Modified release drug formulations containing hydroxypropyl cellulose

Abstract

This disclosure relates to hydroxypropyl cellulose (HPC) having a molar degree of substitution of about 3.0 to about 3.9, a weight-average molecular weight of about 800,000 to about 2,000,000 Daltons, and a volume-average particle size of less than 100 μm, and modified release formulations derived therefrom.

Description

Technical Field

[0001] Currently disclosed processes, steps, methods, products, results, and / or concepts (collectively, “this disclosure”) generally relate to hydroxypropyl cellulose (HPC) and its applications. This disclosure also relates to modified release drug formulations derived from hydroxypropyl cellulose. Background Technology

[0002] Pharmaceutical compositions typically contain polymers to achieve specific desired therapeutic effects, including those used as coating agents, film-forming agents, rate controllers for improved release, stabilizers, suspending agents, tablet binders, and thickeners.

[0003] It has long been known that almost all pharmacologically active compounds are most effective when present in plasma within a certain concentration range, and exceeding this range can lead to harmful side effects. Furthermore, if the concentration of an excessive amount of drug in plasma is significantly higher than the recommended blood level for maximum pharmacological effect, it may be wasteful, making the production and use of the drug formulation unnecessarily expensive. Alternatively, when the drug concentration in plasma is below the most effective range, there is a risk that the active ingredient may not be most effective or may be completely ineffective.

[0004] Oral dosage forms are the preferred route of administration for most drug compounds when physiologically feasible, as they offer easy and low-cost administration. However, patient compliance is a critical factor to consider when using oral drug compounds, especially if the compound must be taken three or four times a day. To maximize patient compliance, it is desirable to reduce the number of daily dose units that patients must take to achieve effective treatment. Using fewer, longer-acting doses also improves the constancy of drug concentrations in the blood over time, and this can improve treatment because the drug can be closer to its ideal therapeutic dose throughout the day.

[0005] One approach to achieving these goals is to use modified-release formulations that effectively maintain therapeutic blood levels over an extended period, thereby achieving optimal treatment. These not only reduce the frequency of administration but also decrease the severity and frequency of side effects because they maintain essentially constant blood levels and avoid the fluctuations associated with conventional immediate-release formulations administered three to four times a day.

[0006] Many different modified release formulations are available on the market. Many of these modified delivery systems utilize a hydrophilic polymer matrix, providing a useful level of control over drug delivery. After ingestion, the active pharmaceutical ingredient is slowly released from the polymer matrix, resulting in prolonged release of the active ingredient. One method of formulating a modified release composition involves dry-mixing one or more polymers with the desired drug to form a composition that, when exposed to a liquid, forms a gel; the drug is then slowly released from the gel by diffusion.

[0007] Tablets designed to improve the release of contained drugs have been developed in the past, but they are not entirely satisfactory. Some are too expensive to manufacture due to costly ingredients or complex equipment or processes, or are too large due to the additives necessary to achieve delayed release. Other tablets are unsatisfactory due to a lack of consistent release time.

[0008] Another important consideration is that the material causing the modified drug release must be physiologically acceptable. It must have no or only mild toxicity to the human body. It must be completely eliminated so that it does not accumulate in human tissues even with prolonged use. Compositions and processes for preparing orally deliverable pharmaceutical formulations as modified release are needed to overcome the problems associated with the aforementioned processes. Summary of the Invention

[0009] In one aspect, this disclosure provides a hydroxypropyl cellulose (HPC) having a molar degree of substitution of about 3.0 to about 3.9, a weight-average molecular weight of about 700,000 to about 2,000,000 Daltons, and a volume-average particle size of less than 100 micrometers. In one non-limiting embodiment of this disclosure, the molar degree of substitution of the hydroxypropyl cellulose is in the range of about 3.2 to about 3.8, or about 3.4 to about 3.7. In one non-limiting embodiment of this disclosure, the weight-average molecular weight of the hydroxypropyl cellulose is in the range of about 1,000,000 to about 1,500,000 Daltons. In one non-limiting embodiment of this disclosure, the viscosity of the hydroxypropyl cellulose in a 1% by weight aqueous solution at 25°C is at least 300 mPa·s. In another non-limiting embodiment of this disclosure, the viscosity of the hydroxypropyl cellulose in a 1% by weight aqueous solution at 25°C can be in the range of about 1,000 to about 3,000 mPa·s.

[0010] In another aspect, this disclosure provides a modified release formulation comprising hydroxypropyl cellulose having a molar degree of substitution of about 3.0 to about 3.9, a weight-average molecular weight of about 700,000 to about 2,000,000 Daltons, and a volume-average particle size of less than 100 μm. In one non-limiting embodiment of this disclosure, the molar degree of substitution of the hydroxypropyl cellulose is in the range of about 3.2 to about 3.8, or about 3.4 to about 3.7. In one non-limiting embodiment of this disclosure, the weight-average molecular weight of the hydroxypropyl cellulose is in the range of 1,000,000 to about 1,500,000 Daltons. The hydroxypropyl cellulose present in the modified release formulation of this disclosure has a viscosity of at least 300 mPa·s in a 1% by weight aqueous solution at 25°C. In one non-limiting embodiment of this disclosure, the viscosity of the hydroxypropyl cellulose in a 1% by weight aqueous solution at 25°C is in the range of about 1,000 to about 3,000 mPa·s.

[0011] In one non-limiting embodiment of this disclosure, the amount of hydroxypropyl cellulose in the modified release formulation ranges from about 5% to about 99% by weight, or about 10% to about 90% by weight, or about 15% to about 75% by weight of the total formulation.

[0012] Furthermore, the modified release formulation of this disclosure also comprises a pharmaceutically effective amount of at least one drug, said drug having a water solubility greater than 1 mg / L at 25°C. In a non-limiting embodiment of this disclosure, the water solubility of said drug is greater than 20 mg / L, or greater than 700 mg / L.

[0013] In one non-limiting embodiment of this disclosure, the drug is selected from the group consisting of: antipyretics, analgesics and anti-inflammatory drugs, anthelmintics, cardiovascular drugs, antibacterial drugs, bronchodilators, antiasthmatic drugs, gastrointestinal drugs, antidiabetic drugs, antiprotozoal drugs, antiviral drugs, antiepileptic drugs, diuretics, or pharmaceutically acceptable salts and esters thereof.

[0014] In another non-limiting embodiment of this disclosure, the drug is selected from the group consisting of: etodoxacin, albendazole, ciprofloxacin, erythromycin and its derivatives, ibuprofen, diclofenac, tofacitinib, carvedilol, metoprolol, sacubitril, valsartan, salbutamol, doxofylline, theophylline, cimetidine, omeprazole, metformin hydrochloride, sitagliptin, tinidazole, chlorothiazide, hydrochlorothiazide, acyclovir, carbamazepine, and their pharmaceutically acceptable salts and esters.

[0015] In another non-limiting embodiment, the modified release formulation of this disclosure further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of fillers, binders, surfactants, disintegrants, lubricants, and flow aids. In one non-limiting embodiment of this disclosure, the pharmaceutically acceptable excipient is a filler selected from the group consisting of monosaccharides, disaccharides, polysaccharides, and combinations thereof. In another non-limiting embodiment of this disclosure, the filler is selected from the group consisting of cellulose, lactose, sucrose, sugars, starch, processed starch, mannitol, sorbitol, xylitol, lactitol, silicic acid, complexes and oxides of calcium sulfate, aluminum silicate and magnesium silicate, calcium diphosphate dihydrate, and hydrogen sulfate.

