JP2023524517A - Modified release formulation containing hydroxypropyl cellulose - Google Patents

Abstract

The present disclosure provides 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

The processes, procedures, methods, products, results, and/or concepts disclosed herein (collectively, the "disclosure") relate generally to hydroxypropyl cellulose (HPC) and its applications. The present disclosure further relates to modified release formulations (modified release pharmaceutical formulations) derived from hydroxypropylcellulose.

Pharmaceutical compositions often have specific desired properties, including use as coating agents, film formers, rate controlling agents for modified release, stabilizers, suspending agents, tablet binders, and viscosity increasing agents. Including polymers to achieve a therapeutic effect.

It has long been known that almost all pharmacologically active compounds are most effective when present in the plasma within a certain concentration range, above which they can cause adverse side effects. It's here. Also, excess drug in the plasma can be wasted if the concentration significantly exceeds the recommended blood concentration for maximal pharmacological effect, thus adding unnecessary costs to both the manufacture and use of drug formulations. It takes. Alternatively, if the plasma drug concentration is below the most effective range, there is a risk that the active ingredient may not be maximally effective or not effective at all.

Where physiologically possible, oral dosage forms are the preferred route of administration for most pharmaceutical compounds because they offer easy and low cost administration. However, patient compliance is an important factor to consider in conjunction with oral administration of pharmaceutical compounds, especially when the compound must be taken three to four times daily. To maximize patient compliance, it is desirable to reduce the number of daily dosage units required by a patient to achieve effective therapy. The use of smaller, longer-acting doses also improves the constancy of blood drug concentrations over time and allows the drug to approach the ideal therapeutic dose throughout the day. Treatment may be improved.

One way to achieve these goals is to use modified release formulations that are effective in maintaining therapeutic blood levels over an extended period of time, resulting in optimal therapy. They maintain near constant blood levels and avoid the fluctuations associated with conventional immediate release formulations that are administered three to four times daily, thus reducing the frequency of dosing as well as the severity and frequency of side effects. also reduce

There are many different modified release dosage forms on the market. Many of these controlled delivery systems utilize hydrophilic polymer matrices that provide a useful level of control over drug delivery. After the formulation is ingested, the active pharmaceutical ingredient is slowly released from the polymer matrix, resulting in a prolonged release of the active ingredient. One approach to formulating a modified release composition involves dry blending one or more polymers with the desired drug to form a composition that forms a gel when exposed to fluid, and then the drug is , released slowly by diffusion from the gel.

Tablets have been prepared in the past that modify the release of the drug contained, but have not been entirely satisfactory. Some of them are too expensive to manufacture because of expensive materials, or because of the complicated equipment or processes used to manufacture them, or because of the additives required to obtain delayed release. Some are too big for Other tablets were unsatisfactory due to lack of uniform release time.

Another important consideration is that the substance causing the modified drug release must be physiologically tolerable. There should be no or negligible toxic effects in humans. It must be completely eliminated so that it does not accumulate in human tissues even after long-term use. There is a need for compositions and processes for manufacturing orally deliverable pharmaceutical formulations as modified release that overcome the problems associated with the processes described above.

In one aspect, the present disclosure has 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 microns. We provide Hydroxypropyl Cellulose (HPC). In one non-limiting embodiment of the present disclosure, the molar degree of substitution of hydroxypropylcellulose varies from about 3.2 to about 3.8, or from about 3.4 to about 3.7. In one non-limiting embodiment of the present disclosure, the weight average molecular weight of hydroxypropylcellulose varies from about 1,000,000 to about 1,500,000 Daltons. In one non-limiting embodiment of the present disclosure, the hydroxypropylcellulose has a viscosity of at least 300 mPa·s in a 1 weight percent (1 wt.%) aqueous solution at 25°C. In another non-limiting embodiment of the present disclosure, the viscosity of hydroxypropylcellulose can vary from about 1000 to about 3000 mPa·s in a 1 wt% aqueous solution at 25°C.

In another aspect, the present disclosure has 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. A modified release formulation comprising hydroxypropylcellulose is provided. In one non-limiting embodiment of the present disclosure, the molar degree of substitution of hydroxypropylcellulose varies from about 3.2 to about 3.8, or from about 3.4 to about 3.7. In one non-limiting embodiment of the present disclosure, the weight average molecular weight of hydroxypropylcellulose varies from 1,000,000 to about 1,500,000 Daltons. The hydroxypropylcellulose present in the modified release formulations of the present disclosure has a viscosity of at least 300 mPa·s in a 1 weight aqueous solution at 25°C. In one non-limiting embodiment of the present disclosure, the viscosity of hydroxypropylcellulose varies from about 1000 mPa·s to about 3000 mPa·s in a 1 weight aqueous solution at 25°C.

In one non-limiting embodiment of the present disclosure, the amount of hydroxypropylcellulose in the modified release formulation is from about 5% to about 99%, or from about 10% to about 90% by weight of the total formulation. %, or varies from about 15% to about 75% by weight.

Additionally, the modified release formulations of the present disclosure also include a pharmaceutically effective amount of at least one drug that has a water solubility of greater than 1 mg/L at 25°C. In one non-limiting embodiment of the present disclosure, the water solubility of the drug is greater than 20 mg/L, or greater than 700 mg/L.

In one non-limiting embodiment of the present disclosure, the drug is antipyretic, analgesic and anti-inflammatory, anthelmintic, cardiovascular, anti-bacterial, bronchodilator, anti-asthmatic, gastrointestinal, anti-diabetic selected from the group consisting of drugs, antiprotozoal agents, antiviral agents, antiepileptic agents, diuretics, or pharmaceutically acceptable salts and esters thereof.

In another non-limiting embodiment of the disclosure, the drug is etodolac, 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.

In another non-limiting embodiment, the modified release formulations of the present disclosure comprise at least one pharmaceutical agent selected from the group consisting of fillers, binders, surfactants, disintegrants, lubricants, and flow aids. further include excipients acceptable for In one non-limiting embodiment of the 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 the disclosure, the filler is cellulose, lactose, sucrose, sugar, starch, modified starch, mannitol, sorbitol, xylitol, lactitol, silicic acid, calcium sulfate, aluminum silicate and magnesium complexes. and oxides, calcium diphosphate dihydrate and hydrogen sulfate.

In another non-limiting embodiment of the present disclosure, the pharmaceutically acceptable excipients are talc, calcium stearate, magnesium stearate, polyethylene glycol, stearic acid, colloidal silicon dioxide, calcium silicate, mineral oil, A lubricant selected from the group consisting of waxes, hydrogenated vegetable oils, glyceryl behenate, sodium benzoate, sodium acetate, sodium stearyl fumarate and combinations thereof.

