhibits high sensitivity (LLOQ of 0.1 ng / mL), strong specificity, and accuracy and precision meeting the requirements for biological sample analysis.

[0072] Experimental conditions: (1) Chromatographic conditions: C18 column 4.6×150mm, flow rate 1.0mL / min, mobile phase is methanol:water (containing 0.5% formic acid) 80:20; (2) Mass spectrometry conditions: ion source is atmospheric pressure chemical ionization source, temperature is 450℃, discharge current is 2A, scanning mode is positive ion MRM, detection ion pair is m / z 315 / 97 progesterone, m / z 295 / 109 norethindrone (internal standard).

[0073] Data processing: using 8.1 software was used to calculate the pharmacokinetic parameters of each group using a non-compartmental model. Results are expressed as mean ± standard deviation (Mean ± SD). SPSS software was used for t-tests, and P < 0.05 was considered statistically significant.

[0074] Results and conclusions:

[0075] Table 1. Main pharmacokinetic parameters

[0076]

[0077] Conclusion: Based on the main pharmacokinetic parameters summarized in Table 1, the sublingual tablets of progesterone and its analogues of this invention exhibit significant pharmacokinetic advantages compared to commercially available oral capsules. The time to peak concentration (Tmax) was significantly shortened, indicating rapid drug absorption; the peak concentration (Cmax) and area under the curve (AUC) were both significantly increased, demonstrating a substantial improvement in absorption. The relative bioavailability was 2.06 times that of the oral formulation, fully validating that the formulation of this invention, administered sublingually, can almost completely avoid the first-pass effect of the liver, thereby achieving a significant leap in absorption rate and extent. The elimination half-life (t) between the two groups was also significantly improved. 1 / 2 There was no significant difference, indicating that the change in dosage form does not affect the final elimination process of the drug in the body.

[0078] Example 3: Formulation Quality Study

[0079] Quality studies were conducted on three batches of small-scale samples (batch numbers: SL20241001, SL20241002, SL20241003) prepared according to the process in Example 1.

[0080] Appearance: All three batches of samples were off-white tablets with a smooth and flat surface, uniform color, and no obvious color spots.

[0081] Disintegration time: Tested according to General Chapter 0921 (Disintegration Time Test Method for Sublingual Tablets) of Part IV of the 2020 edition of the Chinese Pharmacopoeia. Using purified water as the medium, the disintegration times of the three batches of samples were 65 seconds, 58 seconds and 71 seconds, respectively, which are far below the upper limit of 5 minutes specified in the pharmacopoeia, indicating that the tablets can disintegrate rapidly upon contact with saliva.

[0082] Dissolution: The dissolution test method (method II - paddle method) of General Chapter 0931, Part IV, 2020 edition of the Chinese Pharmacopoeia was adopted. However, considering the characteristics of sublingual administration, the small cup method was selected, using 200 ml of phosphate buffer solution at pH 6.8 as the dissolution medium and a paddle speed of 50 rpm. Samples were taken and measured at 5, 10, and 15 minutes. The results are shown in Table 2 below:

[0083] Table 2 Dissolution results of the drugs

[0084] batch number SL20241001 SL20241002 SL20241003 5-minute dissolution 72.3％ 75.1％ 70.8％ Dissolution rate at 10 minutes 88.5％ 91.2％ 87.9％ Dissolution rate at 15 minutes 95.6％ 94.7％ 96.8％

[0085] The results in Table 2 show that the dissolution rate of this product was greater than 85% within 10 minutes, indicating rapid and complete drug release.

[0086] Example 4: Verification Experiment of Key Auxiliary Material Functions

[0087] To verify the synergistic effect of the mucosal promoter and disintegrant in the formulation, a comparative experiment was designed. The following three formulations were prepared: Formulation A: the complete formulation of this invention (same as Example 1); Formulation B: without the mucosal promoter (sodium citrate), otherwise the same as Formulation A; Formulation C: the amount of disintegrant was halved (5%), otherwise the same as Formulation A.

[0088] Evaluation methods and conditions:

[0089] In vitro disintegration time: Following the method in Example 3, a disintegration time limit tester was used to record the time it took for the tablet to completely disintegrate and pass through a sieve.

[0090] In vitro mucosal permeation rate: A Franz vertical diffusion cell was used, with fresh isolated porcine oral mucosa (pretreated, approximately 500-700 μm thick) as the permeation barrier. The supply chamber contained a pH 6.8 phosphate buffer solution with a specific concentration of progesterone and its analogues, while the receiving chamber contained physiological saline containing 30% polyethylene glycol 400. A constant temperature of 37°C with magnetic stirring was maintained. Samples were taken at predetermined time points, and the receiving solution was replenished. The concentration of progesterone and its analogues was determined by HPLC, and the cumulative permeation per unit area (Qn) was calculated. The permeation rate was then measured at a steady-state rate (Jss, μg / cm³). 2 / h) Evaluate permeability performance. For intuitive comparison, the relative permeation rate is calculated with Jss of Formulation A as 100%, see Table 3.

[0091] Table 3. In vitro mucosal permeation rate

[0092]

[0093] From the above experimental data, we can see that:

[0094] 1. Compared with the complete formulation A, the disintegration time of formulation B (without mucosal promoter) was only slightly prolonged, with no significant difference, but its mucosal penetration rate dropped sharply to 42%. This eloquently demonstrates that sodium citrate, as a mucosal promoter, plays a crucial role in promoting the penetration of progesterone and its analogues across biological barriers in this invention; the absence of this component would severely restrict the absorption efficiency of the drug.

