Eflucimide oral compositions

Abstract

The present invention relates to an oral composition comprising a co-formed product of albaconazole and polyethylene glycol and a pharmaceutically acceptable additive. The oral composition of the present invention is stable and has high bioavailability, and thus is excellent in administration effect.

Description

Technical Field

[0001] This invention relates to a stable oral composition of icoconazole that has high bioavailability and excellent administration effect. Background Technology

[0002] Efluconazole is a triazole compound with proven activity in the treatment of onychomycosis. It exhibits antifungal activity by inhibiting the synthesis of ergosterol, a major component of the fungal cell membrane.

[0003] Currently, the commercially available product is Jublia. TM Jublia uses effluconazole as its main ingredient and is used to treat onychomycosis caused by dermatophytes. It received product approval from the food and drug safety department in May 2017 and was officially launched in South Korea.

[0004] Jubyl is a topical formulation. Topical antifungal agents do not have the drawbacks of oral antifungal agents, such as rashes, hepatotoxicity, and digestive system side effects, and have high drug compliance and preference.

[0005] Examples of dosage forms that can be used for the local delivery of icoconazole and other triazole antifungal drugs in the treatment of onychomycosis include, for example, U.S. Patent No. 8,486,978 (Patent Document 1).

[0006] However, topical formulations, due to their ability to penetrate the skin or nails, are somewhat inadequate in inhibiting deep-rooted fungi. Furthermore, because they need to be applied to all affected areas, their effectiveness in inhibiting and preventing fungi that have spread widely throughout the body is limited.

[0007] In fact, the recurrence rate of fungal infections, such as tinea manuum on the hands and feet or fingernails and toenails, is closely related to the limitations of topical formulations. That is, while topical formulations can act well on surface-present fungi, they cannot reach the depth at which the fungi can be completely eradicated at the required effective concentration.

[0008] Therefore, it is important to develop administration methods (e.g., injections, oral tablets, liquids, capsules, suppositories, etc.) that deliver antifungal ingredients to the corresponding tissues via blood or other routes. In particular, it is necessary to develop oral dosage forms that are convenient to consume and have high medication compliance and preference.

[0009] However, icoconazole has a low water solubility of 0.61 mg / mL, which may cause problems with absorption and bioavailability when administered orally.

[0010] Furthermore, solutions containing icofol have stability issues, namely, discoloration within a short shelf life, with the composition changing color from yellow to a range of dark red or brown. To address these stability issues, US Patent No. 9662394 discloses a liquid or semi-solid composition comprising a specific chelating agent, an antioxidant, and an acid, namely ethylenediaminetetraacetic acid (EDTA) or a salt thereof, butylated hydroxytoluene (BHT), and citric acid.

[0011] Therefore, there is a need to develop oral formulations of icoconazole with high bioavailability and stability.

[0012] For reference, the entire contents of the following prior art documents may be cited and incorporated as the background art content of this invention.

[0013] (Patent Document 1) US8486978B2 (July 16, 2013)

[0014] (Patent Document 2) US9662394B2 (2017.05.30)

[0015] (Patent Document 3) US5620994A (April 15, 1997) Summary of the Invention

[0016] In order to solve the above-mentioned problems in the prior art, the present invention provides an oral formulation of icoconazole with high bioavailability and stability.

[0017] This invention is proposed to solve the problems of the prior art described above.

[0018] An oral pharmaceutical composition is provided, characterized in that it comprises a co-formation of icoconazole, polyethylene glycol, and a pharmaceutically acceptable additive.

[0019] In addition, the present invention provides an oral pharmaceutical composition, characterized in that the composition is a tablet or a liquid.

[0020] Furthermore, the present invention provides an oral pharmaceutical composition characterized in that it comprises 0.6-2040 mg of ciproconazole.

[0021] In addition, the present invention provides an oral pharmaceutical composition, characterized in that the weight ratio of icoconazole to polyethylene glycol in the co-formed product is 1:1.

[0022] Furthermore, the present invention provides an oral pharmaceutical composition, characterized in that the pharmaceutically acceptable additive is selected from one or more excipients, binders, disintegrants, surfactants, lubricants, and colorants.

