Sustained Release Matrix System Using Hydroxyethyl Cellulose and Hydroxypropyl Cellulose Polymer Blends

This invention relates to a matrix-like solid dosage form comprising one or more therapeutic agents, hydroxyethyl cellulose (HEC) and hydroxypropyl cellulose (HPC) and other tablet excipients (binders, diluents and coloring agents). More particularly, this invention relates to a polymer blend of HEC and HPC that will release a therapeutic agent or agents for a prolonged or sustained time.

Sustained or extended release dosage forms which comprise a single active component are well known. A matrix tablet system incorporates active ingredients, lubricants, binders, fillers and other excipients, wherein the binders may be hydrophilic, hydrophobic or water insoluble polymers. See for example U.S. Pat. No. 4,389,393.

The mechanism by which sustained release dosage forms act to dispense the active ingredients over a period of time have been described at length in the literature. See for example Manford Robinson, Chapter 14, "Sustained Action Dosage Forms," The Theory and Practice of Industrial Pharmacy, 2nd, ed., ed. L. Lachman, H. Lieberman and J. Kanig (Philadelphia; Lea & Febiger, 1976).

Sustained release dosage forms which combine two or more actives are not common, because of the difficulties encountered in combining multiple actives, each with different chemical and physical characteristics, different release rates, different half-lives and different dosage sizes. However, three U.S. Patents do exist which are directed to the sustained release of two or more actives.

U.S. Pat. Nos. 4,601,894, 4,657,757 and 4,695,591 describe controlled-release dosage forms which incorporate acetaminophen, pseudoephedrine sulfate and dextrobrompheniramine maleate with a polymeric material. Both U.S. Pat. Nos. 4,601,489 and 4,687,757 describe a controlled release system which contains hydroxypropyl methyl cellulose (HPMC) and a second polymer selected from the group consisting of ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose or other cellulose ethers. U.S. Pat. No. 4,695,591 describes a one component controlled release system containing only HPMC U.S.P. 2910.

However, none of these patents recognize that a superior controlled release dosage form can be obtained by incorporating one or more pharmaceutical actives in a polymeric matrix of hydroxypropyl cellulose (HPC) and hydroxyethyl cellulose (HEC).

We have discovered a novel sustained release oral dosage form comprising a homogeneous matrix formed from a wet granulation containing an effective amount of a medicament and a polymer blend of hydroxypropyl cellulose and hydroxyethyl cellulose.

In another embodiment of the present invention, we have discovered a novel process for making a sustained release oral dosage form comprising wet granulating a medicament with a polymer blend of hydroxypropyl cellulose and hydroxyethyl cellulose, wherein the polymer blend is provided in an amount effective to control the release of said medicament to form a homogeneous matrix, then forming the homogenous matrix into a solid oral dosage form.

These and other objects and advantages of the invention will be apparent from the specification examples and claims hereinafter.

The sustained or extended release dosage form which is the subject of this invention represents an advancement of the art since it combines two polymer ingredients, one or more drugs and other tablet excipients, in a single long acting tablet. While antihistamines and decongestants have been combined in sustained release tablets, and antihistamines, decongestants and analgesics have been combined in 2-layer tablets or have been separately microencapsulated and combined in continuous action capsules, the present invention relates to a surprisingly simple combination of one or more actives in a single homogenous matrix, from which matrix each active component is released at an appropriate rate to provide the desired activity over a period of 2 to 24, preferably 8 to 12 hours.

The components of the matrix are preferably chosen so that a dosage form of the present invention releases the actives over precise periods of time.

The compounds of the matrix are preferably chosen so that each active component is released from the matrix at its desired rate despite the differences in solubilities among the actives in gastric, intestinal or aqueous media, indicating that different mechanisms of drug release, i.e. diffusion through, and erosion of the hydrated layer, are occurring simultaneously. The differences in dosage size will not affect the appropriate release of each of the actives. That is, the actives may take up the majority of the total uncoated tablet weight and deliver the desired sustained release rates for the active. It has also been demonstrated that one or more actives with significantly different biological half-lives each demonstrates its own efficacious pharmacological profile when combined in a single sustained release dosage form.

One or more medicaments may be combined in a single dosage form, depending on the chemical compatibility of the combined active ingredients and the ability to obtain the desired release rate from the dosage form for each active ingredient. The determination of the effective amount of the medicament per dosage unit is easily determined by skilled clinicians.