In another non-limiting embodiment of the present disclosure, the pharmaceutically acceptable excipients are polyvinylpyrrolidone, sucrose, lactose, starch, modified starch, sugar, gum arabic, gum tragacanth, guar gum, pectin, wax-based Binder, a binder selected from the group consisting of microcrystalline cellulose (MCC), methylcellulose, carboxymethylcellulose, copovidone, gelatin, sodium alginate, hydroxypropylmethylcellulose, hydroxyethylcellulose and combinations thereof.

In one non-limiting embodiment of the present disclosure, pharmaceutically acceptable excipients are 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 the present disclosure, the modified release formulation is a tablet, capsule, powder, granule, sachet (sachet/sachet/sachet), or lozenge (lozenge/lozenge/sweetened tablet). is in the form of

Objects, features and advantages of the present invention will become apparent from the following description read in conjunction with the drawings/drawings.

FIG. 1 shows the NMR spectrum of a representative hydroxypropylcellulose sample. FIG. 2 shows the hydrochlorothiazide (HCTZ) drug present in the modified release formulation of Example 6 (total released over 24 hours) prepared by using 30% by weight of hydroxypropylcellulose (HPC) of Example 1. % of drug) and the dissolution profile of the HCTZ drug present in the comparative modified release formulation of Example 6A prepared by using 30 wt% HPC of Comparative Example 5. indicates Figure 3 depicts the hydrochlorothiazide (HCTZ) drug present in the modified release formulation of Example 7 prepared by using 60 wt% of the HPC of Example 1 (as % of total drug released over 24 hours). and the dissolution profile of the HCTZ drug present in the comparative modified release formulation of Example 7A prepared by using 30% by weight of HPC of Comparative Example 5. Figure 4 shows the dissolution profile of the ibuprofen drug (as % of total drug released over 24 hours) present in the modified release formulation of Example 8 prepared using 20 wt% HPC of Example 2, and a comparison. 8 shows a comparison with the dissolution profile of ibuprofen drug present in the comparative modified release formulation of Example 8A prepared using 20 wt % HPC of Example 5. FIG. Figure 5 is the dissolution profile of the ibuprofen drug (as % of total drug released over 24 hours) present in the modified release formulation of Example 9 prepared using 10 wt% HPC of Example 2; 9A shows a comparison of dissolution profiles of the ibuprofen drug present in the comparative modified release formulation of Example 9A prepared using 10 wt % HPC of Comparative Example 5 and Comparative Example 5. FIG. FIG. 6 shows the dissolution profile of the ibuprofen drug (as % of total drug released over 24 hours) present in the modified release formulation of Example 10 prepared using 25 wt % of the HPC of Example 2, and 10A shows a comparison of the dissolution profile of the ibuprofen drug present in the comparative modified release formulation of Example 10A prepared using 25% by weight of the HPC of Comparative Example 5. FIG. Figure 7 shows the hydrochlorothiazide (HCTZ) drug present in the modified release formulation of Example 11 prepared by using 15 wt% HPC of Example 3 (as % of total drug released over 24 hours). and the dissolution profile of the comparative modified release formulation of Example 11A prepared by using 15 wt% HPC of Comparative Example 5. Figure 8 depicts the hydrochlorothiazide (HCTZ) drug present in the modified release formulation of Example 12 prepared by using 15 wt% HPC of Example 4 (as % of total drug released over 24 hours). and a comparison with the dissolution profile of the comparative modified release formulation of Example 11A.

Before describing in detail at least one embodiment of the inventive concept by means of illustrative figures, experiments, results and experimental procedures, the inventive concept in its application is described in the following description. , or to the details of construction and arrangement of components shown in the drawings, experiments and/or results. The inventive concept is capable of other embodiments or of being practiced or carried out in various ways. As such, the language used herein is intended to be given the broadest possible scope and meaning, and the embodiments are illustrative and not exhaustive. . Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, the nomenclature used in the chemical associations and techniques described herein are those known and commonly used in the art. Reactions and purification techniques are performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The nomenclature used in connection with analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry laboratory procedures and techniques described herein are those known and commonly used in the art. is. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparations, formulation, delivery, and treatment of patients.

All patents, published patent applications and non-patent publications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All patents, published patent applications, and non-U.S. patent publications referenced in any part of this application, unless specifically and individually indicated that the individual patent or publication is incorporated by reference. To the same extent, it is expressly incorporated herein by reference in its entirety.

All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. Although the compositions and methods of the present invention have been described with reference to preferred embodiments, without departing from the concept, spirit and scope of the present invention, compositions and/or methods described herein, Also, it will be apparent to those skilled in the art that modifications may be made to the steps or order of steps of the method. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the inventive concept as defined by the appended claims.

As utilized in accordance with this disclosure, unless otherwise indicated, the following terms shall be understood to have the following meanings:

The words "a" or "an" when used in conjunction with the word "comprising" in the claims and/or specification can mean "one", but "one or more , "at least one," and "one or more." The use of the term "or" in a claim to mean "and/or" unless explicitly indicated to refer to alternatives only or alternatives are mutually exclusive. , this disclosure supports definitions that refer only to alternatives and "and/or." Throughout this application, the term "about" is used to indicate that a value includes inherent variations in error for an instrument, the method used to determine the value, and/or variations that exist between test subjects. used for Use of the term "at least one" includes, but is not limited to, any amount of one or more It will be understood to include one without. The term "at least one" can extend up to 100 or 1000 or more, depending on the term to which it is attached; It can be generated, so it is considered not restrictive. Further, use of the term "at least one of X, Y and Z" will be understood to include X alone, Y alone, and Z alone, and any combination of X, Y and Z.

As used herein and in the claims, the terms "comprising" (and any form such as "comorise" and "comprises"), "having" (and "having any form such as "have" and "has"), "including" (and any form such as "includes" and "include"), "contains" The term "containing" (and any form of "contains" and "contains", etc.) is inclusive or open-ended and includes additional, uncited elements or methods. Do not exclude processes.

As used herein, "or combinations thereof" refers to all permutations and combinations of the items listed above for 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, the order being important in the particular context. also includes BA, CA, CB, CBA, CBA, BCA, ACB, BAC, or CAB. Following this example, combinations containing repetitions of one or more of the items or terms are expressly included, such as BB, AAA, MB, BBC, AAABCCC, CBBAAA, CABABB. Those skilled in the art will typically understand that there is no upper limit to the number of items or terms in any combination, unless otherwise apparent from the context.

As used herein, "drug" or "active pharmaceutical ingredient" or "API" means a substance or substance intended to be used in the manufacture of a drug (pharmaceutical product). A mixture that, when used in the manufacture of a drug product, becomes the active ingredient of the drug product. Such substances provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or affect the structure or function of the human or other animal body. is intended. Furthermore, the terms "drug" or "active pharmaceutical ingredient" or "API" can be used interchangeably in this disclosure.