[0016] In another non-limiting embodiment of this disclosure, the pharmaceutically acceptable excipient is a lubricant selected from the group consisting of: talc, calcium stearate, magnesium stearate, polyethylene glycol, stearic acid, colloidal silica, calcium silicate, mineral oil, wax, hydrogenated vegetable oil, glyceryl behenate, sodium benzoate, sodium acetate, sodium stearoyl fumarate, and combinations thereof.

[0017] In another non-limiting embodiment of this disclosure, the pharmaceutically acceptable excipient is an adhesive selected from the group consisting of: polyvinylpyrrolidone, sucrose, lactose, starch, processed starch, sugar, gum arabic, tragacanth, guar gum, pectin, wax-based adhesives, microcrystalline cellulose (MCC), methylcellulose, carboxymethylcellulose, copovidone, gelatin, sodium alginate, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and combinations thereof.

[0018] In one non-limiting embodiment of this disclosure, the pharmaceutically acceptable excipient is present in an amount of about 1% to about 85% by weight based on the total weight of the modified release formulation. In another non-limiting embodiment of this disclosure, the modified release formulation is in the form of tablets, capsules, powders, granules, sachets, or lozenges. Attached Figure Description

[0019] The objects, features, and advantages of the present invention will become apparent from the following description taken in conjunction with the accompanying drawings / figures, wherein:

[0020] Figure 1 The NMR spectra of a representative hydroxypropyl cellulose sample are shown.

[0021] Figure 2Dissolution profiles (expressed as a percentage of total drug released over 24 hours) of hydrochlorothiazide (HCTZ) in the modified release formulation of Example 6, prepared using 30% by weight of hydroxypropyl cellulose (HPC) of Example 1, are shown, and compared with the dissolution profiles of HCTZ in the comparative modified release formulation of Example 6A, prepared using 30% by weight of HPC of Comparative Example 5.

[0022] Figure 3 Dissolution profiles (expressed as a percentage of total drug released over 24 hours) of hydrochlorothiazide (HCTZ) in the modified release formulation of Example 7, prepared using 60% by weight of HPC of Example 1, are shown, and compared with the dissolution profiles of HCTZ in the comparative modified release formulation of Example 7A, prepared using 30% by weight of HPC of Comparative Example 5.

[0023] Figure 4 Dissolution profiles (expressed as a percentage of total drug released over 24 hours) of ibuprofen in the modified release formulation of Example 8, prepared using 20% ​​by weight of HPC from Example 2, are shown, and compared with the dissolution profiles of ibuprofen in the comparative modified release formulation of Example 8A, prepared using 20% ​​by weight of HPC from Comparative Example 5.

[0024] Figure 5 Dissolution profiles (expressed as a percentage of total drug released over 24 hours) of ibuprofen in the modified release formulation of Example 9, prepared using 10% by weight of HPC from Example 2, are shown, and compared with the dissolution profiles of ibuprofen in the comparative modified release formulation of Example 9A, prepared using 10% by weight of HPC from Comparative Example 5.

[0025] Figure 6 Dissolution profiles (expressed as a percentage of total drug released over 24 hours) of ibuprofen in the modified release formulation of Example 10, prepared using 25% by weight of HPC from Example 2, are shown, and compared with the dissolution profiles of ibuprofen in the comparative modified release formulation of Example 10A, prepared using 25% by weight of HPC from Comparative Example 5.

[0026] Figure 7Dissolution profiles (expressed as a percentage of total drug released over 24 hours) of hydrochlorothiazide (HCTZ) in the modified release formulation of Example 11 prepared by using 15% by weight of HPC of Example 3 are shown, and compared with the dissolution profile of the comparative modified release formulation of Example 11A prepared by using 15% by weight of HPC of Comparative Example 5.

[0027] Figure 8 Dissolution profiles (expressed as a percentage of total drug released over 24 hours) of hydrochlorothiazide (HCTZ) in the modified release formulation of Example 12, prepared by using 15% by weight of HPC of Example 4, are shown, and a comparison of its dissolution profile with that of the comparative modified release formulation of Example 11A is provided. Detailed Implementation

[0028] Before explaining in detail at least one embodiment of the inventive concept through exemplary drawings, experiments, results, and laboratory procedures, it should be understood that the application of the inventive concept is not limited to the details of the structure and arrangement of the components / components set forth in the following description or shown in the drawings, experiments, and / or results. The inventive concept can have other embodiments or can be implemented or performed in various ways. Therefore, the language used herein is intended to provide the broadest possible scope and meaning; and these embodiments are intended to be exemplary, not exhaustive. Furthermore, it should be understood that the wording and terminology used herein are for descriptive purposes and should not be considered limiting.

[0029] Unless otherwise defined herein, scientific and technical terms used in conjunction with this disclosure shall have the meanings commonly understood by one of ordinary skill in the art. Furthermore, unless the context requires otherwise, singular terms shall include plural terms, and plural terms shall include singular terms. Generally, the terms and chemical techniques associated with the chemical techniques described herein are well-known and commonly used in the art. Reaction and purification techniques are performed according to the manufacturer's instructions or those commonly performed in the art or described herein. The terms, laboratory procedures, and techniques associated with analytical chemistry, synthetic organic chemistry, and pharmaceutical chemistry described herein are well-known and commonly used in the art. Standard techniques are used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment.

[0030] All patents, published patent applications, and non-patent publications mentioned in this specification represent the technical skill of a person skilled in the art to which this disclosure pertains. All patents, published patent applications, and non-patent publications cited in any part of this application are expressly and integrally incorporated herein by reference to the same extent that each individual patent or publication is specifically and individually indicated to be incorporated by reference.

[0031] All compositions and / or methods disclosed and claimed herein can be manufactured and practiced according to this disclosure without excessive experimentation. While the compositions and methods of the invention have been described with reference to preferred embodiments, it will be apparent to those skilled in the art that changes can be made to the compositions and / or methods described herein, as well as the steps or order of steps of said methods, without departing from the concept, spirit, and scope of this disclosure. All such similar substitutions and changes that will be apparent to those skilled in the art are considered to be within the spirit, scope, and concept of the invention as defined by the appended claims.

[0032] As used in accordance with this disclosure, unless otherwise stated, the following terms shall be understood to have the following meanings:

[0033] When used in conjunction with the term “comprising” in the claims and / or description, the use of the indefinite article (“a” or “an”) can mean “one”, but it also means “one or more,” “at least one,” and “one or more.” The use of the term “or” in the claims is used to mean “and / or” unless explicitly stated to refer only to alternatives or to mutually exclusive alternatives, although this disclosure supports the definition of “and / or” referring only to alternatives. Throughout this application, the term “about” is used to indicate that a value includes variations in the device, the inherent error of the method used to determine the value, or variations existing between the objects of study. The use of the term “at least one” is to be understood to include any number of one and more, including but not limited to 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, etc. The term “at least one” can be extended to 100 or 1000 or more, depending on the term it is connected to. Furthermore, the number 100 / 1000 should not be considered a limitation, as higher limitations would also produce satisfactory results. Furthermore, the use of the term "at least one of X, Y, and Z" will be understood to include X alone, Y alone, and Z alone, as well as any combination of X, Y, and Z.

[0034] As used in this specification and claims, the terms “comprising” (and any form of inclusion, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of inclusion, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unreferenced elements or method steps.

[0035] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the items listed preceding the term. For example, "A, B, C or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and may also include BA, CA, CB, CBA, BCA, ACB, BAC, or CAB if the order is important in the particular context. Continuing with this example, what is explicitly included are combinations that contain repetitions of one or more items or terms, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB, and so on. Those skilled in the art will understand that there is generally no limit to the number of items or terms in any combination unless it is obvious from the context.