Representative types of active medicaments include antacids, anti-inflammatory substances, (including but not limited to non-steroidal anti-inflammatory drugs, NSAIDs, vasodilators, coronary vasodilators, cerebral vasodilators, and peripheral vasodilators), anti-infectives, psychotropics, antimanics, stimulants, antihistamines, laxatives, decongestants, vitamins, gastrointestinal sedatives, antidiarrheal preparations, antianginal drugs, antiarrhythmics, antihypertensive drugs, vasoconstrictors and migraine treatments, anticoagulants and anti-thrombotic drugs, analgesics, anti-pyretics, hypnotics, sedatives, antiemetics, anti-nauseants, anticonvulsants, neuromuscular drugs, hyper- and hypoglycemic agents, thyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, antiasthmatics, expectorants, cough suppressants, mucolytics, antiuricemic drugs, and other drugs or substances acting locally in the mouth, such as topical analgesics, local anesthetics, etc. Preferably the active medicament will be at least very slightly soluble in water and more preferably slightly soluble in water (as defined in Remington's Pharmaceutical Sciences, 18th edition, Chapter 16, page 208).

Examples of specific active medicaments include aluminum hydroxide, prednisolone, dexamethasone, aspirin, acetaminophen, ibuprofen, isosorbide dinitrate, nicotinic acid, tetracycline, ampicillin, dexbrompheniramine, chlorpheniramine, albuterol, pseudoephedrine, loratadine theophylline, ascorbic acid, tocopherol, pyridoxine, metoclopramide, magnesium hydroxide, verapamil, procainamide hydrochloride, propranolol, captopril, ergotamine, flurazepam, diazepam, lithium carbonate, insulin, furosemide, hydrochlorothiazide, guaiphenesin, dextromethorphan and benzocaine, although any active medicament which is physically and chemically compatible with the hydroxypropyl cellulose and hydroxyethyl cellulose polymer blend and other tablet ingredients and which demonstrates the desired controlled release characteristics may be used in the present invention.

Formulations containing NSAIDs (including for the purposes of this application acetaminophen) may also contain therapeutic amounts of other pharmaceutical actives conventionally employed with NSAID including but not limited to decongestants or bronchodilators (such as pseudoephedrine, phenylpropanolamine, phenylephrine and pharmaceutically acceptable salts thereof), antitussives (such as caraminophen, dextromethorphan and pharmaceutically acceptable salts thereof), antihistamines (such as chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbrompheniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, pyrilamine, hydroxyzine, promethazine, azatadine and pharmaceutically acceptable salts thereof), non-sedating antihistamines (such as acrivastine, astemizole, cetirizine, ketotifen, loratidine, temelastine, terfenadine (including the metabolites disclosed in U.S. Pat. Nos. 4,254,129 and 4,285,957 hereby incorporated by reference and pharmaceutically acceptable salts thereof), muscle relaxants (such as glycerylmonether SMRS, methocarbamol, mephenesin, mephenesin carbamate, cyclobenzaprine, chlorzoxazone, mephenesin acid succinate, chlorphenesin carbamate, or pharmaceutically acceptable salts thereof) and suspected adjuvants (such as diphenhydramine, caffeine, xanthine derivatives (including those disclosed in U.S. Pat. No. 4,558,051, hereby incorporated by reference) and pharmaceutically acceptable salts thereof) and combinations of any of the aforesaid pharmaceutical. The aforesaid pharmaceutical may be combined with acetaminophen for the treatment of allergies, cough, colds, cold-like and/or flu symptoms in mammals including humans. However, these pharmaceutical maybe combined with acetaminophen as sleep aids (such as diphenhydramine), or for other known purposes.

The specific preferred combination of HPC and HEC of the invention with two or more actives provides a single sustained release medicament which provides the pharmacologic properties of each active. Thus, repeated administration of several single component dosage forms throughout the day may be avoided. Moreover, it is apparent that in addition to the well known pharmacological advantages of a controlled release formulation in general (e.g. more constant blood levels of the drugs), the dosage form of the present invention is easier and more economical to manufacture than microencapsulated or multi-layered dosage forms.

While a number of polymers might be used as a binder for the matrix, this invention particularly contemplates the use of combinations of hydroxypropyl cellulose (HPC) and hydroxyethyl cellulose (HEC). A single HPC ether may be used, or a mixture of HPC ethers of difference molecular weight and structure may be used. A single HEC ether may be used, or a mixture of HEC ethers of difference molecular weight and structure may be used. Suitable grades of HPC and HEC for pharmaceutical purposes are well known and full described in the pharmaceutical literature. Suitable commercially available brands of HPC include but are not limited Klucel.TM. hydroxypropyl cellulose (produced by Aqualon). Suitable commercially available brands of HEC include but are not limited to Natrosol.TM. hydroxyethyl cellulose (produced by Aqualon).