As used herein, the term "modified release" in relation to the compositions of the present disclosure is not intended for immediate release, but controlled release, sustained release, extended release, timed release, retarded release. ) means compositions that include release, extended release and delayed release.

As used herein, the term "modified release pharmaceutical formulation" or "modified release dosage form" means that the drug release profile over time and/or location is such as a solution or immediate release dosage form. It can be described as a dosage form selected to achieve a therapeutic or convenience objective not provided by conventional dosage forms. Modified-release solid oral dosage forms include both extended-release and delayed-release formulations (according to USFDA guidelines for "SUPAC-MR: Modified-Release Solid Oral Dosage Form").

As used herein, the term "pharmaceutically effective amount" can describe a non-toxic and sufficient amount of a drug that may be required for the treatment or prevention of disease, type of disease, disease. severity, type and content of active ingredients or other ingredients contained in the formulation, dosage form, patient age, body weight, health condition, sex and eating behavior, drug administration time, etc. can be adjusted according to the factors of An appropriate effective amount in any individual case can be determined by one of ordinary skill in the art using only routine experimentation.

One aspect of the present disclosure is a molar degree of substitution per mole of anhydroglucose (MS) that varies from about 3.0 to about 3.9 and a weight average molecular weight of from about 700,000 to about 2,000,000 Daltons. A hydroxypropyl cellulose (HPC) having In one non-limiting embodiment of the present disclosure, the molar degree of substitution of hydroxypropylcellulose can vary from about 3.2 to about 3.8. In another non-limiting embodiment of the present disclosure, the molar degree of substitution of hydroxypropylcellulose can vary from about 3.4 to about 3.7.

In one non-limiting embodiment of the present disclosure, the weight average molecular weight of the hydroxypropylcellulose is from about 750,000 to about 2,000,000 Daltons or from about 800,000 to about 2,000,000 Daltons or about 800 ,000 to about 1,700,000 Daltons or from about 1,000,000 to about 1,500,000 Daltons.

Hydroxypropyl cellulose according to the present disclosure can exist in powder form and can have particles with a volume average particle size of less than 100 μm. In one non-limiting embodiment of the present disclosure, the volume average particle size of hydroxypropylcellulose can vary from about 40 μm to about 80 μm or from about 50 μm to about 75 μm. The volume average particle size of the hydroxypropyl cellulose of the present disclosure is the particle size distribution measured using a laser scattering particle size distribution analyzer “Malvern Mastersizer 3000”, and the particle size D50 at the time when the cumulative volume reaches 50%. say.

Hydroxypropyl cellulose (HPC) according to the present disclosure can be prepared by methods known in the relevant art for preparing hydroxyalkyl cellulose. In one non-limiting embodiment of the present disclosure, hydroxypropyl cellulose (HPC) is prepared by (i) reacting a raw cellulose material with an aqueous alkali solution to obtain alkali cellulose, (ii) further reacting the alkali cellulose with propylene oxide. reacting 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 final purified hydroxypropyl cellulose It can be obtained by obtaining the product. The purified hydroxypropylcellulose product can be further ground to obtain hydroxypropylcellulose in powder form, and a 1% by weight aqueous solution of hydroxypropylcellulose obtained according to the present disclosure has a viscosity of at least 300 mPa·s at 25°C. can have a viscosity of In one non-limiting embodiment of the present disclosure, the viscosity of the hydroxypropylcellulose is from about 300 to about 10,000 mPa·s, or from about 500 to about 8000 mPa·s, or from about 1000 to about 5000 mPa·s, or from about 1500 to about It can be changed in the range of 3000 mPa·s.

Another aspect of the present disclosure is the molar degree of substitution per mole of anhydroglucose (MS) varying from about 3.0 to about 3.9 and a weight average of from about 700,000 to about 2,000,000 Daltons. A modified release formulation or dosage form is provided comprising hydroxypropyl cellulose (HPC) having a molecular weight. In one non-limiting embodiment of the present disclosure, the molar degree of substitution of hydroxypropylcellulose can vary from about 3.2 to about 3.8. In another non-limiting embodiment of the present disclosure, the molar degree of substitution of hydroxypropylcellulose can vary from about 3.4 to about 3.7.

In one non-limiting embodiment of the present disclosure, the weight average molecular weight of hydroxypropylcellulose (HPC) can vary from about 750,000 to about 2,000,000 Daltons. In another non-limiting embodiment of the present disclosure, the weight average molecular weight of the hydroxypropylcellulose is from about 800,000 to about 2,000,000 Daltons or from about 800,000 to about 1,700,000 Daltons or about 1 ,000,000 to about 1,500,000 Daltons.

In one non-limiting embodiment of the present disclosure, hydroxypropyl cellulose (HPC) can be present in powder form and can have particles having a volume average particle size of less than 100 μm. In one non-limiting embodiment of the present disclosure, the HPC volume average particle size can vary from about 40 to about 80 μm or from about 50 to 75 μm. The volume average particle size of the hydroxypropyl cellulose of the present disclosure is the particle size distribution obtained by measuring using a laser scattering particle size distribution analyzer “Malvern Mastersizer 3000”, at the time when the cumulative volume reaches 50%. Refers to the median particle size (D50).

Additionally, hydroxypropyl cellulose (HPC) according to the present disclosure can be used in amounts sufficient to modify the release of at least one active pharmaceutical ingredient (API) present in the modified release formulations of the present disclosure. In one non-limiting embodiment of the present disclosure, the amount of hydroxypropylcellulose is from about 5% to about 99%, or from about 10% to about 90%, or about 15% by weight of the total modified release formulation. % to about 75% by weight, or from about 30% to about 60% by weight.

The modified release formulations of the present disclosure can further comprise at least one active pharmaceutical ingredient (API). In one non-limiting embodiment of the present disclosure, the active pharmaceutical ingredient can be a drug. Alternatively, an active pharmaceutical ingredient (API) can be a biofunctional ingredient. Examples of biofunctional ingredients useful for the purposes of this disclosure include vitamins such as vitamin C, vitamins B1, B2, B3, B6, and B12; minerals such as zinc, magnesium, iron, and melatonin; herbs Dietary supplements such as curcumin, ashwagandha, and fenugreek extracts; amino acids such as isoleucine, glycine, L-tryptophan, glucosamine, chondroitin, and the like. Any drug with a wide range of water solubility can be suitably used in the modified release formulations of the present disclosure. In one non-limiting embodiment of the disclosure, the drug is greater than 1 mg/L, or greater than 16 mg/L, or greater than 20 mg/L, or greater than 700 mg/L, or 18,000 mg at 25°C /L or from a group of drugs that have a water solubility greater than 300,000 mg/L. Additionally, suitable drugs for use in the modified release formulations of the present disclosure include antipyretics, analgesics and anti-inflammatory agents, antiparasitic agents, cardiovascular agents, antibacterial agents, bronchodilators, antiasthmatic agents, gastrointestinal agents. , antidiabetics, antiprotozoals, antivirals, antiepileptics, antidiuretics, or pharmaceutically acceptable salts and esters thereof, belonging to different therapeutic classes.