[0036] As used herein, the terms "drug," "active pharmaceutical ingredient," or "API" refer to any substance or mixture of substances intended for use in the manufacture of a pharmaceutical (medicinal) product, which, when used in the manufacture of the pharmaceutical product, becomes the active ingredient of the pharmaceutical product. These substances are intended to provide pharmacological activity or other direct effects in the diagnosis, cure, relief, treatment, or prevention of a disease, or to affect the structure or function of the body in humans or other animals. Furthermore, the terms "drug," "active pharmaceutical ingredient," or "API" are used interchangeably in this disclosure.

[0037] As used herein, the term “modified release” in connection with the compositions of this disclosure means a composition not intended for immediate release and may include controlled release, sustained release, extended release, timed release, delayed release, slow release, and deferred release.

[0038] As used herein, the terms "modified release drug formulation" or "modified release dosage form" can be described as a dosage form whose characteristics of the timing and / or location of drug release are chosen to achieve a therapeutic or convenience purpose that conventional dosage forms such as solutions or immediate-release dosage forms cannot provide. Modified release solid oral dosage forms include delayed-release and slow-release drug products (according to the USFDA guidance on "SUPAC-MR: Modified Release Solid Oral Dosage Forms").

[0039] As used herein, the term "effective amount of drug" can describe the amount of a non-toxic and sufficient drug required to treat or prevent a disease, and can be adjusted for a variety of factors, including but not limited to the type and severity of the disease, the type and amount of the active ingredient or other components contained in the formulation, the dosage form, the patient's age, weight, health status, sex, and dietary behavior, and the timing of drug administration. The appropriate effective amount in any individual case can be determined by a person skilled in the art using only routine laboratory methods.

[0040] One aspect of this disclosure provides a hydroxypropyl cellulose (HPC) having a molar degree of substitution (MS) of about 3.0 to about 3.9 per mole of anhydrous glucose and a weight-average molecular weight of about 700,000 to about 2,000,000 Daltons. In one non-limiting embodiment of this disclosure, the molar degree of substitution of the hydroxypropyl cellulose may be in the range of about 3.2 to about 3.8. In another non-limiting embodiment of this disclosure, the molar degree of substitution of the hydroxypropyl cellulose may be in the range of about 3.4 to about 3.7.

[0041] In one non-limiting embodiment of this disclosure, the weight-average molecular weight of hydroxypropyl cellulose can be in the range of about 750,000 to about 2,000,000 Daltons, or about 800,000 to about 2,000,000 Daltons, or about 800,000 to about 1,700,000 Daltons, or about 1,000,000 to about 1,500,000 Daltons.

[0042] The hydroxypropyl cellulose according to this disclosure can exist in powder form and can have particles with a volume average particle size of less than 100 μm. In a non-limiting embodiment of this disclosure, the volume average particle size of the hydroxypropyl cellulose can be in the range of about 40 μm to about 80 μm or about 50 μm to about 75 μm. The volume average particle size of the hydroxypropyl cellulose in this disclosure refers to the particle size D50 at the point where the cumulative volume reaches 50% in a particle size distribution obtained by measuring using a laser scattering particle size distribution measuring device called Malvern Mastersizer 3000.

[0043] The hydroxypropyl cellulose (HPC) according to this disclosure can be prepared by methods known in the art for preparing hydroxyalkyl cellulose. In a non-limiting embodiment of this disclosure, hydroxypropyl cellulose (HPC) can be obtained by: (i) reacting a cellulose feedstock with an alkaline aqueous solution to obtain alkaline cellulose; (ii) further reacting the alkaline cellulose with propylene oxide to obtain a crude hydroxypropyl cellulose product; (iii) neutralizing the excess alkaline solution with an acidic aqueous solution; and (iv) washing, filtering, and drying the crude product to obtain a finally purified hydroxypropyl cellulose product. The purified hydroxypropyl cellulose product can be further ground to obtain hydroxypropyl cellulose in powder form. A 1% by weight aqueous solution of the hydroxypropyl cellulose obtained according to this disclosure can have a viscosity of at least 300 mPa·s at 25°C. In one non-limiting embodiment of this disclosure, the viscosity of hydroxypropyl cellulose can be in the range of about 300 mPa·s to about 10,000 mPa·s, about 500 mPa·s to about 8,000 mPa·s, about 1,000 mPa·s to about 5,000 mPa·s, or about 1,500 mPa·s to about 3,000 mPa·s.

[0044] Another aspect of this disclosure provides a modified release formulation or modified release dosage form comprising hydroxypropyl cellulose (HPC), said hydroxypropyl cellulose having a molar degree of substitution (MS) in the range of about 3.0 to about 3.9 per mole of anhydrous glucose and a weight-average molecular weight of about 700,000 to about 2,000,000 Daltons. In one non-limiting embodiment of this disclosure, the molar degree of substitution of hydroxypropyl cellulose may be in the range of about 3.2 to about 3.8. In another non-limiting embodiment of this disclosure, the molar degree of substitution of hydroxypropyl cellulose may be in the range of about 3.4 to about 3.7.

[0045] In one non-limiting embodiment of this disclosure, the weight-average molecular weight of hydroxypropyl cellulose (HPC) can be in the range of about 750,000 to about 2,000,000 Daltons. In another non-limiting embodiment of this disclosure, the weight-average molecular weight of hydroxypropyl cellulose can be in the range of about 800,000 to about 2,000,000 Daltons, or about 800,000 to about 1,700,000 Daltons, or about 1,000,000 to about 1,500,000 Daltons.

[0046] In one non-limiting embodiment of this disclosure, hydroxypropyl cellulose (HPC) may be present in powder form and may have particles with a volume average particle size of less than 100 μm. In one non-limiting embodiment of this disclosure, the volume average particle size of HPC may be in the range of about 40 μm to about 80 μm or about 50 μm to 75 μm. The volume average particle size of hydroxypropyl cellulose in this disclosure refers to the median particle size (D50) at the point where the cumulative volume reaches 50% in a particle size distribution obtained by measuring using a laser scattering particle size distribution measuring device called a Malvern Mastersizer 3000.

[0047] Furthermore, the hydroxypropyl cellulose (HPC) according to this disclosure can be used in an amount sufficient to improve the release of at least one active pharmaceutical ingredient (API) present in the modified release formulation of this disclosure. In a non-limiting embodiment of this disclosure, the amount of hydroxypropyl cellulose can be in the range of about 5% to about 99% by weight, or about 10% to about 90% by weight, or about 15% to about 75% by weight, or about 30% to about 60% by weight of the total modified release formulation.

[0048] The improved release formulation of this disclosure may further comprise at least one active pharmaceutical ingredient (API). In one non-limiting embodiment of this disclosure, the active pharmaceutical ingredient may be a drug. Alternatively, the active pharmaceutical ingredient (API) may be a biofunctional ingredient. Examples of biofunctional ingredients used for the purposes of this disclosure include, but are not limited to, dietary supplements, including but not limited to vitamins such as vitamin C, vitamin B1, B2, B3, B6, and B12; minerals such as zinc, magnesium, iron, and melatonin; herbal dietary supplements such as curcumin, ashwagandha, and fenugreek extract; and amino acids such as isoleucine, glycine, L-tryptophan, glucosamine, chondroitin, etc. Any drug with a broad range of water solubility may be suitable for the improved release formulation of this disclosure. In one non-limiting embodiment of this disclosure, the drug may be selected from the group consisting of drugs having water solubility at 25°C greater than 1 mg / L, or greater than 16 mg / L, or greater than 20 mg / L, or greater than 700 mg / L, or greater than 18,000 mg / L, or greater than 300,000 mg / L. Furthermore, drugs suitable for the modified release formulations of this disclosure may be selected from those belonging to different therapeutic classes, such as antipyretics, analgesics, and anti-inflammatory drugs; anthelmintics; cardiovascular drugs; antibacterial drugs; bronchodilators; antiasthmatic drugs; gastrointestinal drugs; antidiabetic drugs; antiprotozoal drugs; antiviral drugs; antiepileptic drugs; antidiuretics; or pharmaceutically acceptable salts and esters thereof.

