Title: Controlled-release, drug-delivery tableted composition including a complex between poly(maleic diacid-alkyl vinyl ether) and polyvinylpyrrolidone
United States Patent: 6,129,931
Inventors: Nerella; Nadhamuni G. (Wayne, NJ); Ulmer; Herbert W. (Hoboken, NJ); Chakrabarti; Sibu (Randolph, NJ); Du Browny; Gregory (Garfield, NJ)Assignee: ISP Investments Inc. (Wilmington, DE)
Appl. No.: 146422Filed: September 3, 1998
A pH-dependent, controlled-release, drug delivery composition is described herein which includes: (a) a complex between poly(maleic diacid-alkyl vinyl ether) and polyvinylpyrrolidone, or their equivalents, and (b) an effective amount of a pharmaceutical medicament.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the invention, pH-sensitive
drug-delivery compositions are provided which are completely or
substantially insoluble in acid solution and only soluble under alkaline
conditions. The inventive component of such compositions is a
hydrogen-bonded complex between for example, the copolymer of maleic acid
(MA) and an alkyl vinyl ether (AVE) and plasdone (polyvinylpyrrolidone (PVP)).
Suitably, the compositions herein are formulated into an oral dosage form,
such as a tablet, by direct compression, high shear or fluid-bed, wet
granulation of its components. The desired complex between MA-MVE and PVP
is formed during granulation or in situ in the water-medium, or during
tablet dissolution.
Since the complex of the invention does not dissociate in aqueous acid
solution, the medicinal composition does not release any substantial
amount of drug into the acid portion of the body (the gastric area), even
at a pH of 1.2. Furthermore, the complex dissociates only slowly under
alkaline conditions, e.g. a pH of 7.4, and, accordingly, the drug is
released only slowly where the body is in an alkaline condition where the
rate of dissociation of the complex is determined by the extent of
hydration of the complex under such alkaline conditions. The rate of
dissolution can be controlled by the ratio of MA/MVE to PVP and the
molecular weight of PVP.
Two modes of controlled-release operation are provided for formulations
containing this hydrogen-bonded complex, namely, (1) a pH-immediate mode,
wherein substantially no drug is released in acid (<20% in 2 hours),
and only immediate release of the drug in alkaline solution (an additional
60% in 2-3 hours or less); and (2) a pH-modified system wherein only a
small amount of drug is released in acid (<20% in 2 hours), followed by
controlled release of the remaining drug in alkaline solution (an
additional 60% in 8 hours or more).
The hydrogen-bonded complex of the invention is formed between (1) two
polymer components, namely, maleic anhydride (MAn), or its equivalent,
such as maleic acid (MA), a maleic anhydride half-ester (MAn-1/2 E); or
their equivalents, and salts thereof; of any desirable molecular weight or
K-value; and as uncrosslinked or crosslinked polymers; and (2) a polymer
of vinylpyrrolidone, or its equivalent, e.g. (polyvinylpyrrolidone (PVP)),
or copolymers of PVP with other comonomers, e.g. vinyl acetate, and the
like; uncrosslinked or crosslinked equivalents. The preferred
hydrogen-bonded complex of the invention is formed in situ in water
between MA and Plasdone K-29/32 (uncrosslinked), at a molar ratio of about
1:1.
The amount of the complex incorporated into the drug formulation may vary
widely; generally about 30-70% by weight, preferably about 50% is used in
such compositions. This amount is dependent on the desired drug release
profile.
To illustrate the invention, a series of controlled-release, drug delivery
studies were carried out using different model drugs in the formulation.
For example, Naproxen sodium was used as the model drug in Study A, and
the compositions in the form of tablets of hardness of 10-12 KP were
prepared by fluid bed granulation of the drug, MA (Gantrez.RTM. S-97 (ISP)
and PVP (Plasdone.RTM. C-15 (ISP), using varying amounts of each in a 1:1
molar ratio. Calcium sulfate was included in the granulation step as an
ionotropic agent to enhance the binding strength of the complex.
These formulations are indicated as Examples 1-8 in Table 1 below, and FIG.
1 shows the extent of drug released from the tablets in acid (0.1 N
HCl, pH 1.2) and in an alkaline medium (phosphate buffer, pH 7.4). Tablet
dissolution studies were conducted in a USP Type I apparatus.
TABLE 1
______________________________________
Naproxen Calcium
Magnesium
Example Sodium Gantrez Plasdone
Sulfate
Stearate
No. (%) S97 (%) C15 (%)
(%) (%)
______________________________________
1 39.8 30.37 19.38 9.95 0.5
2 49.75 30.37 19.38 0 0.5
3 59.7 18.22 11.63 9.95 0.5
4 59.7 24.30 15.50 0 0.5
5 59.7 21.26 13.56 4.975 0.5
6 44.775 30.37 19.38 4.975 0.5
7 54.725 27.34 17.44 0 0.5
8 49.75 24.30 15.50 9.95 0.5
______________________________________
The results in FIG. 1 shows that in the acid medium the test tablets did not dissolve over a period of 2 hours, and that they dissolved at varying rates in alkaline solutions during 12 hours. Example 1, which contained about 50% of the complex, and 9.95% of calcium sulfate dissolved the slowest under alkaline conditions. Example 3, which contained only about 30% of the complex dissolved the fastest in the alkaline medium.
