Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1998-01-20
2001-02-06
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S470000, C424S473000, C424S474000, C424S479000, C514S777000
Reexamination Certificate
active
06183778
ABSTRACT:
PRIOR ART
The development of innovative pharmaceutical forms for drugs administration to humans and animals has lately been a source for considerable research effort in pharmaceutical technology. One of the major innovations in this sector is the targeting of drugs release to a specific site of treatment and/or the release of said drug at a programmed rate. The applications thereof are of consequence not only to human and animal health but also to agriculture. Very many are the pharmaceutical forms already developed and disclosed in patents, which are capable of releasing the drug at zero-order kinetics.
As well known to those skilled in the pharmaceutical art, this means that the pharmaceutical form liberates the drug at a constant rate and over a scheduled period of time. In particular, drug release may occur according to the following empirical relation
Mt/M
∞
=Kt
n
where Mt/M
∞
is the fraction of released substance, K is a constant depending on the diffusion coefficient in the matrix and n is a constant depending on polymeric chains swelling and relaxation rate in swelling front.
Examples of said pharmaceutical forms are amply documented, e.g. in “Novel drug delivery and its therapeutical application” by L. F. Prescott and W. S. Nimmo, J. Wiley, New York, 1989. Examples refer to pharmaceutical forms that may be administered by different routes, i.e. oral, transdermic, vaginal, and ocular. Obviously, due to the great importance and wide utilization of oral drug administration, many and diverse embodiments are for gastroenteric administration. Among the widely known and used embodiments the OROS system, disclosed in U.S. Pat. No. 4,160,020 (1979), should be cited.
A further achievement in the area is the pharmaceutical form disclosed in U.S. Pat. No. 4,839,177 (1989) and in the subsequent U.S. patent application Ser. No. 07/620,577 dated Dec. 3, 1990. Said patents claim the preparation of pharmaceutical forms for oral administration capable of liberating a drug at a constant release rate, i.e. according to zero-order kinetics. In particular, the aforesaid patents disclose and claim the preparation of a tablet which, in its simplest form, consists of a hydrophilic matrix containing a drug and suitable excipients allowing the sustained release of the drug. The drug sustained release is brought about by gelable hydrophilic polymers, which swell by contact with water and/or aqueous fluids, giving a gelled layer wherefrom the drug is liberated according to Fick's type kinetics. The pharmaceutical form claimed in the aforementioned patents is characterized by the matrix being partly coated with a drug-impermeable barrier consisting of a polymeric film insoluble in water or in an aqueous medium, Alternatively, said barrier consists of polymeric mixtures or granular masses with technological adjuvants, applied by compression (Italian patent application No. 22694/89). The barrier obtained is drug-impermeable for at least 4-8 hrs and, therefore, hinders drug dispensing from the coated surface. Therefore, the hydrophilic drug is exclusively released from the free area, generally at a constant rate.
However, the prior art does not envisage the possibility of obtaining products capable of releasing one or more drugs at different rates or else of releasing two different drugs sequentially, i.e. releasing the second drug only after releasing the first drug, both being contained in the same pharmaceutical form. Several treatments require a sequential administration of two drugs and, therefore, involve complex posologic schemes and scrupulous patient's compliance therewith. Obviously, since such compliance is hardly obtainable, the above requirements can often be met only by hospitalized patients, carefully controlled by physicians and paramedical specialists. As well known, complex therapeutic schemes are reluctantly accepted and scarcely followed by cut-patients, the correct compliance with posologic schemes being inversely proportional to the treatment complexity and to the number of daily administrations.
In particular very many are the conditions to be treated with sequentially acting drugs. For example, rheumatic night pain is to be treated with two drug doses, one on pain onset and the other at a later time, or with a pharmaceutical form slowly releasing the second dose so that a sufficiently high plasmatic level be maintained. In these cases, the pharmaceutical form should be capable of releasing the drug at the same rate as drug elimination.
As known, steroid and non-steroid anti-inflammatory agents can induce pyrosis and/or gastric mucosa irritation. A prior protection of the gastric mucosa by agents, such as sucralphate, aluminium glycinate, activated attapulgite or hydrotalcite, followed by the administration of the potentially gastrolesive drug, can increase the patients' tolerance for said drug. Identical remarks can be made about the antibiotic posology, which usually are to be administered at sequential daily doses. The same problems are also co be faced with drugs whose active ingredient is a metabolite thereof, the metabolism occurring at different rates in the various organs.
A typical example is L-dopa used in treating Parkinson's disease. In the organism, L-dopa is metabolized to dopamine, which is the drug active ingredient. However, only the unmodified form, i.e. L-dopa, is capable of crossing the blood-brain barrier. L-dopa is rapidly absorbed into the gastroenteric tract and spreads out in the various organs and tissues, including the CNS. L-dopa has plasmatic half-life of approx. 1 hr and is converted into dopamine mainly by decarboxylation. L-dopa is rapidly decarboxylated to dopamine also in the gastroenteric tract: hence, the quantity of L-dopa reaching the CNS is extremely low. Furthermore, the presence of excess dopamine deriving from peripheral decarboxylation in organs external to the CNS may produce massive side effects. Should drugs inhibiting peripheral decarboxylation, such as benserazide or carbidopa, be administered with or before L-dopa administration, the peripheral conversion of L-dopa into dopamine would be drastically reduced and higher amounts of L-dopa would reach the systemic circulation and the brain, where conversion into dopamine produces the desired therapeutic effect. Thus, much lower L-dopa doses can have a high therapeutic effect and, at the same time, produce lesser side effects.
In such complex pathological situations, the availability of pharmaceutical compositions capable of liberating different drugs at successive times would solve a therapeutic problem also involving a serious social impact, the treatments being mainly addressed to elderly persons.
SUMMARY
it has been found a new pharmaceutical tablet containing one or more drugs and liberating same at different release rates. This achievement solves the problems encountered so far. Said tablet allows the administration of:
a single drug, a portion thereof being released within a short time and the remaining portion being released over a longer period;
two drugs or drug combinations, which are released at different rates. The tablet as per the present invention consists of three layers, i.e.:
a first layer containing one or more drugs with immediate or controlled release formulation, composed of rapidly swelling and/or soluble and/or erodible polymeric substances by contact with aqueous fluids, and adjuvants;
a second layer containing one or more drugs, either equal to or different from those of the first layer, with slow release formulation, composed of swelling and/or gelable and/or erodible polymeric substances by contact with aqueous fluids, and adjuvants;
a low-permeability barrier-type layer coating said second layer, consisting of polymeric materials, adjuvants, plasticizing agents.
The tablet may be enteric coated.
DETAILED DESCRIPTION OF THE INVENTION
The following detailed description sets forth the characteristics of and advantages offered by the claimed pharmaceutical tablets, which are capable of releasing one or more drugs at di
Conte Ubaldo
LaManna Aldo
Maggi Lauretta
Jagotec AG
Leydig , Voit & Mayer, Ltd.
Spear James M.
LandOfFree
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