Generally the amount HPC and HEC and ratio of HPC to HEC used in a particular dosage formulation will vary based on the active medicament and the sustained release profile desired. However, the appropriate amount and ratios of HPC and HEC can readily be determined by systematically testing the dissolution profiles of the active medicament using accepted dissolution test such as those set forth in the U.S. Pharmacopeia XXII (hereby incorporated by reference).

As a general rule the weight range of HPC (or a mixture of HPC ethers) to HEC (or a mixture of HEC ethers) in a solid uncoated dosage form should be in the range of from about 10:90 to about 90:10 (wherein the total of HPC and HEC is 100 weight percent). A preferred combination of HEC and HPC for 8 hour sustained release contains from in the range of from 20 to 37.5 weight percent HEC and from in the range of from 80 to 62.5 weight percent HPC. A preferred combination of HEC and HPC for 12 hour SR tablets contains from in the range of from 62.4 to 37.6 weight percent HEC and from in the range of 62.4 to 37.6 weight percent HPC. A preferred combination of HEC and HPC for 24 hour SR tablets contains from in the range of from 62.5 to 75 weight percent HEC and from in the range of 37.5 to 25 weight percent HPC. With this dual system the total amount of HPC and HEC represents in the range of from about 5 to about 35 percent by weight of the total weight of an uncoated dosage form. A preferred range for the total amount of HPC and HEC present for the 8 hour sustained release (SR) tablet is 5 to 10 percent, for the 12 hour SR tablet 10 to 15 percent and for the 24 hour SR tablet is 12 to 18 percent by weight of the uncoated dosage form.

Additionally present with the HPC, HEC and active medicament may be one or more fillers or bulking agents such as dibasic calcium phosphate dihydrate, lactose or starch, with lactose being the preferred filler. The filler may be present in an amount in the range of from about 0 to about 94 percent of the total weight of the uncoated dosage from, with in the range of from about 1 to about 5 weight percent being preferred for very high dose actives and in the range of from about 80 to 85 weight percent with very low dose actives.

The uncoated dosage form may also contains one or more lubricating agents, e.g., stearic acid, colloidal silicon dioxide, magnesium stearate, calcium stearate, waxes, polyethylene glycol, or magnesium lauryl sulfate, present in an amount of in the range of from about 0.25 to about 3 weight percent of the total weight of the uncoated dosage form.

Other excipients, such as disintegrating agents, coloring agents and flavorings may be added at the discretion of those skilled in the art.

One example of a suitable 12 hour controlled release formulation for a cold or allergy tablet would contain:

Another suitable 12 hour controlled release allergy formulation would contain:

One suitable 8 hour controlled release allergy formulation would contain:

The above components are combined to form the matrix and formed into tablets by conventional means. The tablets may be used as is, but are preferably coated by techniques well known in the art. The sustained-release solid dosage form can be made by direct compression or through conventional wet granulation methods. Although differences in the dissolution profile may be observed by employing wet granulation rather than direct compression. Lower polymer concentrations may be used in the tablet when wet granulation processing. Because high-viscosity polymers are often preferred for sustained release, the normal wet granulation method of first dissolving the polymer may not be possible. However, if one of the two polymers is low viscosity, adding the lower viscosity polymer in solution is often advantageous for better tablet binding. Very acceptable granulations can be made in conventional equipment by dry-blending all the ingredients and adding water or organic solvents as the granulating fluid in conventional equipment. It has also been shown that fluid bed granulation will work. One of the polymers in solution or an additional polymeric binder solution may be necessary to make good, non-friable granules. These granulation processes can be successfully used to improve flow of the powders and increase tablet hardness.

The invention will now be described in greater detail by reference to the following non-limiting examples.

This example describes nine different formulations of a solid oral dosage form containing several active medicaments and a variety of HPC, HEC and HPC/HEC polymer concentrations.

Nine formulations (A-I) containing pseudoephedrine sulfate, chlorpheniramine maleate, magnesium stearate and optionally acetaminophen and dicalcium phosphate were prepared. Various amount of HEC (Natrosol HH) and/or HPC (Klucel HF) were added to the formulations as described below in Tables 4 and 5.

The formulations A-F in Table 4 were direct compression granulations. The formulations in Table 5 were wet granulated and oven dried (to approximately 1.25% L.O.D.). All the granulations were compressed into tablets with a main compression force of 4,000 pounds. The tablets were then tested to determine their dissolution profiles. The dissolution tests were conducted in distilled water at 37.degree. C. with a 50 rpm stirring rate using USP Dissolution Method II with paddles.