[0049] Examples of antipyretics, analgesics, and anti-inflammatory drugs may include, but are not limited to, etodoxacin, ibuprofen, diclofenac, and tofacitinib. Examples of anthelmintic drugs may include, but are not limited to, albendazole. Examples of cardiovascular drugs may include, but are not limited to, carvedilol, metoprolol, sacubitril, and valsartan. Examples of antibacterial drugs may include, but are not limited to, erythromycin, ciprofloxacin, or any pharmaceutically acceptable salt or ester. Examples of bronchodilators may include, but are not limited to, salbutamol. Examples of antiasthmatic drugs may include, but are not limited to, doxophylline and theophylline. Examples of gastrointestinal drugs may include, but are not limited to, cimetidine and omeprazole. Examples of antidiabetic drugs may include, but are not limited to, metformin hydrochloride and sitagliptin. Examples of antiprotozoal drugs may include, but are not limited to, tinidazole. Examples of antiviral drugs may include, but are not limited to, acyclovir. Examples of antiepileptic drugs may include, but are not limited to, carbamazepine. Examples of antidiuretics may include, but are not limited to, chlorothiazide and hydrochlorothiazide.

[0050] Furthermore, the active pharmaceutical ingredient can be present in the modified release formulation of this disclosure at an effective pharmaceutical amount. As mentioned above, the modified release formulation of this disclosure is applicable to any drug with a wide range of water solubility. Therefore, the amount of one or more drugs present in the modified release formulation of this disclosure can vary depending on a variety of factors, including but not limited to the type of one or more drugs used, the nature and severity of the disease treated / cured, the type and content of the active ingredient or other ingredients contained in the formulation, the dosage form, the patient's age, weight, health status, sex and dietary behavior, the timing of drug administration, etc.

[0051] The improved release formulations disclosed herein may also comprise at least one pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients commonly used in pharmaceutical compositions are also suitable for the improved release formulations of this invention, for example, those described in *Handbook of Pharmaceutical Excipients*, Rows et al., Eds., 4th Edition, Pharmaceutical Press (2003) or *Remington: The Science and Practice of Pharmacy*, (formerly called Remington's Pharmaceutical Sciences), Alfonso R. Gennaro, ed., Lippincott Williams & Wilkins; 20th edition (Dec. 15, 2000). Examples of such excipients may include, but are not limited to, fillers, pigments, binders, lubricants, flow aids, flavoring agents, sweeteners, preservatives, stabilizers, antioxidants, etc.

[0052] Pharmaceutically acceptable excipients may be present in amounts that do not affect the therapeutic properties of the modified release formulation. Pharmaceutically acceptable excipients may comprise from about 1% by weight to about 85% by weight of the total modified release formulation. In one non-limiting embodiment of this disclosure, pharmaceutically acceptable excipients may comprise from about 5% by weight to about 75% by weight of the total modified release formulation or from about 5% by weight to about 60% by weight of the total modified release formulation.

[0053] Examples of fillers that may be present in the modified release formulations of this disclosure include, but are not limited to, cellulose; oligosaccharides such as lactose and sucrose; sugars; starch; processed starch; sugar alcohols such as mannitol, sorbitol, xylitol, and lactitol; silicic acid; inorganic acid salts; calcium sulfate, and complexes and oxides of aluminum silicate and magnesium silicate. Specific examples of inorganic acid salt excipients may include, but are not limited to, phosphates such as calcium diphosphate dihydrate and hydrogen sulfate. Furthermore, the filler may be present in an amount from about 5.0% by weight to about 15% by weight of the total modified release formulation.

[0054] Examples of binders that may be present in the modified release formulations of this disclosure include, but are not limited to, polyvinylpyrrolidone (PVP), sucrose, lactose, starch, processed starch, sugar, gum arabic, tragacanth, guar gum, pectin, wax-based binders, microcrystalline cellulose (MCC), methylcellulose, carboxymethyl cellulose, copovidone, gelatin, and sodium alginate. The binder may be present in an amount from about 1% by weight to about 80% by weight of the total modified release formulation.

[0055] Similarly, suitable lubricants that may be present in the modified release formulations of this disclosure may include, but are not limited to, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium stearoyl fumarate, and sucrose fatty acid esters of acids (e.g., stearic acid, palmitic acid, myristic acid, oleic acid, lauric acid, behenic acid, erucic acid). Furthermore, the lubricant may be present in an amount from about 0.1% by weight to about 20% by weight of the total modified release formulation.

[0056] The improved release formulation disclosed herein may also contain at least one additional improved release agent. Examples of such improved release agents may include, but are not limited to, sodium alginate, carboxyvinyl polymers, acrylic polymers such as aminoalkyl methacrylate copolymer RS ​​(Eudragit RS, manufactured by Rohm Pharma GmbH), and ethyl acrylate-methyl methacrylate copolymer suspension (Eudragit NE, manufactured by Rohm Pharma GmbH). The additional improved release agent may be present in an amount of about 5% by weight to about 50% by weight of the total improved release formulation.

[0057] Examples of pH adjusters suitable for the modified release formulations of this disclosure may be inorganic acids, such as hydrochloric acid, sulfuric acid, hydrobromic acid and phosphoric acid; organic acids, such as acetic acid, succinic acid, fumaric acid, malic acid, oxalic acid, lactic acid, glutaric acid, salicylic acid and tartaric acid and their salts; or any combination thereof.

[0058] Other pharmaceutically acceptable excipients may also be present in the modified release formulations of this disclosure. For example, colorants or food dyes, such as Food Yellow 5, Food Red 2 and Food Blue 2, food lake dyes or ferric oxide; pH buffers, such as amine-based buffers or carbonate-based buffers; surfactants, such as sodium dodecyl sulfate, polysorbate 80, hydrogenated oil or polyoxyethylene (160)polyoxypropylene (30) glycol; stabilizers, such as tocopherol, ethylenediaminetetraacetic acid tetrasodium sodium, nicotinamide or cyclodextrin; and acidifiers, such as citric acid, tartaric acid, malic acid or ascorbic acid.

[0059] The modified release formulation of this disclosure can be present in a dry solid dosage form. Dry solid dosage forms are particularly useful for delivering accurate doses to specific sites, typically orally, but can also be administered via other routes known to those skilled in the art, such as sublingual / buccal, rectal, vaginal, and ocular administration. In one non-limiting embodiment of this disclosure, the modified release formulation can be present in a solid dosage form suitable for oral administration. Such dosage forms may include, but are not limited to, tablets, capsules, powders, granules, sachets, or lozenges. In one non-limiting embodiment of this disclosure, the modified release formulation is a tablet.

[0060] Furthermore, for purposes such as masking odor or taste, stabilization, and maintaining efficacy, the tablet form of the improved release formulation disclosed herein can be coated with a matrix material. The coating may contain sugars or film-forming polymers.

[0061] In one non-limiting embodiment of this disclosure, the tablet may be sugar-coated, film-coated, enteric-coated, or coated with a thin layer or film of a release modifier to further improve the release of the drug / active pharmaceutical ingredient from the formulation.