[0023] In addition, the present invention provides an oral pharmaceutical composition, characterized in that the excipient is selected from one or more of the following: lactose hydrate, microcrystalline cellulose, microcrystalline cellulose-lactose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose salt, other substituted and unsubstituted celluloses, corn starch, gelatinized starch, lactose, anhydrous lactose, sugar alcohols, sucrose, xylitol, acrylate polymers and copolymers, glucose binders, dextrin, glucose, maltodextrin, pectin, gelatin, and inorganic diluents.

[0024] Furthermore, the present invention provides an oral pharmaceutical composition, characterized in that the binder is selected from polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone vinyl acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, gelatin, propylene glycol, sodium alginate, and mixtures thereof.

[0025] In addition, the present invention provides an oral pharmaceutical composition, characterized in that the disintegrant is selected from one or more of croscarmellose sodium, croscarmellose, carboxymethyl cellulose salt, hydroxypropyl cellulose, microcrystalline cellulose, gelatinized starch, sodium starch, glycolate and sodium starch glycolate.

[0026] Furthermore, the present invention provides an oral pharmaceutical composition, characterized in that the lubricant is selected from magnesium stearate, sodium stearate fumarate, and glyceryl behenate.

[0027] In addition, the present invention provides an oral pharmaceutical composition, characterized in that its use is for the prevention or treatment of fungal infections.

[0028] Furthermore, the present invention provides an oral pharmaceutical composition, characterized in that the fungal infection is onychomycosis.

[0029] Invention Effects

[0030] This invention demonstrates high stability and bioavailability, and is suitable for oral administration. Attached Figure Description

[0031] Figure 1 This is a powder XRD pattern of the eutectic of icoconazole and polyethylene glycol.

[0032] Figure 2 This is a DSC thermal analysis diagram of the eutectic of icoconazole and polyethylene glycol.

[0033] Figure 3 This is a powder XRD pattern of crystalline ciprofloxacin.

[0034] Figure 4This is a DSC thermal analysis chart of the crystalline form of icoconazole.

[0035] Figure 5 This is a comparison chart of the stability of crystalline and poly(ethylene glycol) co-crystal ieconazole.

[0036] Figure 6 It is a graph showing the time versus blood concentration of voriconazole in preclinical trials.

[0037] Figure 7 It is a graph showing the time versus blood concentration of ciproconazole in preclinical trials. Detailed Implementation

[0038] The present invention will now be described in detail.

[0039] This invention relates to oral pharmaceutical compositions comprising a co-formation of ciproconazole, polyethylene glycol, and pharmaceutically acceptable additives.

[0040] Co-formed products are substances in which two or more substances exhibit unique physical properties as if they were a single substance. They can be classified into amorphous co-amorphous and crystalline co-crystal.

[0041] The term "eutectic" refers to a crystalline structure formed by two or more different molecules in a crystal lattice at a specific stoichiometric ratio. The morphology of intermolecular bonds within a eutectic differs from that in salts and mixtures.

[0042] In addition, cocrystal refers to a crystalline solid with abundant functional groups that can form hydrogen bonds, such as O, OH, N, etc., or with a new crystalline structure formed by coformer molecules and hydrogen bonds in a conventional ratio.

[0043] The coformer refers to an inactive molecule in the molecules constituting the eutectic pharmaceutical crystals, and polyethylene glycol is preferred in this invention.

[0044] The powder XRD pattern and DSC thermal analysis diagram of the eutectic of icoconazole and polyethylene glycol involved in this invention are as follows: Figure 1 and Figure 2 As shown. The XRD pattern and DSC thermal analysis diagram of the crystalline form of iefluconazole are shown below. Figure 3 and Figure 4 As shown.

[0045] Compare Figures 1 to 4 It can be confirmed that the co-formed products of icoconazole involved in this invention have a completely different trend compared to the crystalline form of icoconazole.

[0046] In other words, the co-formed product of iefluconazole and polyethylene glycol has the following crystalline structure: characteristic diffraction angles of 7.78, 11.50, 13.85, 15.49, 16.79, 18.97, 19.22, 23.57, 26.18, and 27.09 (2θI / I0>10%) are observed in the powder XRD pattern, and the maximum endothermic peaks are observed at 61.62℃ and 78.78℃ in the spectrum analyzed by differential scanning calorimetry (DSC). The above XRD pattern or DSC thermal analysis pattern is significantly different from the crystalline form of iefluconazole.