[0095] 2. The disintegration time of formulation C (half-dose disintegrant) was significantly prolonged to nearly 3 minutes, while its penetration rate also decreased to 85%. This indicates that sufficient disintegrant is a prerequisite for ensuring rapid tablet disintegration and rapid drug dissolution. Slow disintegration leads to a reduction in the effective surface area of ​​the drug and a delay in the establishment of the concentration gradient, which indirectly but significantly affects the rate of mucosal penetration.

[0096] 3. This experiment fully verifies the synergistic effect of the disintegrant and the mucosal promoter in the formulation of this invention: the disintegrant ensures the rapid release of the drug to the absorption site, while the mucosal promoter strongly promotes the transmembrane transport of the drug. Both are indispensable and together constitute the core technology of this invention to achieve efficient sublingual drug delivery.

[0097] discuss

[0098] In summary, the progesterone and its analogue sublingual tablets provided by this invention have a scientifically sound and reasonable formulation design. The selected excipients are all commonly used pharmaceutical excipients listed in domestic and international pharmacopoeias, readily available, and inexpensive, thus eliminating any access barriers. The direct compression manufacturing process is concise, eliminating the need for complex unit operations such as granulation and drying. This not only saves energy and reduces consumption, shortening the production cycle, but also avoids the potential impact of wet and hot processes on drug stability. Product quality (such as content, impurities, and dissolution behavior) is easier to control, and the process reproducibility is excellent.

[0099] This invention successfully solves the long-standing clinical problem of low oral bioavailability of progesterone, providing a new option for the administration of progesterone and its analogues that is rapid-acting, convenient and discreet to use, has high patient compliance, and is expected to have better safety profiles in fields such as assisted reproduction, perimenopausal hormone replacement therapy, and the treatment of gynecological endocrine disorders. This invention has a clear market positioning and broad application prospects; its promotion and implementation will generate significant social and economic benefits.

[0100] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A sublingual tablet containing progesterone and its analogues, characterized in that, The sublingual tablet, by weight 100%, comprises the following components: Progesterone and its analogues 2%–5%; Filler 40%–70%; Disintegrant 5%–15%; Mucosal promoter 1%–5%; Flavoring agent 1%–3%; Lubricant 0.5%–2%.

2. A sublingual tablet containing progesterone and its analogues according to claim 1, characterized in that: The progesterone and its analogues are selected from one or more of progesterone, levonorgestrel, mifepristone, dydrogesterone, and medroxyprogesterone acetate.

3. A sublingual tablet containing progesterone and its analogues according to claim 2, characterized in that: The filler is selected from one or more of mannitol, lactose, microcrystalline cellulose, and pregelatinized starch.

4. A sublingual tablet containing progesterone and its analogues according to claim 1, characterized in that: The disintegrant is selected from one or more of croscarmellose sodium, croscarmellose sodium, and low-substituted hydroxypropyl cellulose.

5. A sublingual tablet containing progesterone and its analogues according to claim 1, characterized in that: The mucosal promoter is selected from one or more of cholates, sodium citrate, polyoxyethylene lauryl ether, chitosan and its derivatives.

6. A sublingual tablet containing progesterone and its analogues according to claim 5, characterized in that: The flavoring agent is selected from one or more of menthol, peppermint flavoring, aspartame, sucralose, and steviol glycosides; the lubricant is selected from one or more of magnesium stearate, micronized silica gel, and sodium stearate fumarate.

7. A sublingual tablet containing progesterone and its analogues according to claim 5, characterized in that: The particle size distribution of the progesterone and its analogues is D90 < 30 μm; the unit weight of the sublingual tablet is 50 mg to 150 mg; the hardness of the sublingual tablet is 2 to 4 kg / cm². 2 The disintegration time of the sublingual tablet is less than 2 minutes, preferably less than 1.5 minutes; the in vitro dissolution rate of the sublingual tablet is not less than 85% within 10 minutes.

8. A method for preparing a sublingual tablet of progesterone and its analogues as described in any one of claims 1 to 7, characterized in that, Includes the following steps: 1) The progesterone and its analogue raw materials are mixed with fillers, disintegrants, mucosal promoters and flavoring agents in the first mixing to obtain the main mixture; 2) Add lubricant to the main mixture obtained in step 1) and mix a second time to obtain the final mixture; 3) Compress the final mixture obtained in step 2) into sheets.

9. A method for preparing a sublingual tablet of progesterone and its analogues as described in claim 8, characterized in that, The first mixing in step 1) is carried out in a three-dimensional motion mixer or a V-type mixer at a speed of 15-30 rpm for 20-40 minutes until a uniform color and sufficient dispersion of each component are obtained; the lubricant in step 2) is sieved through an 80-mesh sieve before being added; the second mixing is carried out at a speed of 10-20 rpm for 3-8 minutes until the lubricant is evenly distributed; after being pressed into sheets in step 3), the sheets are packaged at a relative humidity of <30%.

10. Use of a sublingual tablet of progesterone and its analogues as described in any one of claims 1 to 7 in the preparation of a medicament for exerting progesterone effects via sublingual administration; in the preparation of a medicament for luteal support in assisted reproductive technologies; in the preparation of a medicament for hormone replacement therapy during or after menopause; in the preparation of a medicament for treating threatened abortion, recurrent miscarriage, or menstrual cycle disorders.

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