Examples of antipyretic, analgesic and anti-inflammatory agents include, but are not limited to etodolac, ibuprofen, diclofenac and tofacitinib. Examples of anthelmintics include, but are not limited to, albendazole. Examples of cardiovascular agents include, but are not limited to, carvedilol, metoprolol, sacubitril and valsartan. Examples of antimicrobial agents include, but are not limited to, erythromycin, ciprofloxacin or any pharmaceutically acceptable salt or ester. Examples of bronchodilators include, but are not limited to salbutamol. Examples of anti-asthma agents include, but are not limited to, doxophylline and theophylline. Examples of gastrointestinal agents include, but are not limited to, cimetidine, and omeprazole. Examples of antidiabetic agents include, but are not limited to, metformin hydrochloride and sitagliptin. Examples of antiprotozoal agents include, but are not limited to, tinidazole. Examples of antiviral agents include, but are not limited to, acyclovir. Examples of antiepileptic drugs include, but are not limited to, carbamazepine. Examples of antidiuretics include, but are not limited to, chlorothiazide and hydrochlorothiazide.

Additionally, the active pharmaceutical ingredient can be present in a pharmaceutically effective amount in the modified release formulations of the disclosure. As noted above, the modified release formulations of the present disclosure may be suitable for any drug with a wide range of water solubility. Therefore, the drug or amount of drug present in the modified release formulations of the present disclosure depends on the type of drug or drug used, the nature and severity of the disease to be treated/cured, the active ingredients or other It can be changed according to various factors including, but not limited to, the type and content of ingredients, dosage form, patient's age, weight, health condition, sex and eating behavior, drug administration time, and the like.

Modified release formulations of the present disclosure can further comprise at least one pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients commonly used in pharmaceutical compositions, e.g., Handbook of Pharmaceutical Excipients, Rows et al., Eds., ^4th Edition, Pharmaceutical Press (2003) or Remington: The Science and Practice of Pharmacy, (formerly Remington's Pharmaceutical Sciences), Alfonso R. Gennaro, ed., Lippincott Williams &Wilkins; 20th edition (Dec. 15, 2000). Also suitable for use in Examples of such excipients include, but are not limited to, fillers, pigments, binders, lubricants, flow aids, flavors, sweeteners, preservatives, stabilizers, antioxidants, and the like. Not limited.

Pharmaceutically acceptable excipients can be present in amounts that do not affect the therapeutic properties of the modified release formulations of the invention. Pharmaceutically acceptable excipients can comprise from about 1% to about 85% by weight of the total modified release formulation. In one non-limiting embodiment of the present disclosure, the pharmaceutically acceptable excipient is from about 5% to about 75% by weight of the total modified release formulation, or from about 5% to about 5% by weight of the total modified release formulation. It can constitute about 60% by weight.

Specific examples of fillers that may be present in the modified release formulations of the disclosure are cellulose; oligosaccharides such as lactose and sucrose; sugars; starch; can include, but are not limited to, inorganic acid salts; calcium sulfate; and aluminum and magnesium silicate complexes and oxides. Specific examples of inorganic acid salt excipients can include, but are not limited to, phosphate salts such as calcium diphosphate dihydrate and hydrogen sulfate. Additionally, fillers can be present in an amount from about 5.0% to about 15% by weight of the total modified release formulation.

Examples of binders that can be present in the modified release formulations of the present disclosure include polyvinylpyrrolidone (PVP), sucrose, lactose, starch, modified starch, sugar, gum arabic, gum tragacanth, guar gum, pectin, wax-based binders. , microcrystalline cellulose (MCC), methylcellulose, carboxymethylcellulose, copovidone, gelatin and sodium alginate. Binders can be present in an amount from about 1% to about 80% by weight of the total modified release formulation.

Similarly, suitable lubricants that can be present in the modified release formulations of the disclosure include magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycol, stearyl fumarate. and sucrose fatty acid esters of acids such as, but not limited to, stearic acid, palmitic acid, myristic acid, oleic acid, lauric acid, behenic acid, erucic acid, and the like. Additionally, a lubricant can be present in an amount from about 0.1% to about 20% by weight of the total modified release formulation.

The modified release formulations of the present disclosure can further comprise at least one additional modified release agent. Examples of such release modifiers include sodium alginate, carboxyvinyl polymers, acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS (Eudragit RS, manufactured by Rohm Pharma GmbH) and ethyl acrylate-methyl methacrylate copolymer suspensions. (Eudragit NE, manufactured by Rohm Pharma GmbH), but are not limited to these. Additional modified release agents can be present in an amount from about 5% to about 50% by weight of the total modified release formulation.

Examples of suitable pH modifiers for use in the modified release formulations of the present disclosure include 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 salts thereof; or any combination thereof.

Other pharmaceutically acceptable excipients can also be present in the modified release formulations of the present disclosure. For example, food yellow (food yellow) No. 5, Hood Red No. 2 and food blue no. 2. Colorants or food dyes such as food lake (pigment) dyes, or iron sesquioxide; pH buffers such as amine-based buffers or carbonate-based buffers; sodium lauryl sulfate, polysorbate 80, hydrogenated oils or surfactants such as polyoxyethylene (160) polyoxypropylene (30) glycol; stabilizers such as tocopherol, tetrasodium edetate, nicotinamide or cyclodextrin; and citric, tartaric, malic acid. Or an acidifying agent such as ascorbic acid.

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

Additionally, tablet forms of the modified release formulations of the present disclosure can be coated with substrates for the purposes of olfactory or taste masking, stabilizing, maintaining efficacy, and the like. The coating can contain sugars or film-forming polymers.

In one non-limiting embodiment of the present disclosure, the tablets are sugar-coated, film-coated, enteric-coated, or release-coated to further modulate the release of the drug/active pharmaceutical ingredient from the formulation. It may be coated with a thin layer or film of modifier.