[0062] In one non-limiting embodiment of this disclosure, the tablet may be sugar-coated. A sugar coating of a tablet is essentially a thick, rigid sugar coating that surrounds the surface of the tablet to mask the taste of the drug or any other active pharmaceutical ingredient, especially if the taste is unpleasant, and to provide stability to the tablet, preventing it from cracking under the influence of light and moisture. The sugar coating of the tablet according to this disclosure may be made using glycosyl materials. Examples of glycosyl materials suitable for the purposes of this disclosure include, but are not limited to, granulated sugar. Additional pharmaceutically acceptable excipients may also be added to the glycosyl material to enhance the properties of the glycosyl coating, such as improved binding capacity and mechanical strength, and anti-sticking properties. Examples of such additional excipients include, but are not limited to, gelatin, gum arabic, polyvinylpyrrolidone, pullulan, talc, precipitated calcium carbonate, calcium phosphate, calcium, etc. Furthermore, the glycosyl coating may also contain edible flavorings or colorings / pigments as additional pharmaceutical excipients.

[0063] In another non-limiting embodiment of this disclosure, the tablet may be a film-coated tablet. Film coating of a tablet typically involves wrapping the tablet core with a protective polymer film. Therefore, the tablets of this disclosure may contain a polymer film, particularly a water-based film-based polymer as the coating layer. Both synthetic and natural polymers can be used for tablet film coating. Examples of synthetic polymers may include, but are not limited to, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymers, polyvinyl alcohol-acrylate-methyl methacrylate copolymers, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymers, polyvinylpyrrolidone, and polyethylene glycol. Examples of natural polymers may include, but are not limited to, polysaccharides, such as pullulan.

[0064] In another non-limiting embodiment of this disclosure, the tablet may be enteric-coated. The enteric coating on the tablet is intended to protect the stomach from the effects of the tablet formulation; protect the drug from gastric acid; and release the active pharmaceutical ingredient at a specific location (typically the lower region of the stomach or intestine). The enteric coating of this tablet may be achieved using an enteric coating matrix material. Examples of such materials may include, but are not limited to, acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S; and natural materials such as shellac.

[0065] Furthermore, the tablet form of the improved release formulation of this disclosure can be coated with a thin layer or film of the improved release agent to further enhance or improve the improved release efficiency of the improved release formulation. Therefore, the tablets of this disclosure can be coated with a thin layer or film of the improved release formulation, or a thin layer or film of additional improved release agents, or a combination of both.

[0066] In one non-limiting embodiment, the tablet can be coated with a thin layer or film of the improved release formulation of this disclosure. The improved release formulation for coating purposes may also comprise at least one coating material for sugar coating, film coating, and enteric coating, as described above in this disclosure.

[0067] In another non-limiting embodiment of this disclosure, the tablet may be coated with a thin layer or film of an additional release modifier. Examples of such additional release modifiers may include, but are not limited to, hydroxypropyl methylcellulose, polyethylene oxide, hydroxyethylcellulose, ethylcellulose, methacrylic acid copolymers, guar gum, xanthan gum, alginate, starch derivatives, waxes, and fats.

[0068] The coating material used for the purposes of this disclosure may also contain at least one pharmaceutically acceptable excipient described above in this disclosure, such as an adhesive, lubricant, plasticizer, stabilizer, colorant, etc.

[0069] There are no limitations on the methods used to prepare the improved release formulations of this disclosure, particularly the improved release formulations of solid oral dosage forms such as tablets. Any tableting method known in the pharmaceutical field, such as wet granulation tableting, dry granulation tableting, or dry direct tableting, is suitable for the purposes of this disclosure. In one non-limiting embodiment, the improved release formulation in tablet form can be prepared by wet granulation, wherein the method comprises the following steps: (i) mixing a mixture of hydroxypropyl cellulose, an active pharmaceutical ingredient such as a drug, and other desired pharmaceutically acceptable excipients to prepare a homogeneous blend; (ii) adding a wetting agent to obtain a kneaded blend, which is then granulated to obtain the resulting particles; (iii) drying and sieving the resulting particles to an optimal size suitable for compression; (iv) blending the sieved particles obtained from step (iii) with a suitable pharmaceutically acceptable lubricant such as magnesium stearate; and finally (v) compressing the blended particles obtained from step (iv) into tablets.

[0070] In another non-limiting embodiment, the improved release formulation of this disclosure can be prepared by dry granulation, the method comprising the steps of: (i) dispensing and mixing predetermined amounts of various components of the improved release formulation of this disclosure, such as hydroxypropyl cellulose, the active pharmaceutical ingredient, and pharmaceutically acceptable excipients, to obtain a homogeneous powder blend; (ii) compacting the homogeneous powder blend by slugging or rolling to obtain flattened large tablets or pellets; (iii) grinding and sieving the flattened large tablets or pellets to obtain homogeneous granules; and (iv) compressing the granules. Lubricants such as magnesium stearate and other excipients such as disintegrants, glidants, etc., may also be added prior to compressing the homogeneous granules.

[0071] In another non-limiting embodiment, the improved release formulation of this disclosure can be prepared by a dry direct compression method or a direct compressible method, the method comprising the steps of: (i) pre-grinding or sieving various components of the improved release formulation of this disclosure, such as hydroxypropyl cellulose, active pharmaceutical ingredients such as pharmaceuticals, and pharmaceutically acceptable excipients including lubricants, to obtain a powder component; (ii) uniformly blending or mixing the powder component to obtain a homogeneous blend; and (iii) compressing the homogeneous blend to obtain a tablet.

[0072] In one non-limiting embodiment of this disclosure, hydroxypropyl cellulose present in the modified release formulation: (i) provides low-dose dumping of the active pharmaceutical ingredient, (ii) provides uniform release of the active pharmaceutical ingredient over a period of time, (iii) provides effective tablet compression properties, and (iv) provides controlled release of the active pharmaceutical ingredient at lower polymer dosage levels.

[0073] Unless otherwise stated, the following examples illustrate this disclosure, and all parts and percentages are by weight. Each example is provided by way of interpretation rather than limitation of this disclosure. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to this disclosure without departing from the scope or spirit of the invention. For example, features shown or described as part of one embodiment may be used in another embodiment to produce yet another embodiment. Therefore, this disclosure is intended to cover such modifications and variations that fall within the scope of the appended claims and their equivalents.

[0074] Example

[0075] Examples 1-4 of this disclosure provide the hydroxypropyl cellulose (HPC) of this disclosure.

[0076] Example 1 (Ex.1): Preparation of hydroxypropyl cellulose (HPC) with an HP-MS value of 3.72

[0077] One part of the cut purified cellulose was immersed in a mixture of 7 parts heptane, 2 parts tert-butanol, 0.5 parts water, and 0.2 parts 50% sodium hydroxide aqueous solution to obtain a slurry. The slurry was stirred to obtain basic cellulose. Then, 2.6 parts propylene oxide (PO) was added to the slurry containing basic cellulose to obtain a reaction mixture. The resulting reaction mixture was then heated to 105°C and maintained at this temperature until all PO reacted. The reaction mixture containing crude hydroxypropyl cellulose product was then cooled to room temperature, and excess sodium hydroxide was neutralized with acetic acid. The solvent was removed by filtration, and the product was then washed with hot water, and salts and impurities were removed by filtration. The purified filter cake thus obtained was dried at about 130°C-140°C until the moisture content was <5%. The dried hydroxypropyl cellulose thus obtained was milled until a product with D was obtained. 50 Hydroxypropyl cellulose in powder form with particles <100 μm. The molar degree of hydroxypropyl substitution was analyzed to be 3.7. The Mw is 1,510,000 Daltons, and the viscosity of a 1 wt% aqueous solution in water is 1,800 mPa·s. The volume average particle size (D50) is 52 μm.