[0047] Therefore, it can be determined that the co-formed product of elfluconazole of the present invention is a novel substance with physicochemical properties completely different from the existing elfluconazole crystal form.

[0048] Furthermore, since icoconazole is an unstable drug, its stability needs to be improved in order to be used as an active ingredient in a pharmaceutical composition. Its stability can be improved by forming co-formation products.

[0049] That is, such as Figure 5 As shown, the co-formed products of efconazole of the present invention exhibit excellent stability.

[0050] Moreover, co-formations of iefluconazole can increase drug solubility and dissolution rate, altering the absorption rate of the drug in the human body and thus changing bioavailability.

[0051] That is, such as Figure 6 As shown, the bioavailability of the efconazole co-formation product involved in this invention is excellent.

[0052] Based on the above characteristics, the co-formed products of icoconazole involved in this invention can fully meet the requirements for active ingredients in pharmaceutical compositions, namely, chemical purity of crystals, stability of the composition solution and temperature, and bioavailability when administered orally.

[0053] The stability or bioavailability of the co-formed products of icoconazole involved in this invention will be described in detail through the examples described later.

[0054] In the oral pharmaceutical composition of the present invention, the active ingredient, iefluconazole, comprises a preventive or therapeutically effective amount, based on stability and efficacy data. In some specific examples, the therapeutically effective amount is from about 0.01 to about 30 mg / kg; in some particular specific examples, it may be from about 0.01 to about 6 mg / kg. Therefore, the content of iefluconazole in the oral dosage form is 0.6-2040 mg, or contains 0.6-410 mg, but is not necessarily limited thereto and may vary based on clinical findings.

[0055] The pharmaceutically acceptable additive may be, without limitation, a pharmaceutical additive that is obvious and well known to those skilled in the art, including stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, bases, adsorbents, flavoring agents, binders, suspending agents, curing agents, antioxidants, brighteners, flavorings, tasters, pigments, coatings, wetting agents, wetting control agents, fillers, defoamers, refrigerants, chewing agents, antistatic agents, colorants, sugar coatings, isotonic agents, softeners, emulsifiers, adhesives, thickeners, foaming agents, pH adjusters, excipients, dispersants, disintegrants, waterproofing agents, preservatives, freshness preservers, solubilizers, solvents, and flow agents; more specifically, the pharmaceutically acceptable additive may be selected from one or more of excipients, binders, disintegrants, surfactants, lubricants, and colorants.

[0056] Examples of the excipients are selected from one or more of the following: lactose hydrate, microcrystalline cellulose, microcrystalline cellulose-lactose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose salt, other substituted and unsubstituted cellulose, corn starch, gelatinized starch, lactose, anhydrous lactose, sugar alcohols, sucrose, xylitol, acrylate polymers and copolymers, glucose binders, dextran, glucose, maltodextrin, pectin, gelatin, and inorganic diluents.

[0057] Examples of adhesives are selected from polyvinyl alcohol-polyethylene glycol graft copolymers, polyvinylpyrrolidone vinyl acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, gelatin, propylene glycol, sodium alginate, and mixtures thereof.

[0058] Examples of the disintegrants are selected from one or more of crostomeric sodium carboxymethyl cellulose, crostomeric povidone, carboxymethyl cellulose salt, hydroxypropyl cellulose, microcrystalline cellulose, gelatinized starch, sodium starch, glycolate, and sodium starch glycolate.

[0059] Examples of surfactants include sodium dodecyl sulfonate (SDS), sodium lauryl sulfate (SLS), Pluronic F127, Pluronic F68, poly(ethylene glycol) (PEG), polyoxyethylene sorbitan monooleate (Tween 80), poloxamer (Lutrol F68), polyethylene glycol-15-hydroxystearate (Solutol HS15), hydroxypropyl methyl cellulose (HPMC), poly(N-vinyl-2-pyrrolidone) (PVP), Silwet L77, poly(vinyl alcohol) (PVA), and bovine serum albumin. Albumin (BSA) and sucrose fatty acid esters, etc.

