Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-05-07
2001-09-25
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S489000, C514S223500, C514S223200, C514S222800
Reexamination Certificate
active
06294197
ABSTRACT:
The invention relates to solid oral dosage forms containing valsartan, in particular solid oral dosage forms containing valsartan and hydrochlorothiazide (HCTZ) and a process of forming the same.
The angiotensin II receptor antagonist—Valsartan—is known to be effective in the treatment of congestive heart failure and reducing blood pressure irrespective of age, sex or race and is also well tolerated. Its combination with HCTZ is also known for the treatment of hypertension.
The oral administration of such pharmaceutical agents as tablets or capsules has certain advantages over parenteral administration such as i.v. or i.m.: Diseases requiring treatment with painful injectable formulations are considered to be more serious than those conditions which can be treated with oral dosage forms. However, the major advantage with oral formulations is held to be their suitability for self administration whereas parenteral formulations have to be administered in most cases by a physician or paramedical personnel.
However, valsartan is difficult to formulate and heretofore it has not been possible to make oral formulations in the form of tablets in a reliable and robust way.
Capsules are undesirable since large capsules must be used to accommodate effective amounts of active agent, which in the case of valsartan, is of low density and is therefore rather bulky.
We have now found a solid oral dosage form containing valsartan or a pharmaceutically acceptable salt thereof optionally in combination with HCTZ which can be produced according to a reliable and robust process, which solid oral dosage form is small relative to the amount of active agent used. Said solid oral dosage forms are smaller, for a given amount of active agent, than any known formulations of this active substance.
According to the invention there is provided a solid oral dosage form comprising
a) an active agent containing an effective amount of valsartan or a pharmaceutically acceptable salt thereof and
b) pharmaceutically acceptable additives suitable for the preparation of solid oral dosage forms by compression methods
preferably wherein the active agent is present in an amount of more than 35% by weight, preferably more than 50% by weight based on the total weight of the solid oral dosage form. In particular, the amount of active agent may be present in an amount of from 45 to 65% by weight, e.g. 57 to 62% by weight.
Solid oral dosage forms according to the invention provide for the administration of the active substance in a smaller oral form than was heretofore possible for a given unit dose of active agent. Furthermore, the oral dosage forms obtained are stable both to the production process and during storage, e.g. for 2 years in conventional packaging, e.g. sealed aluminium blister packs.
By “effective amount” is meant the amount of active agent which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition. Such an amount can be easily determined by a person skilled in the art by routine experimentation and with no undue burden.
In a solid oral dosage form according to the invention wherein the active agent consists entirely of valsartan or a pharmaceutically acceptable salt thereof, it is preferred if the active agent is present in an amount of from 10 to 250 mg, more preferable 40 to 160 mg, most preferably 40 to 80 mg, e.g. 40, 80 or 160 mg.
The active agent valsartan is particularly suitable for combination with other active agents, e.g. HCTZ.
Accordingly, in an further embodiment of the invention there is provided a solid oral dosage form as hereinabove described additionally containing HCTZ as a component of the active agent.
It has been found that valsartan, or a pharmaceutically acceptable salt thereof, combined in a dose range from about 10 to 250 mg with hydrochlorothiazide in a dose range from about 6 to 60 mg, is suitable for more efficient treatment of hypertension. With these dose ranges of the combined active agents, valsartan is found to have a greater efficacy in reducing elevated blood pressure to normal levels than it would have if used at the same dose range in monotherapy. Moreover, when hydrochlorothiazide is being administered in combination with valsartan, the diuretic agent is more effective as compared to monotherapy at the dose range indicated. Particularly suitable is a dose range from about 50 and 100 mg valsartan or a pharmaceutically acceptable salt thereof and from about 10 to 30 mg hydrochlorothiazide. More preferred is a unit dose of about 80 mg valsartan and 12.5 mg or 25 mg of hydrochlorothiazide and 160 mg valsartan and 12.5 mg or 25 mg of hydrochlorothiazide. The weight ratio of valsartan or a pharmaceutically acceptable salt thereof to hydrochlorothiazide is from about 1:6 to about 42: 1, more preferably 2:1 to 13:1, most preferably 2:1 to 10:1.
The present invention particularly relates to a solid oral dosage form, which contain as the active agent a) a unit dose between about 10 and 250 mg, especially between about 50 and 100 mg, of valsartan or a pharmaceutically acceptable salt thereof; and a unit dose between about 6 and 60 mg, especially between about 10 and 30 mg, of hydrochlorothiazide.
An especially preferred embodiment of the invention is a solid oral dosage form, which contain as the active agent a) a unit dose of about 80 mg or 160 mg of valsartan or a pharmaceutically acceptable salt thereof; and a unit dose of about 12.5 mg hydrochlorothiazide.
The preparation of valsartan is described in the U.S. patent specification No. 5,399,578 which is incorporated herein by reference. A pharmaceutically acceptable salt of valsartan can be prepared in a manner known per se. Thus for example, acid addition salts are obtained by treatment with an acid or a suitable ion exchange agent. Such salts can be converted to free acid in a conventional manner by treatment with a suitable basic agent.
Valsartan is preferably in its free form, that is, not in one of its salt forms.
Hydrochlorothiazide is a known therapeutic agent which is useful in the treatment of hypertension.
A solid oral dosage form according to the invention comprises additives conventional in the dosage form in question. Tabletting aids, commonly used in tablet formulation can be used and reference is made to the extensive literature on the subject, see in particular Fiedler's “Lexicon der Hilfstoffe”, 4th Edition, ECV Aulendorf 1996 which is incorporated herein by reference. These include but are not limited to disintegrants, binders, lubricants, glidants, stabilising agents, fillers or diluents, surfactants and the like.
As disintegrants one can particularly mention CMC-Ca, CMC-Na, crosslinked PVP (Crospovidone, Polyplasdone of Kollidon XL), Alginic acid, sodium alginate and guar gum, most preferably crosslinked PVP, Crospovidone, crosslinked CMC and Ac-Di-Sol.
As binders one can particularly mention starches, e.g. potato starch, wheat starch, corn starch, microcrystalline cellulose, e.g. products known under the registered trade marks Avicel, Filtrak, Heweten or Pharmacel, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose, e.g. hydroxypropyl cellulose having a hydroxypropyl content of 5 to 16% by weight and a Mw of from 80000 to 1150000, more particularly 140 000 to 850 000.
As glidants one can mention in particular colloidal silica, e.g. Aerosil, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
As fillers or diluents one can mention confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcellulose, in particular having a density of about 0.45 g/cm
3
, e.g. Avicel, powdered cellulose, sorbitol, sucrose and talc.
As lubricants one can mention in particular Mg, Al or Ca stearate, PEG 4000-8000 and talc.
One or more of these additives can be selected and used by the skilled artisan having regard to the particular desired properties of the solid oral dosage form by routine experimentation and without any undu
Katakuse Yoshimitsu
Kohlmeyer Manfred
Taike Takashi
Wagner Robert Frank
Yamato Fujiki
Di Nola-Baron Liliana
Novartis AG
Page Thurman K.
Tso Diane P.
LandOfFree
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