[0078] Example 2 (Ex.2): Preparation of HPC with an HP-MS resolution of 3.72

[0079] The HPC of this example was prepared in the same manner as described in Example 1, except that 2.8 parts of propylene oxide were used.

[0080] Example 3 (Ex.3): Preparation of HPC with an HP-MS resolution of 3.56

[0081] The HPC of this example was prepared using the steps described in Example 1, except that 2.0 parts of propylene oxide were used.

[0082] Example 4 (Ex.4): Preparation of HPC with an HP-MS resolution of 3.56

[0083] The HPC of this example was prepared in the same manner as described in Example 1, except that 2.1 parts of propylene oxide were used.

[0084] Comparative Example 5 (Comp.Ex.5):

[0085] The benefits of the HPCs of Examples 1-4 of this disclosure are illustrated using a commercially available HPC purchased from Ashland Specialty Ingredient GP and a Klucel HXF as a comparative example.

[0086] Following the test methods described below, the hydroxypropyl molar substitution degree (HP-MS), molecular weight (MW) distribution, viscosity, and volume average particle size of the hydroxypropyl cellulose from Examples 1-4 and Comparative Example 5 were measured. The measured values ​​are given in Table 1.

[0087] Table 1: Feature details of HPC in Examples 1-4 and Comparative Example 5

[0088]

[0089]

[0090] Test method:

[0091] 1. Measurement of the molar degree of hydroxypropyl substitution:

[0092] The HP-MS values ​​of HPC in Examples 1-4 and Comparative Example 5 were determined by NMR, as follows:

[0093] Sample hydrolysis: First, 25 mg of sample was swollen in 1.00 gm D₂O for 30 minutes. Then, 0.5 gm 35% DCl was added to the swollen sample. The vial was kept at 70°C for 1 hour in a heating block. The sample solution was cooled for approximately 30 minutes and then transferred to a 5 mm NMR tube for analysis.

[0094] NMR Measurement: Quantitative

[0095] ¹H NMR spectra were recorded using a Bruker 400MHz NMR spectrometer and processed using Topspin software. Acquisition parameters were as follows: temperature 300K, scan width 20ppm, pulse width 45deg, number of scans 32, relaxation delay 30s. Processing parameters were as follows: spectral line broadening 0.3Hz.

[0096] Phase and baseline corrections were performed on the spectrum using standard practices. The center of the highest field signal (hydroxypropyl-substituted methyl group) was referenced at 1.05 ppm. The spectral integrals are as follows:

[0097] Region A (IA) = 1.90 - 0.15 ppm (integrated area calibrated to a value of 300; other integrated areas are related to this integral value).

[0098] Zone B (IB) = 5.70-2.15 ppm.

[0099] NMR spectra of representative HPC samples are as follows Figure 1 As shown.

[0100] HP MS and weight % HP are calculated as follows: :

[0101] HP MS = (7 / (IB–IA)) * 100

[0102] Weight%HP=((HP MS*MW OC3H6OH) / (MW AHG+(HP MS*(MW C3H6OH–MW H))))*100

[0103] MW OC3H6OH=75.086

[0104] MW C3H6OH=59.087

[0105] MW AHG = 162.141

[0106] MW H = 1.008

[0107] 2. Molecular weight (MW) distribution:

[0108] The molecular weight (MW) distribution of hydroxypropyl cellulose in Examples 1-4 and Comparative Example 5 was determined using size exclusion chromatography. Molecular weight is the sum of the atomic weights of the atoms in a molecule. As used herein with respect to polymers, the terms molecular weight, average molecular weight, mean molecular weight, and apparent molecular weight refer to the arithmetic mean of the molecular weights of individual macromolecules measured by size exclusion chromatography (SEC). The relative molecular weight average from the analytical SEC was calculated relative to a poly(ethylene glycol / ethylene oxide) (PEG / PEO) standard with a narrow molecular weight distribution. Size exclusion chromatography was performed according to the following method:

[0109] (a) Chromatographic apparatus

[0110] All Waters modules in the unit were manufactured by Waters Corporation (34 Maple Street, Milford, MA 01757, USA). This unit can be replaced by similar units from different manufacturers.

[0111] Waters M515 Solvent Delivery System

[0112] Waters M717 Automatic Sampler

[0113] Waters M2414 Differential Refractive Index Detector (DRI) for use relative to SEC*

[0114] Column setup - please see the "Analytical Conditions" section below for details.

[0115] Waters Empower 2 software

[0116] *RI range 1.00 to 1.75 RIU

[0117] Measurement range 7x10-7RIU

[0118] Drift - 2x10-7RIU

[0119] (b) SEC's analytical conditions

[0120] Mobile phase - 55% 0.1M lithium acetate / 45% ethanol

[0121] Flow rate - 0.8 ml / min

[0122] Chromatographic column - TSK gel guard (6mm x 40mm) + 2 Linear TSK GMPWXL columns; 13μm; 300mm x 7.8mm (TOSOH Bioscience LLC, 3604 Horizon Drive, Suite 100, King of Prussia, PA19406, USA)

[0123] Column temperature -35℃

[0124] DRI (Differential Refractive Index) detector temperature -35℃

[0125] Calibration - PEO / PEG standards with narrow molecular weight distribution (PSS-USA, Inc. Amherst Fields Research Park, 160 Old Farm Road, Amherst, MA 01002)

[0126] Sample concentration - typically 1 mg / ml (unless otherwise specified)

[0127] Injection volume - 200 μl

[0128] 3. Viscosity measurement:

[0129] Slowly add HPC to the stirred deionized water and stir for 1 hour. Equilibrate the temperature in a 25°C bath for 1 hour. Measure the viscosity using an LV spindle #4 at 30 rpm through a Brookfield viscometer, and read the value after 3 minutes.

[0130] 4. Particle size measurement:

[0131] The particle size of hydroxypropyl cellulose in powder form from Examples 1-4 and Comparative Example 5 was measured using a Malvern Mastersizer 3000 laser scattering particle size analyzer. The powder samples were measured using an Aero S dry powder feeder equipped with a universal hopper / sample tray pair and a standard stainless steel Venturi powder dispenser. The Aero S hopper gap was set to 4.0 mm. The powder sample was measured by completely filling a 1 / 4 teaspoon measuring scoop and loading it into the hopper. The powder feed rate was set to 30%, and the air pressure was set to 3.0 bar. With obscuration filtering off, the obscuration limits were set to a lower limit of 0.2% and an upper limit of 10%. The background measurement time was set to 10 seconds, and the sample measurement time was set to 20 seconds. Measurements were set to begin once the obscuration was within the set range and after a 0.1-second settling time. The Fraunhofer scattering model and the "General Purpose" analysis model were used for data analysis, converting the data to particle diameter using volume distribution.

[0132] A commercially available HPC, traded under the name Nisso HPC H, has a molecular weight of 652,000, a viscosity of 146 mPa·s in a 1% aqueous solution at 25°C, and a particle size D50 of 170 μm. It is expected to exhibit worse improved drug release performance than the HPC disclosed herein. The molecular weight, viscosity, and particle size of Nisso HPC H were measured according to the test methods described above.

[0133] Modified drug release test

[0134] The hydroxypropyl cellulose of Examples 1-4 is further used in modified release formulations along with the pharmaceutical ingredients and other pharmaceutically acceptable excipients. Table 2 lists the pharmaceutical ingredients used in the production of these modified release formulations.