[0060] Examples of the lubricants are selected from magnesium stearate, sodium stearate fumarate and glyceryl behenate, but are not limited thereto. Pharmaceutical additives that are obvious and well known to those skilled in the art may be used without limitation.

[0061] The compositions of the present invention can be used for the prevention or treatment of fungal infections. Specific examples of indications include, but are not limited to, candidal vaginitis, tinea versicolor, tinea corporis, tinea cruris (jock itch) caused by dermatophytes, tinea manuum, tinea pedis, oral candidiasis, fungal keratitis, onychomycosis, aspergillosis, candidiasis, candida albicans, candidemia, cryptococcosis (including cryptococcal meningitis), brasiliensis, systemic fungal infections, seborrheic dermatitis, and yeast-induced dandruff.

[0062] The present invention will now be explained in more detail with reference to the embodiments. However, it should be noted that these embodiments are merely for illustrating the invention in more detail and are not intended to limit the scope of the invention.

[0063] Example

[0064] Example 1 - Preparation of eutectic of icoconazole and polyethylene glycol (1:1 ratio)

[0065] Ifluconazole (1g) was dissolved in acetonitrile (5mL) at room temperature with stirring. Polyethylene glycol-6000 (1g) was added to the reaction solution, and after stirring for 1 hour, the solvent was removed by vacuum distillation. A crystalline form of eutectic eutectic of iefluconazole and polyethylene glycol-6000 spontaneously formed within a short time. Only the crystals were recovered under vacuum drying, with a yield of 95% and a purity of 99.5%. The powder XRD spectrum and differential scanning calorimeter thermogram of the iefluconazole and polyethylene glycol-6000 eutectic prepared in Example 1 are shown below. Figure 1 and Figure 2 As shown.

[0066] Example 2 - Preparation of oral liquid preparation

[0067] The product prepared in Example 1 and a solution of 0.5% methylcellulose dispersed in distilled water containing 1% surfactant were vortexed and sonicated to prepare a homogeneous oral liquid. The specific composition is shown in Table 1 below.

[0068] Table 1

[0069]

[0070] Example 3 - Preparation of oral tablets

[0071] The product and excipient prepared in Example 1 were kneaded together, and disintegrants and lubricants were added sequentially. After granulation, the particles were compressed to obtain uncoated tablets. The specific composition is shown in Table 2 below.

[0072] Table 2

[0073]

[0074] Example 4 - Preparation of oral capsules

[0075] The formulation prepared in Example 3 was not compressed into tablets, but instead placed into gelatin capsules to prepare capsules.

[0076] Test case

[0077] [Stability Test]

[0078] To confirm the stability of the icostyle of icostyle of the present invention with respect to temperature and composition solution, the following experiments were conducted to compare the stability of icostyle of icostyle with respect to temperature and composition solution.

[0079] *Experimental Methods

[0080] The crystalline form of icoconazole and the product of Example 1 were placed in a solution of the composition at room temperature and in an oven at 65°C for one week, two weeks and four weeks respectively, and then the purity was determined by high performance liquid chromatography (HPLC).

[0081] The results are shown in Table 3 below. Figure 5 As shown.

[0082] Table 3

[0083]

[0084] From Table 3 and Figure 5 As can be seen, compared with existing crystalline forms of ieconazole, the ieconazole cocrystal of this invention is more stable in terms of temperature and solubility in the composition solution, and has more useful advantages in drug preparation. Moreover, the ieconazole cocrystal of this invention is a novel substance that meets all the requirements for the active ingredient in pharmaceutical compositions.

[0085] [Preclinical Trials]

[0086] Twenty-four male beagle dogs were divided into four groups of six each. Under fasting conditions, the control drug voriconazole was administered orally once, while the test drug icofol was administered intravenously and orally once. PK profiles for each drug were then obtained to calculate PK parameters and assess pharmacokinetics. Specific experimental conditions and methods are as follows.

[0087] 1. Preparation of test drug

[0088] In the case of the test drug being administered orally, during the preparation of the test drug, based on the measured body weight, voriconazole (oral administration group G1), eficonazole (oral administration group G2), and the eficonazole cocrystal prepared in Example 1 (oral administration group G3 - Efinaconazole copolymer) were weighed using an electronic balance and added to a glass container. The container was then subjected to vortexing and ultrasonic treatment using an excipient (0.5% methylcellulose in 1% Tween 80 solution (distilled water)) to prepare it into a homogeneous state.