While Examples 3-5 show pH-immediate type drug release, Examples 1, 2, 6-8 exhibit pH-modified type of drug release.
Study B below (Example 9) was formulated with 40% of Gantrez.RTM. MS955 (the disodium salt of MAn-methyl vinyl ether) and Plasdone C-15 and Plasdone K 29/32 (PVP), granulated with 50% of theophylline as the model drug. The composition of the formulation is given in Table 2 below.
TABLE 2
______________________________________
Theophylline 50%
Gantrez MS955 + Plasdone
40%
Calcium Sulfate 9.5%
Magnesium Stearate 0.5%
______________________________________
FIG. 2 shows the cumulative % drug released over 12 hours in acid and alkaline conditions. The results are consistent with a pH-modified release system.
Example C used propranolol HCl as the model drug in a tablet containing 40% of the complex formed between Gantrez S-97 and Plasdone. Its composition is shown in Table 3 below.
TABLE 3
______________________________________
Propranolol HCl 50%
Gantrez S-97 + Plasdone 40%
Calcium Sulfate 9.5%
Magnesium Stearate 0.5%
______________________________________
Preparation of a Drug-Containing Composition The Active Ingredient (Drug)
Any of the drugs used to treat the body, both topical and systemic, can be incorporated as the active agent in the polymeric carrier of this invention. "Drug" is used herein in its broadest sense as including any composition of matter that will produce a pharmacological or biological response.
Suitable drugs for use in therapy according to this invention include, without limitations; those listed in U.S. Pat. No. 3,732,865 (columns 10 and 11).
Other drugs having the same or different physiological activity as those recited above can be employed in carriers within the scope of the present invention. Suitable mixtures of drugs can, of course, be dispensed with equal facility as with single component systems.
Drugs can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, e.g. the hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartarate, salicylate, etc. For acidic drugs, salts of metals, amines, or organic cations (e.g. quaternary ammonium) can be employed. Furthermore, simple derivatives of the drugs (such as ethers, esters, amides, etc.) which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, etc., can be employed.
The amount of drug incorporated in the carrier varies widely depending on the particular drug. The desired therapeutic effect, and the time span for which it takes the drug to be released. Since a variety of carriers in a variety of sizes and shapes are intended to provide complete dosage regimen for therapy for a variety of maladies, there is no critical upper limit on the amount of drug incorporated in the carrier. The lower limit, too, will depend on the activity of the drug and the span of its release from the carrier. Thus, it is not practical to define a range for the therapeutically effective amount of drug to be released by the carrier.
Preferred drugs to be incorporated according to the present invention are those designed for long-term treatment so that multiple daily doses can be avoided. For example, smooth muscle relaxants, e.g. theophylline, anabolics, e.g. methandrostenolone; analgesics, e.g. acetylsalicyclic acid, phenylbutazone or methadone; androgens, e.g. methyltestosterone; antibiotics, e.g. rifampin; antidepressants, e.g. imipramine or maprotiline; antidiabetics, e.g. phenformin; anticonvulsives, e.g. cabamazepine, antihistamines, e.g. tripelennamine; antihypertensives, e.g. hydrolazine; antiinfectives, e.g. trimethoprim; antiparasitics, e.g. nifurimox; antiparkinson agents, e.g. levodopa; antiphlogistics, e.g. naproxen; antitussives, e.g. benzostate; appetite depressants, e.g. mazndol; bronchodilators, e.g. fenoterol; coronary dilators, e.g. fenalcomine; corticoids, e.g. dexamethasone; cytostatics, e.g. floxuridine; diuretics, e.g. hydrochlorothiazide; hypnotics, e.g. glutethimide; neuroleptics, e.g. reserpine or thioridazine; psychoanaleptics, e.g. methylpenidate; tranquilizers, e.g. diazepam; uricosutics, e.g. sulfinpyrazone; vasodilators, e.g. isoproterenol.
Among the most preferred drugs are naproxen sodium, diclofenac sodium, baclofen, metropolol.HCl, beta blockers, such as oxprenolol and propanolol; calcium channel blockers, such as Nifedipine and Verapamil, and anti-asthmatics, such as theophylline.
Claim 1 of 6 Claims
What is claimed is:
1. A controlled-release, drug delivery tableted composition consisting
essentially of,
(a) a complex formed by hydrogen bonding in water between poly(maleic
diacid-alkyl vinyl ether) and polyvinylpyrrolidone, in about a 1:1 molar
ratio and
(b) an effective amount of a pharmaceutical medicament, which remains
substantially insoluble under aqueous acidic conditions and only slowly
dissolves in aqueous alkaline medium.
____________________________________________
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