[0135] Table 2: List of test drugs used in this modified release formulation

[0136]

[0137] Example 6: A modified release formulation of HPC from Example 1 comprising 30% by weight (Ex. 6)

[0138] Hydrochlorothiazide, HPC from Example 1, and spray-dried lactose (components 1-3) were weighed according to the weight ratios listed in Table 3, sieved through a USP sieve #20, and co-mixed in a Turbula mixer for 10 minutes. Sodium stearoyl fumarate, colloidal silica, and magnesium stearate were also weighed separately, sieved through a USP sieve #20, and added to the blends of components 1-3. The resulting powder blends were then co-mixed again in a Turbula mixer for 2 minutes to obtain a homogeneous powder blend. The homogeneous powder blend was then compressed into tablets using a compaction simulator STYL'one, simulating a manestybeta press operating at a compression speed of 67 RPM (64,320 tablets / hour), using an 11.28 flat punch and a die with a pressure of 25 kN. Tablets were obtained with a single tablet weight of approximately 500 mg.

[0139] Table 3: Improved release formulations of Examples 6 and 6A

[0140]

[0141]

[0142] Example 6A: A comparative modified release formulation of HPC from Comparative Example 5, comprising 30% by weight (Ex. 6A)

[0143] Using the amounts of ingredients listed in Table 3 above, a comparative modified release formulation (Ex. 6A) of HPC from Comparative Example 5 was prepared in the same manner as described in Example 6 above, using 30.0% by weight of the ingredients listed in Table 3 above.

[0144] Dissolution tests were performed on the tablets of Examples 6 and 6A using a USP apparatus I at a dose of 50 mg in 0.05 M phosphate at pH 6.8 with a constant stirring speed of 100 RPM. Samples were taken at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 22, and 24 hours and filtered through a 0.45 μm nylon membrane. Samples were analyzed at 272 nm by inline UV detection. Figure 2 Dissolution profiles of hydrochlorothiazide (HCTZ), expressed as a percentage of total drug released over 24 hours, are shown for two formulations, Ex.6 and Ex.6A. Figure 2 It is evident that the drug is released more slowly from the improved release formulation of Example 6 than from the comparative improved release formulation of Example 6A.

[0145] Example 7: A modified release formulation of HPC from Example 1 comprising 60% by weight (Ex. 7)

[0146] In this embodiment, a modified release formulation (Ex.7) comprising 60% by weight of the HPC of Example 1 was prepared. The modified release formulation of this embodiment was prepared in the same manner as in Example 6 above, using the amounts of the ingredients listed in Table 4 below.

[0147] Table 4: Improved release formulations of Examples 7 and 7A

[0148]

[0149]

[0150] Example 7A: A comparative modified release formulation of HPC from Comparative Example 5, comprising 60% by weight (Ex. 7A)

[0151] Using the amounts of ingredients listed in Table 4 above, a control modified release formulation (Ex. 7A) containing 60.0% by weight of HPC from Comparative Example 5 was prepared in the same manner as the modified release formulation of Example 7 above.

[0152] Dissolution tests of the tablets of Examples 7 and 7A were performed using a USP apparatus I at a dose of 50 mg in 0.05 M phosphate at pH 6.8 with a constant stirring speed of 100 RPM. In the same manner as in Examples 6 and 6A above, the tablets of Examples 7 and 7A were performed in 0.05 M phosphate at pH 6.8 with a constant stirring speed of 100 RPM. Figure 3 Dissolution profiles of hydrochlorothiazide (HCTZ), expressed as a percentage of total drug released over 24 hours, are shown for two formulations, Ex.7 and Ex.7A. Figure 3 It is evident that the drug is released more slowly from the improved release formulation of Example 7 than from the comparative improved release formulation of Example 7A.

[0153] Example 8: A modified release formulation of HPC from Example 2 comprising 20% ​​by weight (Ex. 8)

[0154] In this embodiment, a modified release formulation tablet (Ex. 8) with a single tablet weight of approximately 860 mg was prepared using 20% ​​by weight of the HPC from Example 2. The modified release formulation (Ex. 8) of this embodiment was prepared in the same manner as in Example 6 above, using the amounts of ingredients listed in Table 5 below.

[0155] Table 5: Improved release formulations of Examples 8 and 8A

[0156]

[0157] Example 8A: A comparative modified release formulation of HPC having 20% ​​by weight of Comparative Example 5 (Ex. 8A)

[0158] Using the amounts of ingredients listed in Table 5 above, a comparative modified release formulation (Ex. 8A) containing 20.0% by weight of HPC from Comparative Example 5 was prepared in the same manner as the modified release formulation of Example 8 above.

[0159] Dissolution tests of the tablets from Examples 8 and 8A were performed using a USP apparatus I at a dose of 60 mg in 0.05 M phosphate at pH 7.2 with a constant stirring speed of 100 RPM. Samples were analyzed at 221 nm using online UV detection. (The same procedure as in Examples 6 and 6A described above was followed by dissolution testing of the tablets in 0.05 M phosphate at pH 7.2 with a constant stirring speed of 100 RPM.) Figure 4 Dissolution profiles of ibuprofen, expressed as a percentage of total drug released over 24 hours, are shown for two formulations, Ex.8 and Ex.8A. Drug release from the improved release formulation of Example 8 is slower than drug release from the comparative improved release formulation of Example 8A.

[0160] Example 9: A modified release formulation of HPC from Example 2 comprising 10% by weight (Ex. 9)

[0161] Similar to the formulation of Example 8, this example describes the preparation of a modified release formulation with a single tablet weight of approximately 860 mg using the same ingredients and steps as described in Example 8, except that 10% by weight of the HPC from Example 2 is used. Therefore, the weight proportions of other ingredients have been adjusted and are listed in Table 6 below.

[0162] Table 6: Improved release formulations of Examples 9 and 9A

[0163]

[0164]

[0165] Example 9A: A comparative modified release formulation of HPC from Comparative Example 5, comprising 10% by weight (Ex. 9A)

[0166] Using the amounts of ingredients listed in Table 6 above, a comparative modified release formulation (Ex. 9A) containing 10.0% by weight of HPC from Comparative Example 5 was prepared in the same manner as the modified release formulation of Example 9 above.

[0167] Using the same steps as in Examples 6 and 6A above, dissolution tests of the tablets of Examples 9 and 9A were performed in 0.05M phosphate at pH 7.2 using USP device I at a dose of 600 mg. Figure 5 Dissolution profiles of ibuprofen, expressed as a percentage of total drug released over 24 hours, are shown for two formulations, Ex.9 and Ex.9A. Drug release from the improved release formulation of Example 9 is slower than drug release from the comparative improved release formulation of Example 9A.

[0168] Example 10: A modified release formulation of HPC from Example 2 comprising 25% by weight (Ex. 10)

[0169] In this embodiment, 25% by weight of the HPC from Example 2 was used to prepare a modified release formulation tablet (Ex. 10) with a single tablet weight of approximately 500 mg. The modified release formulation (Ex. 10) of this embodiment was prepared in the same manner as in Example 6 above, using the amounts of ingredients listed in Table 7 below.

[0170] Table 7: Improved release formulations of Examples 10 and 10A

[0171]

[0172]

[0173] Example 10A: A comparative modified release formulation of HPC from Comparative Example 5, comprising 25% by weight (Ex. 10A).

[0174] Using the amounts of ingredients listed in Table 7 above, a comparative modified release formulation (Ex. 10A) containing 25.0% by weight of HPC from Comparative Example 5 was also prepared in the same manner as the modified release formulation of Example 10 above.