[0089] In the case of intravenous administration, iefluconazole (intravenous G1 group) and PEG400 as an excipient, equivalent to 30% of the total formulation volume, were added based on the dosage measurement. The mixture was then completely dissolved by vortexing and sonication. Ethanol, equivalent to 20% of the total formulation volume, was added and homogenized by sonication. Then, 0.9% saline, equivalent to 50% of the total formulation volume, was added, followed by vortexing and sonication to prepare a homogenized test drug.

[0090] 2. Administration

[0091] –Route of administration: Intravenous (IV), oral (PO)

[0092] –Dosage: G1 [Voriconazole] - 6 mg / 5 mL / kg (PO); G2 [Efinaconazole] - 6 mg / 5 mL / kg (PO); G3 [Efinaconazole-Polymer] - 6 mg / 5 mL / kg (PO); G1 [Efinaconazole] - 0.5 mg / 1 mL / kg (IV)

[0093] – Dosage frequency: Single dose (once daily) (QD)

[0094] The composition of the test groups based on the drug administration is shown in Table 4 below.

[0095] Table 4

[0096] • Oral administration

[0097]

[0098] • Intravenous administration

[0099]

[0100] 3. Test Results

[0101] During the experiment, the following allocation methods were used: oral administration: Group G1 received sizes 1-6; Group G2 received sizes 7-12; Group G3 received sizes 13-18; intravenous administration: Group G1 received sizes 1-6. On the day of the experiment, the average body weight of each group was confirmed as follows: oral administration: Group G1 11.5 ± 1.2 kg; Group G2 11.5 ± 1.3 kg; Group G3 11.5 ± 1.0 kg; intravenous administration: Group G1 11.6 ± 1.6 kg.

[0102] During the trial, no abnormal symptoms (including vomiting, lameness, diarrhea, and behavioral abnormalities) related to the administration of the test substance were observed. No individual deaths occurred throughout the trial, and blood collection proceeded smoothly. 4 mL of blood was collected at each site. After centrifugation, 500 μL of plasma supernatant was aliquoted into 1.5 mL EP tubes, and the remaining plasma was aliquoted into another 1.5 mL EP tube set. The tubes were stored in a deep freezer at -80°C. After the trial, the blood collection record book, sample information certificate, medication record book, clinical symptom observation record book, medication / blood collection results, and test sample (plasma) were delivered to a professional analytical institution.

[0103] The delivered samples were kept in a freezer until analysis was performed. The samples were analyzed by LC / MS / MS, and pharmacokinetic parameters were calculated using the noncompartmental method with Phoenix WinNonlin (version 8.2 or higher Certara LP).

[0104] When analyzing plasma samples, the voriconazole (6 mg / kg, PO) groups were assigned to group G1 (No. 1-6), and the afluconazole groups were assigned to group G2 - 0.6 mg / kg IV (No. 1-6), group G3 - 6 mg / kg PO (No. 7-12), and group G4 - copolymer 6 mg / kg PO (No. 13-18), as shown in Table 5 below.

[0105] Table 5

[0106]

[0107] Six mice were assigned to each group. After a single dose, the blood concentration trends of voriconazole and icoconazole in a total of 24 mice were analyzed. Figure 6 and 7 And as shown in Tables 6 and 7. For samples where peak values ​​were detected, those below the minimum quantitation limit were treated with BLQ.

[0108] Table 6

[0109] Unit: mg / ml

[0110]

[0111] Table 7

[0112] Unit: mg / ml

[0113]

[0114] AUCt is a bioavailability parameter, which is the area under the plasma concentration-time curve from the time of drug administration to the last measurable blood collection point, calculated using the trapezoidal rule. max The highest plasma drug concentration, T, is read from the plasma drug concentration-time curve for each individual. max AUC is the time taken to reach the peak plasma drug concentration from each individual's plasma drug concentration-time curve. ∞ This is the area under the plasma concentration-time curve from the time of administration to infinity. The calculated PK parameters for voriconazole and icoconazole are shown in Table 8 below.

