A doxycycline hydrochloride-vinolauric acid fumarate double-layer tablet and a preparation method thereof

Abstract

The application provides a doxycycline hydrochloride fumarate vunoral double-layer tablet and a preparation method and application thereof. The first layer of the double-layer tablet comprises doxycycline hydrochloride and is mainly composed of doxycycline hydrochloride, a lubricant and a filler with direct compression performance; the second layer comprises fumarate vunoral and mainly comprises fumarate vunoral, a filler, a disintegrating agent, a binder, an organic acid and a lubricant. The double-layer tablet is obtained by tabletting after granulation and then subjected to film coating treatment to form the final double-layer tablet. The double-layer tablet prepared by the application has high solubility and good stability, and has the advantages of stable and reliable process and low cost.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to a pharmaceutical composition comprising the broad-spectrum antibiotic doxycycline hydrochloride and the PPI-potassium ion competitive acid blocker vonoprazan fumarate, particularly to a bilayer tablet pharmaceutical composition of doxycycline hydrochloride and vonoprazan fumarate and its preparation. Background Technology

[0002] Doxycycline hydrochloride belongs to the tetracycline class and has broad-spectrum antibacterial activity. Sensitive bacteria include Gram-positive bacteria such as Bacillus anthracis, Clostridium tetani, Streptococcus pneumoniae, Streptococcus, some Staphylococcus aureus, and Corynebacterium, as well as Gram-negative bacteria such as Helicobacter pylori, Salmonella, Brucella, Haemophilus influenzae, Escherichia coli, Pasteurella multocida, Klebsiella pneumoniae, and Burkholderia glandulae. It also has some inhibitory effect on Rickettsia, Mycoplasma, and Spirochetes. It is rapidly absorbed orally, has strong tissue penetration, high bioavailability, a long duration of effective blood concentration, easily enters cells, has a wide distribution, and is less affected by food. Its structural formula is as follows:

[0003]

[0004] Vonoprazan fumarate is a novel PPI (potassium-competitive acid blocker, P-CAB). It is a reversible potassium antagonist that works by competitively inhibiting potassium in hydrogen / potassium ATPase. Compared to traditional PPIs, it clinically significantly reduces the occurrence of nocturnal acid breakthrough (a phenomenon where pH < 4.0 occurs for more than one hour after taking a proton pump inhibitor at night), and its acid-suppressing effect is independent of proton pump activation. Its structural formula is as follows:

[0005]

[0006] The original Japanese-marketed doxycycline hydrochloride tablets (trade name: Vibramycin, licensee: Pfizer Japan Inc.) are prepared using a wet granulation method. The main process steps include premixing, wet granulation, drying, sizing, and mixing to obtain the intermediate product for tableting. The original Takeda patent CN102743330B discloses vonoprazan fumarate tablets, which use a one-step fluidized bed granulation method. The main process steps include premixing, fluidized bed granulation, drying, sizing, and mixing to obtain the intermediate product for tableting. However, these processes are relatively complex and suffer from high energy consumption, low production efficiency, and high costs. To improve the instability and degradation characteristics of vonoprazan fumarate under light conditions, this patent suggests adding titanium dioxide, plasticizers (such as polyethylene glycol), and chain organic acids to improve the photostability of its solid formulation. However, due to the low melting point of polyethylene glycol, commonly used polyethylene glycols have melting points between approximately 40-70°C, with polyethylene glycol 6000 having a melting point of 55-63°C. This makes it prone to melting under high-temperature and accelerated testing conditions during stability studies, thus affecting the stability of vonoprazan fumarate tablets.

[0007] The classic treatment regimen for Helicobacter pylori infection usually uses triple therapy (PPI + 2 antibiotics) or quadruple therapy (PPI + bismuth + 2 antibiotics). If this formulation is used, the clinical dosing regimen can be adjusted to triple therapy (this formulation + 1 antibiotic) or quadruple therapy (this formulation + bismuth + 1 antibiotic).

[0008] However, no drug combination of doxycycline hydrochloride and vonoprazan fumarate has been found to date, especially in the literature regarding its preparation as a bilayer tablet. This invention aims to develop a novel pharmaceutical composition for treating gastric diseases caused by certain susceptible bacteria, particularly Helicobacter pylori infection, while providing an improved combination administration method to enhance patient compliance and thus improve clinical efficacy. Summary of the Invention

[0009] The primary objective of this invention is to provide a bilayer tablet formulation of doxycycline hydrochloride and vonoprazan fumarate, which has a good appearance (smooth surface, uniform color), good physical properties (hardness, disintegration time, friability), and dissolution curves (0.1N hydrochloric acid, pH 4.5 acetate, pH 6.8 phosphate buffer, and aqueous medium, etc.) similar to those of single-component tablets. Its stability (influencing factors over 30 days) is comparable to that of single-component tablets. The product features high safety, high production efficiency, low energy consumption, and low cost, and can meet the requirements for synergistic drug delivery.