[0175] Dissolution tests of the tablets of Examples 10 and 10A were conducted using a USP apparatus I at a dose of 600 mg in 0.05 M phosphate at pH 7.2 with a constant stirring speed of 100 RPM. In the same manner as in Examples 6 and 6A above, the tablets were tested in 0.05 M phosphate at a constant stirring speed of 100 RPM. Figure 6 Dissolution profiles for de ibuprofen, expressed as a percentage of total drug released over 24 hours, are shown for two formulations, Ex.10 and Ex.10A. Drug release from the improved release formulation of Example 10 was slower than drug release from the comparative improved release formulation of Example 10A.

[0176] Example 11: A modified release formulation of HPC from Example 3 comprising 15% by weight (Ex. 11)

[0177] In this embodiment, a modified release formulation tablet with a single tablet weight of approximately 500 mg was prepared using 15% by weight of the HPC from Example 3. The tablet was prepared in the same manner as described in Example 6 above, using the amounts of ingredients listed in Table 8 below.

[0178] Table 8: Improved release formulations of Examples 11 and 11A

[0179]

[0180]

[0181] Example 11A: A comparative modified release formulation of HPC from Comparative Example 5, comprising 15% by weight (Ex. 11A).

[0182] Using the amounts of ingredients listed in Table 8 above, a comparative modified release formulation (Ex. 11A) containing 15.0% by weight of HPC from Comparative Example 5 was prepared in the same manner as the modified release formulation of Example 11 above.

[0183] Dissolution tests of the tablets of Examples 11 and 11A were conducted using a USP apparatus I at a dose of 50 mg in 0.05 M phosphate at pH 6.8 with a constant stirring speed of 100 RPM, in the same manner as in Example 6 above. The dissolution profile of the modified release formulation (Ex. 11) of Example 11 is shown in... Figure 7 The dissolution profiles of the modified release formulation of Example 11 (Ex.11) were compared with those of the comparative modified release formulation of Example 11A. Drug release from the modified release formulation of Example 11 (Ex.11) was slower than drug release from the comparative modified release formulation of Example 11A (Ex.11A).

[0184] Example 12: A modified release formulation of HPC from Example 4 (Ex. 12) comprising 15% by weight.

[0185] In this embodiment, a modified release formulation tablet with a single tablet weight of approximately 500 mg was prepared using 15% by weight of the HPC from Example 4. The tablet was prepared in the same manner as described in Example 6 above, using the amounts of ingredients listed in Table 9 below.

[0186] Table 9: Improved release formulation of Example 12

[0187]

[0188] Dissolution testing of the tablets of this example was conducted using the USP apparatus I at a dose of 50 mg in 0.15 M phosphate at pH 6.8 with a constant stirring speed of 100 RPM, in the same manner as in Example 6 above. The samples were analyzed at 272 nm using online UV detection. The dissolution profile of the modified release formulation (Ex. 12) of Example 12 is shown in... Figure 8 The dissolution profiles of the modified release formulation of Example 12 were compared with those of the control modified release formulation Ex.11A. Drug release from the modified release formulation of Example 12 was slower than drug release from the control modified release formulation of Example 11A.

Claims

1. A hydroxypropyl cellulose having a molar degree of substitution of 3.4 to 3.8, a weight-average molecular weight of 700,000 to 2,000,000 Daltons, a viscosity of 1,000 to 3,000 mPa·s in a 1% aqueous solution at 25°C, and a volume-average particle size of less than 100 μm.

2. The hydroxypropyl cellulose of claim 1, wherein the weight-average molecular weight is in the range of 1,000,000 to 1,500,000 Daltons.

3. A modified release formulation comprising hydroxypropyl cellulose, said hydroxypropyl cellulose having a molar degree of substitution of 3.4 to 3.8, a weight-average molecular weight of 700,000 to 2,000,000 Daltons, a viscosity in a 1% by weight aqueous solution at 25°C ranging from 1,000 to 3,000 mPa·s, and a volume-average particle size of less than 100 μm.

4. The modified release formulation of claim 3, wherein the hydroxypropyl cellulose comprises 5% of the total formulation. weight % to 99 weight The range of % exists.

5. The improved release formulation of claim 3, wherein the hydroxypropyl cellulose comprises 10% of the total formulation. weight % to 90 weight The range of % exists.

6. The improved release formulation of claim 3, wherein the hydroxypropyl cellulose comprises 15% of the total formulation. weight % to 75 weight The range of % exists.

7. The modified release formulation of claim 3 further comprises a pharmaceutically effective amount of at least one drug, said drug having a water solubility greater than 1 mg / L at 25°C.

8. The modified release formulation of claim 7, wherein the water solubility of the drug is greater than 20 mg / L.

9. The modified release formulation of claim 7, wherein the water solubility of the drug is greater than 700 mg / L.

10. The modified release formulation of claim 7, wherein the drug is selected from the group consisting of: antipyretics, analgesics, anti-inflammatory drugs, anthelmintics, cardiovascular drugs, antibacterial drugs, bronchodilators, anti-asthmatic drugs, gastrointestinal drugs, antidiabetic drugs, antiprotozoal drugs, antiviral drugs, antiepileptic drugs, antidiuretic drugs, and pharmaceutically acceptable salts and esters thereof.

11. The modified release formulation of claim 7, wherein the drug is selected from the group consisting of: etodoxacin, albendazole, ciprofloxacin, erythromycin and its derivatives, ibuprofen, diclofenac, tofacitinib, carvedilol, metoprolol, sacubitril, valsartan, salbutamol, doxofylline, theophylline, cimetidine, omeprazole, metformin hydrochloride, sitagliptin, tinidazole, chlorothiazide, hydrochlorothiazide, acyclovir, carbamazepine, and pharmaceutically acceptable salts and esters thereof.

12. The modified release formulation of claim 3 further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of fillers, binders, surfactants, disintegrants, lubricants, and flow aids.

13. The improved release formulation of claim 12, wherein the filler is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, inorganic acid salts, and combinations thereof.

14. The improved release formulation of claim 12, wherein the filler is selected from the group consisting of: cellulose, sugar, starch, processed starch, mannitol, sorbitol, xylitol, lactitol, silicic acid, calcium sulfate, complexes and oxides of aluminum silicate and magnesium silicate, calcium diphosphate dihydrate and hydrogen sulfate.

15. The modified release formulation of claim 12 or 14, wherein the filler is lactose or sucrose.

16. The improved release formulation of claim 12, wherein the lubricant is selected from the group consisting of: talc, calcium stearate, magnesium stearate, polyethylene glycol, stearic acid, palmitic acid, colloidal silica, calcium silicate, mineral oil, wax, carnauba wax hydrogenated vegetable oil, glyceryl behenate, sodium benzoate, sodium acetate, sodium stearoyl fumarate, sucrose fatty acid esters of stearic acid, palmitic acid, myristic acid, oleic acid, lauric acid, behenic acid, and erucic acid, and any combination thereof.

17. The improved release formulation of claim 12, wherein the binder is selected from the group consisting of: polyvinylpyrrolidone, starch, processed starch, sugar, gum arabic, tragacanth, guar gum, pectin, wax-based binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, copovidone, gelatin, sodium alginate, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and any combination thereof.

18. The modified release formulation of claim 12 or 17, wherein the binder is lactose or sucrose.

19. The improved release formulation of claim 12, wherein the pharmaceutically acceptable excipient constitutes 1% of the total formulation. weight % to 85 weight A certain percentage exists.

20. The modified release formulation of claim 3, wherein the formulation is in the form of tablets, capsules, powders, granules, sachets or lozenges.

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