Pharmaceutical preparation and process for its manufacture

Details Pharmaceutical preparation and process for its manufacture Pharmaceutical preparation and process for its manufacture

1994-12-12

1996-06-11

Nutter, Nathan M.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

424452, 424457, 424458, 424459, 424461, 424462, 424463, 424464, 424465, 424468, 424469, 424470, 424474, 424475, 424479, 424480, 424482, 424489, 424490, 424493, 424494, 424497, 424499, 424500, 424501, 514553, 514578, 514738, A61K 930, A61K 3166

Patent

active

055253547

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The object of the present invention is a pharmaceutical preparation for oral use, especially a tablet, which as its active ingredient contains a pharmacologically acceptable salt of dichloromethylene bisphoshonic acid, i.e. a clodronate, especially disodium clodronate.
Dichloromethylene bisphosphonic acid, especially in the form of its salt, such as the disodium salt, is a known drug for example for the treatment of diseases relating to the calcium metabolism and to the sceletal system, such as to the metabolism of the bone, for example for osteoporosis.
Clodronate has previously been administered orally in the form of conventional compressed tablets or capsules. Such a tablet or capsule disintegrates in the stomach of the patient releasing the active agent, which in the acidic environment of the stomach is converted to the free acid form. As clodronic acid is poorly absorbed, the bioavailability of the active agent will be low, and consequently the required dosage level has to be increased. This in turn is a disadvantage as a large tablet has to be used, which is inconvenient for the patient and reduces patient compliance. Also a large dose increases the risk for side-effects.


SUMMARY OF THE INVENTION

According to the invention it has now been discovered that it is possible to achieve a substantially improved bioavailability if the active agent is prevented from being transformed into its acid form, that is, if it is allowed to pass the stomach region in unliberated form into the lower digestive tract to be released at a site thereof which is optimal from the point of view of the absorption of the active agent.
According to the invention it has now been discovered that the said objective is reached if the preparation is a drug delivery form which is enteric coated with a film which dissolves at a pH of from 5 to 7.2.
Preferably the film dissolves at a pH of from 5.0 to 6.5.
There is a number of film forming agents suitable for the purpose of the invention. Important from the point of view of the invention is that the agent used dissolves at the pH mentioned, i.e. at pH 5 to 7.2. These agents are known as such and there is a number of commercially available substances. Of such agents may be mentioned i.a. shellac, cellulose acetate phthalate (CAP) (e.g. Aquateric.RTM. by FMC Corporation), hydroxypropyl methylcellulose acetate succinate (HPMCAS, e.g. Aqoat.RTM. by ShinEtsu), hydroxypropyl methylcellulose phthalate (HPMCP, HP 50 and HP 55 by ShinEtsu), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate (CAT, by e.g. Eastman Fine Chemicals), as well as various methacrylic acid derivatives (Eudragits by RohmPharma).
The film forming agents are used dissolved either in suitable organic solvents (e.g. alcohols, chlorinated hydrocarbons, acetone etc), or in water, optionally in mixture with an organic solvent, and optionally using plasticizers, also known in the art, e.g. phthalic esters, citric esters, triacetin.
A preferred film forming agent to be used in the invention is hydroxypropyl methylcellulose phthalate, which is e.g. commercially available in forms that dissolve at pH 5 or alternatively pH 5.5.
The pharmaceutical preparation can be of any shape and form suitable to be provided with an enteric coating, representative examples being a tablet, granule, pellet, capsule or the like.
It has, according to the invention, surprisingly been discovered that the level of absorption of clodronate from a drug delivery form, which is enteric coated with a film forming agent which dissolves at the said pH of 5.0 to 7.2, is more than twice as high as from a corresponding drug delivery form which is uncoated, and even 4 to 5 times better than the absorption from a tablet suspended in water or from a sachet. This is be apparent from the absorption tests and their results presented later.
In the preparation according to the invention clodronate is used preferably as its disodium salt, either as the anhydrate or as a hydrate (tetrahydrate), the latter forming needle-shaped c

REFERENCES:
patent: 4980171 (1990-12-01), Fels et al.

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