[0010] The second objective of this invention is to provide a method for preparing doxycycline hydrochloride and vonoprazan fumarate bilayer tablets.

[0011] The third objective of this invention is to provide a novel administration method for a marketed drug for use in the treatment of gastric diseases caused by susceptible bacteria, particularly in synergistic administration in eradication regimens for Helicobacter pylori infection, thereby improving patient compliance and enhancing efficacy.

[0012] To achieve the above-mentioned objectives, the technical solution adopted is as follows:

[0013] In a first aspect, the present invention provides a bilayer tablet of doxycycline hydrochloride and vonoprazan fumarate, comprising:

[0014] (1) The first layer contains doxycycline hydrochloride;

[0015] (2) The second layer contains vonoprazan fumarate;

[0016] (3) Optionally, it also includes a film coating layer.

[0017] Furthermore, the first layer comprises, based on the total weight of the first layer: 10-50% doxycycline hydrochloride; 0.5-5.0% lubricant; and the balance being a compressible filler.

[0018] The compressible filler in the first layer is selected from one or more combinations of microcrystalline cellulose, starch fillers, sugars and / or sugar alcohols, and composite fillers;

[0019] Preferably, the starch filler is pregelatinized starch;

[0020] Preferably, the sugar is glucose;

[0021] Preferably, the sugar alcohol includes at least one of maltitol, xylitol, or mannitol;

[0022] Preferably, the composite filler includes at least one of mannitol starch complex, starch lactose complex, or cellulose lactose;

[0023] The lubricant includes magnesium stearate and / or sodium stearate fumarate;

[0024] Optionally, the lubricant may also include talc.

[0025] Furthermore, the second layer comprises, based on the total weight of the second layer: 5-30% vonoprazan fumarate; 60-90% filler; 1-20% disintegrant; 1-10% binder; 0-5% organic acid; and 0.5-5% lubricant.

[0026] The filler in the second layer is selected from one or more combinations of lactose, mannitol, starch, and microcrystalline cellulose; the disintegrant is selected from one or more combinations of cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and povidone; the binder is selected from one or more combinations of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone; the lubricant is selected from one or more combinations of magnesium stearate, talc, and silica; and the organic acid is selected from fumaric acid.

[0027] Furthermore, in the bilayer sheet, the weight ratio of doxycycline to vonoprazan, based on free base, is 2.0 to 10:1, preferably 2.0 to 5:1.

[0028] Secondly, the present invention provides a method for preparing doxycycline hydrochloride and vonoprazan fumarate bilayer tablets, comprising the following steps:

[0029] 1) Preparation of the first layer of total mixed particles: After sieving and dispersing doxycycline hydrochloride and filler, add them to a mixer and mix evenly. Then add the prescribed amount of lubricant and continue to mix evenly to obtain the first layer of total mixed intermediate product.

[0030] 2) Preparation of the second layer of total mixed particles: After sieving and dispersing the fumaric acid vonoprazan and the filler, the particles are placed in a multifunctional fluidized bed for one-step granulation. The binder of the prepared hydroxypropyl cellulose and fumaric acid solution is added, along with the disintegrant and lubricant. The particles are then placed in a mixer and mixed evenly to obtain the second layer of total mixed particles.

[0031] 3) Tableting and Coating: The two layers of material are compressed into tablets using a rotary tablet press to obtain tablet cores, which are then coated to finally produce double-layer tablets of doxycycline hydrochloride and vonoprazan fumarate.

[0032] Thirdly, the present invention provides the above-prepared doxycycline hydrochloride and vonoprazan fumarate bilayer tablets for use in the treatment of gastric diseases caused by susceptible bacteria, especially in the eradication regimen of Helicobacter pylori infection, to improve patient compliance and enhance efficacy. Invention Details

[0034] To facilitate understanding of this invention, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0035] The term "double-layer tablet" refers to a tablet formed by compressing two layers of drug powder under pressure two or more times. Its characteristic is that each layer typically contains a different drug or excipient to meet specific therapeutic needs. Its compression principle is similar to that of ordinary tablets (single-layer tablets), but it is not simply a matter of two compression processes being superimposed. During compression, the first layer of the tablet press's feeding system first overfills the bottom layer of drug powder. Then, a metering guide lifts the lower punch to eject and scrape off the excess drug powder from the middle die. The scraped-off drug powder can be recycled or directly removed. Afterward, the bottom layer is compressed by the first-layer pre-compression system (or main compression system). At this point, the bottom layer drug column is not lifted out of the tablet but directly enters the second-layer feeding system. After cleaning the worktable, the same steps are used for overfilling, metering, scraping, pre-compression, and main compression of the second layer of drug powder, ultimately completing the compression and forming of the double-layer tablet.