[0115] Table 8

[0116]

[0117] As shown in the table above, the AUC values ​​for the voriconazole (6 mg / kg, PO), ioconazole (0.6 mg / kg, IV), ioconazole (6 mg / kg, PO), and ioconazole copolymer (6 mg / kg, PO) groups in the PK parameters are as follows: t The values ​​were 53905.19±7138.87, 253.28±74.20, 1494.88±475.14, and 987.98±271.62, respectively; AUC ∞ The values ​​were confirmed as 109208.24±24516.63, 270.71±84.91, 1610.32±540.33 and 1114.49±323.58; C max The values ​​were confirmed to be 3674.45±169.60, 322.20±58.61, 925.10±236.42 and 827.06±349.93.

[0118] In the statistical analysis results, compared with the icoconazole (6 mg / kg, PO) group, the C of the icoconazole copolymer (6 mg / kg, PO) group was significantly lower. max and AUC t The indicators showed significantly lower results. (See Tables 9 to 12 below) [Table 9]

[0119]

[0120] Table 10

[0121]

[0122] Table 11

[0123]

[0124] Table 12

[0125]

[0126] The bioavailability of the icoconazole copolymer (6 mg / kg, PO) group and the icoconazole (6 mg / kg, PO) group were 35.69 ± 22.61% and 51.36 ± 24.63%, respectively (Tables 13 and 14 below).

[0127] Table 13

[0128]

[0129] F(%)=[AUC(po) / Dose(po)] / [AUC(iv) / Dose(iv)]*100

[0130] Table 14

[0131]

[0132] F(%) = [AUC(po) / Dose(po)] / [AUC(iv) / Dose(iv)]*100. The results showed that, compared to the icoconazole (6 mg / kg, PO) group, the AUC of the icoconazole copolymer (6 mg / kg, PO) group was significantly lower. t The value is equivalent to 66%, which is significantly low, but considering that the content of the raw material component in the copolymer formulation is 50%, it can be confirmed that it exceeds this level.

[0133] Furthermore, the bioavailability of the icoconazole copolymer (6 mg / kg, PO) group was 35.69%, which, under the condition that dosage linearity is established, is approximately 70% of that of the icoconazole (6 mg / kg, PO) group, which showed 51.36%. This indicates that the exposure of the test substance icoconazole copolymer formulation in beagle dogs is much higher than the theoretically expected level (50%).

[0134] These test results show that even at low oral doses, iefluconazole has higher bioavailability than other antifungal drugs, such as voriconazole and itraconazole. Therefore, oral administration can be expected to provide higher therapeutic efficacy.

Claims

1. An oral pharmaceutical composition comprising a eutectic of icoconazole and polyethylene glycol-6000 and pharmaceutically acceptable additives.

2. The oral pharmaceutical composition according to claim 1, characterized in that, The composition is in the form of tablets or liquids.

3. The oral pharmaceutical composition according to claim 1, characterized in that, Contains 0.6-2040mg of ciproconazole.

4. The oral pharmaceutical composition according to claim 1, characterized in that, In the eutectic, the weight ratio of icoconazole to polyethylene glycol-6000 is 1:

1.

5. The oral pharmaceutical composition according to claim 1, wherein, The pharmaceutically acceptable additive is selected from one or more of the following: excipients, binders, disintegrants, surfactants, lubricants, and colorants.

6. The oral pharmaceutical composition according to claim 5, wherein, The excipient is selected from one or more of the following: lactose hydrate, microcrystalline cellulose, microcrystalline cellulose-lactose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose salt, corn starch, gelatinized starch, anhydrous lactose, sugar alcohol, sucrose, acrylate polymer, glucose binder, dextrin, glucose, maltodextrin, pectin, gelatin, and inorganic diluent.

7. The oral pharmaceutical composition according to claim 5, wherein, The adhesive is selected from polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone vinyl acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, gelatin, propylene glycol, sodium alginate, and mixtures thereof.

8. The oral pharmaceutical composition according to claim 5, wherein, The disintegrant is selected from one or more of crospovidone, carboxymethyl cellulose salt, hydroxypropyl cellulose, microcrystalline cellulose, gelatinized starch, and sodium starch glycolate.

9. The oral pharmaceutical composition according to claim 5, wherein, The lubricant is selected from magnesium stearate, sodium stearate fumarate, and glyceryl behenate.

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