In one non-limiting embodiment of the present disclosure, tablets may be sugar coated. A sugar coating on a tablet is basically a thick, hard coating of sugar that surrounds the surface of the tablet, which is desirable to mask the taste of certain unpleasant flavoring drugs or any other active pharmaceutical ingredients, and , it is also desirable to provide stability against tablet breakage under the influence of light and moisture. Sugar-coating of tablets according to the present disclosure can be performed using sugar-based materials (substrates). Examples of sugar-based materials useful for the purposes of this disclosure include, but are not limited to, white soft sugar. Additional pharmaceutically acceptable excipients can also be added to the sugar-based material to improve the properties of the sugar-based coating, such as improving binding capacity and mechanical strength, and anti-adhesive properties. Examples of such additional excipients include, but are not limited to, gelatin, gum arabic, polyvinylpyrrolidone, pullulan, talc, precipitated calcium carbonate, calcium phosphate, calcium, and the like. In addition, sugar-based coatings may also contain flavorants or colorants/pigments as additional pharmaceutical excipients.

In another non-limiting embodiment of the present disclosure, tablets can be film coated. Film coating of tablets generally involves wrapping a tablet core with a thin film of protective polymer. Accordingly, the tablets of the present disclosure can include a thin film of polymer, particularly a water-soluble film-based polymer as a coating layer. Both synthetic and natural polymers can be used in tablet film coatings. Examples of synthetic polymers can include polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymers, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymers, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymers, polyvinylpyrrolidone and macrogol. but not limited to these. Examples of natural polymers can include, but are not limited to, polysaccharides such as pullulan.

In another non-limiting embodiment of the present disclosure, tablets may be enteric film coated. An enteric film coating on the tablet is desirable to protect the stomach from the tablet formulation, protect the drug from stomach acid, and release the active pharmaceutical ingredient at a specific location, usually the stomach or lower region of the small intestine. Enteric film coating of the tablets can be performed using an enteric film coating base material. Examples of such substances are not particularly limited, but examples include acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S, and natural substances such as shellac. can.

Additionally, the tablet form of the modified release formulation of the present disclosure can be coated with a thin layer or film of a modified release agent to further enhance or improve the modified release efficiency of the modified release formulation. To this end, the tablets of the present disclosure can be coated with a thin layer or film of the modified release formulation, or a thin layer or film of an additional modified release agent, or a combination of both.

In one non-limiting embodiment, tablets can be coated with a thin layer or film of the modified release formulation of the present disclosure. Modified release formulations used for coating purposes further include at least one of the coating materials used for sugar coating, film coating, and enteric coating, as described hereinabove in this disclosure. can contain.

In another non-limiting embodiment of the present disclosure, tablets can be coated with an additional thin layer or film of a release modifier. Examples of such additional release modifiers can include, but are not limited to, hypromellose, polyethylene oxide, hydroxyethylcellulose, ethylcellulose, methacrylic acid copolymers, guar, guar gum, alginates, starch derivatives, waxes and fats. .

The coating material used for the purposes of this disclosure contains at least one of the pharmaceutically acceptable excipients described above in this disclosure, such as binders, lubricants, plasticizers, stabilizers, colorants, and the like. can further include

There is no limitation with respect to the methods used to prepare the modified release formulations of the present disclosure, particularly modified release formulations in solid oral dosage forms such as tablets. Any tableting method known to those skilled in the pharmaceutical arts can be suitably used for the purposes of the present disclosure, such as wet granulation tableting, dry granulation tableting, or dry direct tableting. In one non-limiting embodiment, the modified release formulation in tablet form can be prepared by a wet granulation method, which comprises (i) active pharmaceutical ingredients such as hydroxypropylcellulose, drug(s), and other necessary pharmaceutically acceptable excipients to form a uniform homogenous blend, (ii) adding a wetting agent to obtain a kneaded blend, followed by granulating it. obtaining the obtained granules, (iii) drying and sizing the obtained granules to an optimal size suitable for compression, (iv) treating the sized granules obtained from the processing step (iii) with magnesium stearate and (v) compressing the mixed granules obtained from processing step (iv) into tablets.

In another non-limiting embodiment, the modified release formulation of the disclosure comprises: (i) various components of the modified release formulation of the disclosure, such as hydroxypropylcellulose, active pharmaceutical ingredients and pharmaceutically acceptable excipients; (ii) compressing the uniform powder blend by either slugging or roller compaction to obtain large flat tablets or pellets. and (iii) crushing and sieving flat large tablets or pellets to obtain uniform granules, and (iv) subjecting the granules to tablet compression. be able to. Lubricants such as magnesium stearate, and other excipients such as disintegrants, glidants, etc., can also be added into the uniform granules prior to tablet compression.

In another non-limiting embodiment, a modified release formulation of the disclosure can be prepared by a dry direct tablet method or a direct compressible method, which comprises (i) a release agent of the disclosure, such as hydroxypropylcellulose. pre-milling or sieving the various components of the modified formulation, active pharmaceutical ingredients such as drugs, and pharmaceutically acceptable excipients including lubricants to obtain a powder component, (ii) uniformly blending the powder component; or mixing to obtain a homogeneous blend; and (iii) subjecting the homogeneous blend to tablet compression to obtain tablets.

In one non-limiting embodiment of the present disclosure, the hydroxypropylcellulose present in the modified release formulation can (i) provide low dose dumping of the active pharmaceutical ingredient and (ii) reduce the active pharmaceutical ingredient to It can provide uniform release over a period of time, (iii) can provide effective tablet compression properties, and (iv) can provide controlled release of the active pharmaceutical ingredient at lower polymer usage levels.

The following examples illustrate the present disclosure and parts and percentages are by weight, unless otherwise stated. Each example is provided by way of explanation of the disclosure, not limitation of the disclosure. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made in this disclosure without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be used on another embodiment to yield a still further embodiment. Thus, the present disclosure is intended to embrace such modifications and variations as come within the scope of the appended claims and their equivalents.
Example

Examples 1-4 of the present disclosure provide hydroxypropyl cellulose (HPC) of the present disclosure.
Example 1 (Ex1): Preparation of Hydroxypropyl Cellulose (HPC) by HP-MS at 3.72

One part of the cut purified cellulose was immersed in a mixture of 7 parts of heptane, 2 parts of tert-butanol, 0.5 parts of water and 0.2 parts of a 50% aqueous sodium hydroxide solution to obtain a slurry. The slurry was stirred to obtain alkali cellulose. Next, 2.6 parts of propylene oxide (PO) was added to the slurry containing alkali cellulose to obtain a reaction mixture. The resulting reaction mixture was then heated to 105° C. and held there until all the PO had reacted. The reaction mixture containing the crude hydroxypropylcellulose product was then cooled to room temperature and excess sodium hydroxide was neutralized with acetic acid. The solvent was removed by filtration, then the product was washed with hot water and filtered to remove salts and impurities. The refined cake thus obtained was dried at about 130-140° C. until reaching <5% moisture. The dry hydroxypropylcellulose thus obtained was milled until powdery hydroxypropylcellulose with fine particles of D ₅₀ <100 μm was obtained. The hydroxypropyl molar substitution was analyzed as 3.7. Mw was 1,510,000 daltons and the aqueous solution viscosity was 1800 mPa·s at 1 wt % in water. The volume average particle size (D50) was 52 μm.
Example 2 (Ex2): Preparation of HPC using HP-MS3.72

The HPC of this example was made in the same manner as in Example 1, except that 2.8 parts of propylene oxide were used.
Example 3 (Ex3): Preparation of HPC by HP-MS3.56

The HPC of this example was prepared using the procedure described in Example 1, except that 2.0 parts of propylene oxide were used.
Example 4 (Ex4): Preparation of HPC by HP-MS3.56

The HPC of this example was made in the same manner as in Example 1, except that 2.1 parts of propylene oxide were used.
Comparative Example 5 (Comp.Ex.5):

A commercial HPC, Klucel HXF, sold by Ashland Specialty Ingredient G.P. was used as a comparative example to illustrate the HPC benefits of Examples 1-4 of the present disclosure.