[0036] The term "film coating" is a conventional solid dosage form technology with advantages such as low dosage, short processing time, simple operation, and taste masking. Coated tablets not only isolate unpleasant tastes but also improve swallowability. After core coating, we examined the appearance and physical properties of the coated tablets to assess good clinical adherence. Referring to the dissolution methods for single-component formulations, we compared dissolution profiles in four media (0.1N hydrochloric acid, pH 4.5 acetate, pH 6.8 phosphate buffer, and water) to ensure similar dissolution behavior, comparable in vivo absorption, and clinical efficacy. We also tested the stability of the coated tablets using the same packaging as the single-component formulations, comparing the results to ensure comparable stability and safety.

[0037] The term "directly compressible filler" refers to a filler that can be directly used in powder tableting without the need for powder granulation before tableting.

[0038] Compared with the prior art, the beneficial effects of this invention are as follows:

[0039] 1. Compared with the prior art, the present invention prepares doxycycline hydrochloride and vonoprazan fumarate into a bilayer tablet, which can improve the dissolution rate and stability of the drug; by preparing a bilayer tablet, the ratio of the effective components of doxycycline hydrochloride and vonoprazan fumarate is limited, which can reduce the step of determining the ratio and dosage of the two components in the treatment process, improve the accuracy of medication, and facilitate patients' medication.

[0040] 2. The bilayer tablets prepared by the method of this invention utilize microcrystalline cellulose (direct compression type) as a filler in the first layer to ensure uniform distribution and molding of doxycycline hydrochloride, while also possessing excellent flowability and compressibility. The use of lubricants not only facilitates the tableting process and prevents sticking, but also ensures a smooth tablet surface. Furthermore, the overall process is simple and cost-effective. In the second layer, plasticizers are avoided; polyethylene glycol 6000 and hydroxypropyl cellulose are selected as film-forming materials, and light-blocking agents such as titanium dioxide are added to enhance stability. This results in bilayer tablets of this invention exhibiting excellent stability under light conditions, comparable to single-component formulations.

[0041] 3. After 30 days of accelerated testing, the bilayer sheet still exhibits good stability under conditions such as high temperature (60℃), high humidity (25℃-90%RH), and light exposure (4500lux±500lux). Detailed Implementation

[0042] The embodiments of the present invention will be described in detail below with reference to specific examples. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention.

[0043] Example 1: Sample 1 (Specification: 100mg / 20mg)

[0044] Table 1. Prescription composition of Sample 1

[0045]

[0046] Note: "100mg / 20mg" indicates that the sample contains 100mg of doxycycline (calculated as free base) and 20mg of vonoprazan (calculated as free base).

[0047] Preparation method:

[0048] (1) Preparation of the first layer of total mixed particles: First, doxycycline hydrochloride and microcrystalline cellulose are sieved and dispersed, then added to a mixer and mixed evenly. Then, the prescribed amount of magnesium stearate is added and mixed evenly to obtain the first layer of total mixed intermediate product.

[0049] (2) Preparation of the second layer of total mixed particles: Vonoprazan fumarate, mannitol, and microcrystalline cellulose were dispersed by sieving and then granulated in a multifunctional fluidized bed in one step. The prepared hydroxypropyl cellulose and fumaric acid solution was used as a binder. Crosslinked sodium carboxymethyl cellulose and magnesium stearate were added and mixed evenly in a mixer to obtain the second layer of total mixed particles.

[0050] (3) Tableting: The two layers of material are pressed together using a rotary tablet press to obtain tablet cores.

[0051] (4) Coating: Place the tablet cores obtained above into a coating machine, select Carbohydrate (same as the formulation in Table 1) coating powder, and coat the uncoated tablets. After preparing the final coated tablet samples according to the formulation in Table 1, examine the appearance, hardness, disintegration time, and dissolution curve of the coated tablets, and compare them with single-component formulations of doxycycline hydrochloride tablets and vonoprazan fumarate tablets.