Table 6 provides a comparison of the effects of the various combinations of HPC and HEC on the dissolution profiles of pseudoephedrine sulfate.

As can be seen from Table 6 the wet granulation of 2.5 weight percent HEC and 5 weight percent HPC provided a significantly prolonged release profile for pseudoephedrine as compared to tablets containing HPC only at 10%, 15% and 25%. Approximately five times the amount of HEC (Natrosol 250 HH) was necessary to provide the same release profile as the combination of 2.5 weight percent HEC and 5 weight percent HPC. It appears from the data that wet granulations of HPC and HEC at 2.5 to 5.0 weight percent provide prolonged sustained release profile for pharmaceutical actives which was not previously recognized in the art.

This example describes three different formulations of a solid oral dosage form containing three active medicaments and a variety of HPC, HEC and HPC/HEC polymer concentrations.

Three formulations (J, K and L) containing 650 mg acetaminophen, 4 mg chlorpheniramine maleate and 60 mg pseudoephedrine sulfate and were lubricated with 0.5% stearic acid and 0.25% Cab-o-sil were prepared. Various amount of HEC (Natrosol HH) and/or HPC (Klucel HF) were added to the formulations as described below in Table 7.

HPC (Klucel HF) and HEC (Natrosol 250 HH) Combination or Alone, in Tablets containing Acetaminophen, Chlorpheniramine Maleate and Pseudoephedrine Sulfate.

The formulations were wet granulated (with water) using high shear equipment and oven dried (to approximately 1.25% L.O.D.). The dried granulations were milled and lubricated. The granulations were then compressed into equal strength tablets. Formulas J and L granulations were compressed with a main compression force of 20 kN into tablets. Formula K required precompression (2.5 kN) and main compression (28 kN) for adequate tablet hardness. The tablets were then tested to determine their dissolution profiles. The dissolution tests were conducted in distilled water at 37.degree. C. with a 50 rpm stirring rate using USP Dissolution Apparatus 2 or Hanson Dissolution Apparatus with paddles.

Table 8 provides a comparison of the dissolution profiles of acetaminophen, pseudoephedrine sulfate and chlorpheniramine maleate.

The data presented in Table 8 demonstrates that the combination of HPC and HEC provide a sustain release profile to various active medicaments.

This example demonstrates the effect of using high and low viscosity HEC in controlled release formulation which contain HPC and a therapeutic medicament

Two formulation (M and N) were prepared containing the ingredients listed in Table 9.

The ingredients were wet granulated and compressed with a main compression force of 20 kN into tablets which would deliver 650 mg of APAP and 60 mg of PE. The dissolution of the tablets were then tested using USP Dissolution Apparatus 2 with paddles containing distilled water maintained at 37.degree. C. with a 50 rpm stirring rate. The results of these tests are reported in Table 10.

The results reported in Table 10 demonstrate that both high and low viscosity HEC maybe used in the practice of the present invention. It is apparent from the data, however, that the high viscosity HEC has a greater sustained release affect as compared to low viscosity HEC. Those skilled in the art will readily appreciate that the HEC viscosity can be varied for particular medicaments to provide the desired release profile.

This example demonstrates the effect of increasing the polymers content of HEC/HPC on the dissolution profile of acetaminophen.

Three formulations (O, P and Q) containing 650 mg acetaminophen, 4 mg chlorpheniramine maleate and 60 mg pseudoephedrine sulfate, 0.5% stearic acid, 0.25% Cab-o-sil and varying amounts of HPC (Klucel) and HEC (Natrosol HH) were prepared. The amount of HEC (Natrosol HH) and/or HPC (Klucel HF) added to the formulations is described below in Table 11.

The ingredients were wet granulated and compressed with a main compression force of 20 kN into tablets. The dissolution of the tablets were then tested using a USP Dissolution Apparatus 2 containing simulated intestinal fluid without pancreatic enzymes maintained at 37.degree. C. The dissolution test was conducted with a stirring rate of 50 rpm. The results of these tests are reported in Table 12.

The data in Table 12 demonstrates that by increasing the amount of HEC and HPC used in the tablet formulations, the duration of the sustained release effect may be lengthened.

This example provides a preferred formulation for a 12 hour cold/allergy caplet. This caplet is preferably made using a high shear granulation process.

This example provides a preferred formulation for a 8 hour sinus caplet containing acetaminophen and pseudoephedrine. This caplet is preferably made using a high shear granulation process.

This example provides a preferred formulation for a 12 hour sinus caplet containing terfenadine and acetaminophen. This caplet is preferably made using a high shear granulation process.