The hydroxypropyl cellulose of Examples 1 to 4 and Comparative Example 5 were measured for hydroxypropyl molar substitution (HP-MS), molecular weight (MW) distribution, viscosity, and volume average particle size according to the following test methods. Table 1 shows the measured values.

Test method:
1. Hydroxypropyl molar substitution measurement:
The HP-MS values of the HPCs of Examples 1-4 and Comparative Example 5 were determined by NMR as follows:

Sample hydrolysis: A 25 mg sample was first swelled in 1.00 g _D2O for 30 minutes. To the swollen samples was added 0.5 gm of 35% DCl. The solution vial was kept at 70° C. in a heat block for 1 hour. Sample solutions were cooled for approximately 30 minutes and transferred to 5 mm NMR tubes for analysis.
NMR measurement: quantitative

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

Spectra were baseline and basal corrected using standard practice. The center of the most up-field signal (hydroxypropyl-substituted methyl) was set at 1.05 ppm. The spectrum was integrated as follows:
Area A (IA) = 1.90-0.15 ppm (the integrated area was calibrated to a value of 300 and the other integrated areas were relative to this integrated value).
Region B (IB) = 5.70-2.15 ppm.
NMR spectra of representative HPC samples are shown in FIG.
HP MS and weight percent HP were calculated as follows:
HPMS = (7/(IB-IA))*100
Wt.% HP = ((HP MS * MW OC3H6OH)/(MW AHG + (HP MS*(MW C3H6OH - MW H))))*100
MW OC3H6OH = 75.086
MW C3H6OH = 59.087
MW AHG = 162.141
MWH = 1.008
2. Molecular weight (MW) distribution:

Analysis of the molecular weight (MW) distribution of the hydroxypropylcelluloses of Examples 1-4 and Comparative Example 5 was determined by using size exclusion chromatography. Molecular weight is the sum of the atomic weights of the atoms in the molecule. As used herein with respect to polymers, the terms molecular weight, average molecular weight, average molecular weight, and apparent molecular weight refer to the arithmetic average of the molecular weights of individual macromolecules as determined by size exclusion chromatography (SEC). . Relative molecular weight averages from analytical SEC were calculated relative to poly(ethylene glycol/ethylene oxide) (PEG/PEO) standards with narrow molecular weight distributions. Size exclusion chromatography was performed according to the following method:
(a) Chromatographic setup

All Waters modules included in the setup are manufactured by Waters Corporation, 34 Maple Street, Milford, MA 01757, USA. Setups can be interchanged with similar ones from different manufacturers.
Waters M515 Solvent Delivery System
Waters M717 Autosampler Waters M2414 Differential Refractive Index Detector (DRI) with Relative SEC ^*
Column bank - see details in the Analytical Conditions section below
Waters Empower2 software
* RI range 1.00 to 1.75 RIU
Measuring range 7 x 10-7 RIU
Drift - 2 x 10-7 RIU
(b) SEC analysis conditions Mobile phase: 55% 0.1M lithium acetate/45% ethanol Flow rate: 0.8 ml/min
Columns - TSKgel guard (6mm x 40 mm) + 2 Linear TSK GMPWXL columns, 13 µm; 300 mm x 7.8mm (TOSOH Bioscience LLC, 3604 Horizon Drive, Suite 100, King of Prussia, PA 19406, USA
Column temperature -35°C
DRI (differential refractive index) detector temperature -35°C
Calibration - PEO/PEG standards with narrow molecular weight distribution (PSS-USA, Inc. Amherst Fields Research Park, 160 Old Farm Road, Amherst, MA 01002)
Sample concentration - usually 1 mg/ml (unless otherwise stated)
Injection volume - 200 μl
3. Viscosity measurement:

HPC was slowly added to the stirred ion-exchanged water and stirred for 1 hour. The temperature is equilibrated in a 25° C. temperature bath for 1 hour. Using a Brookfield viscometer, measure viscosity at 30 rpm with LV spindle #4 and read after 3 minutes.
4. Particle size measurement:

The particle sizes of the powder forms of hydroxypropylcellulose of Examples 1-4 and Comparative Example 5 were measured using a Malvern Mastersizer 3000 laser diffraction granulometer. Measurements were made on powder-formed samples using an Aero S dry powder feeder equipped with a universal hopper/sample tray pair and a standard stainless steel venturi tube powder dispenser. Aero S hopper gap was set at 4.0 mm. Powder samples were measured by fully filling a 1/4 teaspoon measuring spoon and loaded into the hopper. The powder feed rate was set at 30% and the air pressure was set at 3.0 bar. Obscuration limits were set at a lower limit of 0.2% and an upper limit of 10% with obscuration filtering turned off. The background measurement time was set to 10 seconds, the sample measurement time to 20 seconds, and the measurement was set to start after a stabilization time of 0.1 seconds once the obscuration was within the set range. The Fraunhofer scattering model, which was converted to particle size using volume distribution, and the "generic" analytical model were used for data analysis.

A commercially available HPC commercially available as Nisso HPC H with a molecular weight of 652,000, a 1 wt% aqueous solution viscosity of 146 mPa s at 25° C., and a particle size D50 of 170 μm was a modified drug inferior to the HPC of the present disclosure. expected to exhibit release performance. The molecular weight, viscosity and particle size of Nisso HPC H were measured according to the test methods described above.
Modified drug release study

The hydroxypropylcellulose of Examples 1-4 is further used in modified release formulations with drugs and other pharmaceutically acceptable excipients. Table 2 is a list of drugs used to manufacture the modified release formulations of the present invention.