[0052] Influencing factors:

[0053] The stability of the coated tablets and single-component formulations of this product was compared under high temperature (60℃), high humidity (25℃-90%RH), and light (4500lux±500lux).

[0054] Example 2: Sample 2 (Specification: 50mg / 20mg)

[0055] Table 2. Prescription composition of Sample 2

[0056]

[0057] Note: "50mg / 20mg" indicates that the sample contains 50mg of doxycycline (calculated as free base) and 20mg of vonoprazan (calculated as free base).

[0058] Preparation method: Same as in Example 1.

[0059] Influencing factors: Same as in Example 1.

[0060] Example 3: Sample 3 (Specification: 100mg / 10mg)

[0061] Table 3. Prescription composition of Sample 3

[0062]

[0063]

[0064] Note: "100mg / 10mg" indicates that the sample contains 100mg of doxycycline (calculated as free base) and 10mg of vonoprazan (calculated as free base).

[0065] Preparation method: Same as in Example 1.

[0066] Influencing factors: Same as in Example 1.

[0067] Example 4: Sample 4 (Specification: 50mg / 10mg)

[0068] Table 4. Prescription composition of Sample 4

[0069]

[0070]

[0071] Note: "50mg / 10mg" indicates that the sample contains 50mg of doxycycline (calculated as free base) and 10mg of vonoprazan (calculated as free base).

[0072] Preparation method: Same as in Example 1.

[0073] Influencing factors: Same as in Example 1.

[0074] Example 5: Sample 5 (Specification: 100mg / 20mg)

[0075] Table 5. Prescription composition of Sample 5

[0076]

[0077] Note: "100mg / 20mg" indicates that the sample contains 100mg of doxycycline (calculated as free base) and 20mg of vonoprazan (calculated as free base).

[0078] Preparation method: Same as in Example 1.

[0079] Influencing factors: Same as in Example 1.

[0080] Experimental Result 1: Appearance of Coated Flakes

[0081] Table 5. Appearance of Coated Sheets

[0082]

[0083]

[0084] In summary, the bilayer tablet pharmaceutical composition of the present invention has a good appearance and meets the formulation requirements.

[0085] Experimental Result 2: Physical Properties of Coated Sheets

[0086] Table 6 Physical properties of coated sheets

[0087]

[0088] In summary, based on the appearance of the coated tablets, the bilayer tablet pharmaceutical composition of the present invention has a suitable hardness and qualified brittleness. The disintegration time of the pharmaceutical composition of the present invention is comparable to that of the single-component formulation (reference formulation), thus meeting the formulation requirements.

[0089] Experimental Result 3: Dissolution Curve of Coated Tablets

[0090] Table 7. Multi-media dissolution curves of bilayer tablets and doxycycline hydrochloride tablets (100 mg)

[0091]

[0092]

[0093] In summary, the bilayer tablet drug composition (100mg / 20mg, 100mg / 10mg) of this invention has a similar multi-media dissolution curve to that of doxycycline hydrochloride tablet (100mg) monoprenograph (f2>50).

[0094] Table 8. Multi-media dissolution curves of bilayer tablets and doxycycline hydrochloride tablets (50 mg)

[0095]

[0096]

[0097] In summary, the bilayer tablet drug compositions (50mg / 20mg, 50mg / 10mg) of this invention have similar multi-media dissolution curves to the single-component formulation of doxycycline hydrochloride tablets (50mg) (f2>50).

[0098] Table 9. Multimedia dissolution curves of bilayer tablets and vonoprazan fumarate tablets (20 mg).

[0099]

[0100]

[0101] Summary: The bilayer tablet drug composition (100mg / 20mg, 50mg / 20mg) of this invention has a similar multi-media dissolution curve to vonoprazan fumarate tablet (20mg) monopren.

[0102] Table 10 Multimedia Dissolution Curves of Bilayer Tablets and Vonoprazan Fumarate Tablets (10 mg)

[0103]

[0104]

[0105] Summary: The bilayer tablet drug composition (100mg / 10mg, 50mg / 10mg) of this invention has a similar multi-media dissolution curve to vonoprazan fumarate tablet (10mg) monopren.

[0106] Experimental Result 4: Stability of Coated Tablets

[0107] The stability of the bilayer tablet drug composition and the single-component formulation of this invention were investigated under conditions of high temperature (60℃), high humidity (25℃-90%RH), and light (4500lux±500lux), respectively. The data are detailed in Tables 11, 12 and 13.