実施例６：実施例１の３０重量％のHPCを有する放出調節製剤（Ex．６）

Example 6: Modified release formulation with 30 wt% HPC of Example 1 (Ex. 6)

Hydrochlorothiazide, HPC of Example 1, and spray dried lactose (ingredients 1-3) were weighed in the weight ratios listed in Table 3, screened through USP sieve #20, and blended in a Turbula mixer for 10 minutes. . Sodium stearyl fumarate, colloidal silicon dioxide and magnesium stearate were also separately weighed, screened through USP Sieve #20 and added to the blend of ingredients 1-3. The resulting powder blend thus obtained was blended again in the Turbula mixer for 2 minutes to obtain a homogeneous powder blend. The homogeneous powder blend is then compressed into tablets using a compression simulator STYL'one, operating at a press speed of 67 RPM (64320 tablets/hour) using 11.28 flat face punches and dies with a compaction force of 25 kN. Simulated manestee beta press. Tablets with an individual tablet weight of approximately 500 mg were obtained.

Example 6A: Comparative Modified Release Formulation with 30 wt% HPC of Comparative Example 5 (Ex. 6A)
A comparative modified release formulation (Ex. 6A) using 30.0 wt% HPC of Comparative Example 5 was prepared in the same manner as described above in Example 6 using the ingredients in the amounts listed in Table 3 above. prepared in

Dissolution testing of the tablets of Examples 6 and 6A was performed using USP Apparatus I in 0.05 M phosphate at pH=6.8 with a constant stirring speed of 100 RPM at a dose of 50 mg. Samples were taken at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 22, 24 hours and passed through a 0.45 μm nylon membrane. filtered. Samples were analyzed by in-line UV detection at 272 nm. Figure 2 shows the dissolution profile of hydrochlorothiazide (HCTZ) in both formulations, Ex. 6 and Ex. Shown as % of total drug released over 24 hours for 6A. From Figure 2, it is clear that the drug release from the modified release formulation of Example 6 is slower than the drug release from the comparative modified release formulation of Example 6A.
Example 7: Modified release formulation with 60 wt% HPC of Example 1 (Ex.7)

A modified release formulation (Ex. 7) containing 60% by weight of the HPC of Example 1 was prepared in this example. The modified release formulation of this example was prepared in the same manner as described in Example 6 using the amounts of ingredients listed in Table 4 below.

Example 7A: Comparative Modified Release Formulation with 60 wt% HPC of Comparative Example 5 (Ex.7A)
A controlled release formulation (Ex. 7A) containing 60.0 wt% HPC of Comparative Example 5 was prepared as described above for the modified release formulation of Example 7 using the ingredients in the amounts listed in Table 4 above. Prepared in the same way.

Dissolution testing of the tablets of Examples 7 and 7A was performed using USP Apparatus I in 0.05 M phosphate pH=6.8 at 100 RPM constant stirring as described above in Examples 6 and 6A. A dose of 50 mg was performed at speed. Figure 3 shows the dissolution profile of hydrochlorothiazide (HCTZ) as % of total drug released over 24 hours for both formulations, Ex.7 and Ex.7A. From Figure 3, it is clear that the drug release from the modified release formulation of Example 7 is slow compared to the modified release formulation of Example 7A.
Example 8: Modified release formulation with 20 wt% HPC of Example 2 (Ex.8)

In this example, modified release formulation tablets (Ex. 8) with an individual tablet weight of approximately 860 mg were prepared using 20 wt% HPC of Example 2. The modified release formulation (Ex. 8) of this example was prepared in the same manner as described above in Example 6 using the amounts of ingredients listed in Table 5 below.

Example 8A: Comparative Modified Release Formulation with 20 wt% HPC of Comparative Example 5 (Ex. 8A)
A comparative modified release formulation (Ex. 8A) containing 20.0% by weight of the HPC of Comparative Example 5 was prepared as described above for the modified release formulation of Example 8 using the ingredients in the amounts listed in Table 5 above. Prepared in the same way.

Dissolution testing of the tablets of Examples 8 and 8A was performed using USP Apparatus I in 0.05 M phosphate at pH=7.2 and a constant stirring speed of 100 RPM at a dose of 60 mg of Examples 6 and 6A. was performed in the same manner as above. Samples were analyzed by in-line UV detection at 221 nm. Figure 4 shows the dissolution profile of ibuprofen as % of total drug released over 24 hours for both formulations, Ex. 8 and Ex.8A. The drug release from the modified release formulation of Example 8 was slower than the drug release from the modified release formulation of Example 8A.
Example 9: Modified Release Formulation with 10 wt% HPC of Example 2 (Ex.9)

Similar to the formulation of Example 8, this example used the same ingredients and procedure as described in Example 8, except that 10 wt% HPC of Example 2 was used, and approximately 860 mg of The preparation of modified release formulations with individual tablet weights is described. Accordingly, the weight percentages of the other ingredients were adjusted and listed in Table 6 below.

Example 9A: Comparative Modified Release Formulation with 10 wt% HPC of Comparative Example 5 (Ex. 9A)
A comparative modified release formulation (Ex. 9A) containing 10.0% by weight of the HPC of Comparative Example 5 was prepared as described above for the modified release formulation of Example 9 using the ingredients in the amounts listed in Table 6 above. Prepared in the same way.

Dissolution testing of the tablets of Examples 9 and 9A was performed using USP Apparatus I in 0.05 M phosphate at pH = 7.2 using the same procedure as described above for Examples 6 and 6A. Dose was performed. Samples were analyzed by in-line UV detection at 221 nm. Figure 5 shows the dissolution profile of ibuprofen as % of total drug released over 24 hours for both formulations Ex.9 and Ex.9A. The drug release from the modified release formulation of Example 9 was slower than the drug release from the modified release formulation of Example 9A.
Example 10: Modified release formulation with 25 wt% HPC of Example 2 (Ex.10)

In this example, modified release formulation tablets (Ex. 10) with individual tablet weights of approximately 500 mg were prepared using 25 wt% HPC of Example 2. The modified release formulation (Ex. 10) of this example was prepared in the same manner as described in Example 6 using the ingredients in the amounts listed in Table 7 below.

Example 10A: Comparative Modified Release Formulation with 25 wt% HPC of Comparative Example 5 (Ex. 10A)
A comparative modified release formulation (Ex. 10A) containing 25.0% by weight of the HPC of Comparative Example 5 was also prepared as described above for the modified release formulation of Example 10 using the amounts of ingredients listed in Table 7 above. Prepared in the same way.

Dissolution testing of the tablets of Examples 10 and 10A was performed in 0.05 M phosphate at pH=7.2 and a USP apparatus at a constant stirring speed of 100 RPM in the same manner as described above for Examples 6 and 6A. I was performed at a dose of 600 mg. Samples were analyzed by in-line UV detection at 221 nm. Figure 6 shows the dissolution profile of ibuprofen as % of total drug released over 24 hours for both formulations, Ex.10 and Ex.10A. The drug release from the modified release formulation of Example 10 was slower than the drug release from the comparative modified release formulation of Example 10A.
Example 11: Modified Release Formulation with 15 wt% HPC of Example 3 (Ex.11)

In this example, the 15 wt% HPC of Example 3 was used to prepare tablets of modified release formulation with an individual tablet weight of approximately 500 mg. Tablets were prepared in the same manner as described in Example 6 using the amounts of ingredients listed in Table 8 below.