[0108] Table 11. Stability study of bilayer tablet formulations and single-component formulations (high temperature 60℃, 30 days)

[0109]

[0110]

[0111] In summary, the stability of the bilayer tablet drug composition (100mg / 10mg, 50mg / 10mg, 100mg / 20mg, 50mg / 20mg) of this invention is comparable to that of doxycycline hydrochloride tablets (100mg, 50mg) and vonoprazan fumarate tablets (10mg, 20mg) monoprena under high temperature (60°C) conditions.

[0112] Table 12 Stability Study of Bilayer Tablet and Single-Ingredient Formulations (High Humidity 25℃-90%RH, 30 days)

[0113]

[0114] In summary, the stability of the bilayer tablet drug composition (100mg / 10mg, 50mg / 10mg, 100mg / 20mg, 50mg / 20mg) of this invention is comparable to that of doxycycline hydrochloride tablets (100mg, 50mg) and vonoprazan fumarate tablets (10mg, 20mg) under high humidity (25℃-90%RH) conditions.

[0115] Table 13 Stability study of bilayer tablet formulations and single-component formulations (4500 lux ± 500 lux light exposure, 30 days)

[0116]

[0117] In summary, the stability of the bilayer tablet drug composition (100mg / 10mg, 50mg / 10mg, 100mg / 20mg, 50mg / 20mg) of this invention is comparable to that of doxycycline hydrochloride tablets (100mg, 50mg) and vonoprazan fumarate tablets (10mg, 20mg) under light exposure (4500lux±500lux).

Claims

1. A bilayer tablet of doxycycline hydrochloride and vonoprazan fumarate, characterized in that, Include: (1) The first layer contains doxycycline hydrochloride; (2) The second layer contains vonoprazan fumarate; (3) Optionally, it also includes a film coating layer.

2. The double-layer sheet according to claim 1, characterized in that, The first layer comprises, based on the total weight of the first layer: 10-50% doxycycline hydrochloride; 0.5-5.0% lubricant; and the balance being a compressible filler.

3. The double-layer sheet according to claim 2, characterized in that, The compressible filler is selected from one or more combinations of microcrystalline cellulose, starch fillers, sugars and / or sugar alcohols, and composite fillers.

4. The double-layer sheet according to claim 3, characterized in that, The starch filler is pregelatinized starch; the sugar is glucose; the sugar alcohol includes at least one of maltitol, xylitol, or mannitol; the composite filler includes at least one of mannitol-starch complex, starch-lactose complex, or cellulose-lactose.

5. The double-layer sheet according to claim 2, characterized in that, The lubricant of the first layer comprises magnesium stearate and / or sodium stearate fumarate; optionally, the lubricant also comprises talc.

6. The double-layer sheet according to claim 1, characterized in that, The second layer comprises, based on the total weight of the second layer: 5-30% vonoprazan fumarate; 60-90% filler; 1-20% disintegrant; 1-10% binder; 0-5% organic acid; and 0.5-5% lubricant.

7. The double-layer sheet according to claim 6, characterized in that, The filler is selected from one or more combinations of lactose, mannitol, starch, and microcrystalline cellulose; the disintegrant is selected from one or more combinations of croscarmellose sodium, carboxymethyl cellulose calcium, and povidone; the binder is selected from one or more combinations of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone; the lubricant is selected from one or more combinations of magnesium stearate, talc, and silica; and the organic acid is selected from fumaric acid.

8. The double-layer sheet according to claim 1, characterized in that, The weight ratio of doxycycline to vonoprazan, calculated as free base, is 2.0 to 10:

1.

9. The method for preparing a bilayer sheet according to any one of claims 1 to 8, characterized in that, Includes the following steps: 1) Preparation of the first layer of total mixed particles: After sieving and dispersing doxycycline hydrochloride and filler, add them to a mixer and mix evenly. Then add the prescribed amount of lubricant and continue to mix evenly to obtain the first layer of total mixed intermediate product. 2) Preparation of the second layer of total mixed particles: After sieving and dispersing the fumaric acid vonoprazan and the filler, the particles are placed in a multifunctional fluidized bed for one-step granulation. The binder of the prepared hydroxypropyl cellulose and fumaric acid solution is added, along with the disintegrant and lubricant. The particles are then placed in a mixer and mixed evenly to obtain the second layer of total mixed particles. 3) Tableting and Coating: The two layers of material are compressed into tablets using a rotary tablet press to obtain tablet cores, which are then coated to finally produce double-layer tablets of doxycycline hydrochloride and vonoprazan fumarate.

Images