Example 11A: Comparative Modified Release Formulation with 15 wt% HPC of Comparative Example 5 (Ex. 11A)
Comparative Modified Release Formulation (Ex. 11A) 15.0 wt% HPC of Comparative Example 5 was prepared in the same manner as described above for the modified release formulation of Example 11 using the amounts of ingredients listed in Table 8 above. Created with

Dissolution testing of the tablets of Examples 11 and 11A was performed in the same manner as described in Example 6 in 0.15 M phosphate at pH=6.8 and using USP Apparatus I at a constant stirring speed of 100 RPM. was performed at a dose of 50 mg. The dissolution profile of the modified release formulation of Example 11 (Ex. 11) is shown in Figure 7 and compared to the dissolution profile of the comparative modified release formulation of Example 11A. The drug release from the modified release formulation of Example 11 (Ex.11) was slower than the drug release from the comparative modified release formulation of Example 11A (Ex.11A).
Example 12: Modified release formulation with 15 wt% HPC of Example 4 (Example 12)

In this example, the 15 wt% HPC of Example 4 was used to prepare tablets of modified release formulation with an individual tablet weight of approximately 500 mg. Tablets were prepared in the same manner as described in Example 6 using the amounts of ingredients listed in Table 9 below.

Dissolution testing of the tablets of this example was performed as in Example 6 using USP Apparatus I at a dose of 50 mg in 0.15 M phosphate at pH=6.8 and a constant stirring rate of 100 RPM. . Samples were analyzed by in-line UV detection at 272 nm. The dissolution profile of the modified release formulation of Example 12 (Ex.12) is shown in Figure 8 and compared to the dissolution profile of the control modified release formulation Ex.11A. The drug release from the modified release formulation of Example 12 was slower than the drug release from the comparative modified release formulation of Example 11A.

Claims (26)

Hydroxypropyl cellulose having a molar degree of substitution of from about 3.0 to about 3.9, a weight average molecular weight of from about 700,000 to about 2,000,000 Daltons, and a volume average particle size of less than 100 microns. 2. The hydroxypropyl cellulose of claim 1, wherein said molar degree of substitution is from about 3.2 to about 3.8. 2. The hydroxypropylcellulose of claim 1, wherein said molar degree of substitution is from about 3.4 to about 3.7. The hydroxypropylcellulose of claim 1, wherein said weight average molecular weight varies from 1,000,000 to 1,500,000 Daltons. 2. Hydroxypropyl cellulose according to claim 1, wherein said hydroxypropyl cellulose has a viscosity of at least 300 mPa-s in a 1 wt% aqueous solution at 25[deg.]C. 2. The hydroxypropylcellulose of claim 1, wherein the viscosity varies from about 1000 to about 3000 mPa·s in a 1% aqueous solution at 25°C. A modified release formulation comprising hydroxypropylcellulose 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. 8. The modified release formulation of claim 7, wherein said molar substitution is from about 3.2 to about 3.8. 8. The modified release formulation of claim 7, wherein said molar substitution is from about 3.4 to about 3.7. 8. The modified release formulation of claim 7, wherein said hydroxypropylcellulose is present in the range of about 5% to about 99% by weight of the total formulation. 8. The modified release formulation of claim 7, wherein said hydroxypropylcellulose is present in the range of about 10% to about 90% by weight of the total formulation. 8. The modified release formulation of claim 7, wherein said hydroxypropylcellulose is present in the range of about 15% to about 75% by weight of the total formulation. 8. The modified release formulation of claim 7, wherein the hydroxypropylcellulose has a viscosity of at least 300 mPa-s in a 1 wt% aqueous solution at 25[deg.]C. 8. The modified release formulation according to claim 7, wherein said hydroxypropylcellulose has a viscosity in a 1 wt% aqueous solution at 25°C in the range of about 1000-3000 mPa·s. 8. The modified release formulation of Claim 7, further comprising a pharmaceutically effective amount of at least one drug having a water solubility of greater than 1 mg/L at 25[deg.]C. 16. The modified release formulation of claim 15, wherein the drug has a water solubility greater than 20 mg/L. 16. The modified release formulation of claim 15, wherein the drug has a water solubility greater than 700 mg/L. The drug is an antipyretic, an analgesic, an anti-inflammatory drug, an anthelmintic, a cardiovascular drug, an antibacterial drug, a bronchodilator, an antiasthmatic drug, a gastrointestinal drug, an antidiabetic drug, an antiprotozoal drug, an antiviral drug, an antiepileptic drug. 16. The modified release formulation of claim 15 selected from the group consisting of: , antidiuretics, and pharmaceutically acceptable salts and esters thereof. The drug is etodolac, 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. 8. The release of claim 7, further comprising at least one pharmaceutically acceptable excipient selected from the group consisting of fillers, binders, surfactants, disintegrants, lubricants, and flow aids. Modulating formulation. 21. The modified release formulation of Claim 20, wherein the filler is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, inorganic acid salts, and combinations thereof. The filler is cellulose, lactose, sucrose, sugar, starch, modified starch, mannitol, sorbitol, xylitol, lactitol, silicic acid, calcium sulfate, aluminum silicate and magnesium silicate complexes and oxides, calcium diphosphate dihydrate and bisulfate salts. The lubricant is talc, calcium stearate, magnesium stearate, polyethylene glycol, stearic acid, palmitic acid, colloidal silicon dioxide, calcium silicate, mineral oil, wax, carnauba wax hydrogenated vegetable oil, glyceryl behenate, sodium benzoate, selected from the group consisting of sodium acetate and sodium stearyl fumarate, sucrose fatty acid esters of stearic acid, palmitic acid, myristic acid, oleic acid, lauric acid, behenic acid, erucic acid, and any combination thereof; 21. The modified release formulation of claim 20. The binder may be polyvinylpyrrolidone, sucrose, lactose, starch, modified starch, sugar, gum arabic, gum tragacanth, guar gum, pectin, wax-based binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, copovidone, gelatin, sodium hydroxy alginate. 21. The modified release formulation of Claim 20 selected from the group consisting of propylmethylcellulose, hydroxyethylcellulose, and any combination thereof. 21. The modified release formulation of claim 20, wherein said pharmaceutically acceptable excipient is present in an amount of about 1% to about 85% by weight of the total formulation. 8. The modified release formulation of claim 7 in the form of tablets, capsules, powders, granules, sachets, or lozenges.

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