Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-07-20
2003-09-30
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S489000, C424S466000, C424S451000, C424S452000, C424S441000, C514S108000
Reexamination Certificate
active
06627221
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a solid pharmaceutical form of administration containing a diphosphonic acid, a physiologically compatible salt or hydrate thereof as the active substance and stearic acid as lubricant in the outer phase. The invention also relates to a process for preparing the form of administration.
Pharmaceutical forms of administration of diphosphonic acids are known for treatment of calcium metabolism diseases. Drugs containing these active substances are used for treating hypercalcaemia and also for treating tumour osteolysis resulting from bone metastases. They can also be successfully used for treatment of osteoporosis and resulting pain.
Since the active substances for treating diseases of this kind frequently have to be administered over a long period, oral application is very advantageous since it is usually more acceptable to the patient.
Oral forms of administration are known in the case of some diphosphonic acids and salts thereof. For example EP-B 0 275 468, EP-B 0 625 355 (both Boehringer Mannheim) and WO 93/21907 (Leiras Oy) disclose pharmaceutical preparations containing clodronic acid (dichloromethylene diphosphonic acid) or salts thereof. WO 93/09785 (Procter & Gamble Pharmaceuticals) discloses oral forms of administration of risedronate (the salt of 3-pyridyl-1-hydroxyethylidene-1,1-diphosphonic acid). WO 93/21907 and WO 93/09785 describe oral forms of administration provided with a coating which dissolves only at pH above 5 or 5.5. The aim is to ensure that the forms of administration travel through the stomach and the active principle is released only in the intestinal tract.
The solid forms of administration of diphosphonic acids or salts thereof described in the prior art contain the active substance and selected pharmaceutical adjuvants, with which the active principle must be compatible, in the inner phase and selected pharmaceutical adjuvants in the outer phase, more particularly for ensuring that the preparation can be easily processed in a capsule-filling machine or tablet press. For example EP-B 0 275 468 describes clodronate-containing drugs with a high proportion of 80-95% active substance, a filler content of 2-10% and a lubricant content of 0-5% in the granulate, to which is added an outer phase in the form of a lubricant, preferably magnesium stearate and talcum, in a proportion of 1-5%.
During the development of a capsule or tablet or other solid form of administration, special attention is usually paid to the adjuvants in the outer phase.
The selection and proportion of a suitable lubricant in the outer phase is particularly important, since it has great influence on the physical properties of the forms of administration under development. The choice and proportion determine whether the substance filling the capsule or tablet can be processed without difficulty on a suitable machine over a prolonged period or whether the tablets stick to the compression moulding dies in the machine. Sufficient lubricant must therefore be added to the outer phase. If however the proportion of lubricant is too high, there may be other adverse effects. For example the granulate may become so water-repellent that the resulting drug disintegrates only slowly and the desired dissolution rate (practically complete release of the active substance after 30 minutes) is not reached.
The following known lubricants can be used in the outer phase: magnesium stearate, calcium stearate, talcum, sodium stearyl fumarate, macrogol or hydrogenated esters of fatty acids with glycerine and stearic acid.
For example in EP-B 0 275 468, which describes oral forms of administration for clodronate, magnesium stearate and talcum are together used as a lubricant in the outer phase. EP-B 0 625 355 (Boehringer Mannheim GmbH) discloses magnesium stearate as the only lubricant in the outer phase of clodronate forms of administration. WO 93/21907 (Leiras Oy, clodronate) Example 1, describes the use of talcum and magnesium stearate as a lubricant in the outer phase and stearic acid as a lubricant in the inner phase. WO 93/09785 (Procter & Gamble, risedronate) Example 3, discloses stearic acid lubricant in a proportion of 5.8% by weight relative to the tablet core.
It has been found, however, that particularly when the proportions of active substance are low, the lubricant or the concentrations thereof are not optimum, since dissolution rates of 85% after 30 minutes, indicating uniform and almost complete release of the active substance, are not obtained or else the dissolution rates fall rapidly after stress through heating above room temperature.
SUMMARY OF THE INVENTION
The object of the invention therefore is to develop a pharmaceutical form for administration as a unit dose, i.e., a pharmaceutical form of administration in which the active substances are diphosphonic acids or physiologically compatible salts thereof and which is stable enough for the active substance to be released uniformly and almost completely within 30 minutes and for no reduction in the rate of dissolution to occur even after temperature stress. This should apply both to high and low contents of active substance in the form of administration.
Surprisingly it has been found that solid forms of administration containing less than 5% by weight of stearic acid lubricant in the outer phase, relative to the total weight of the form of administration, e.g. 0.1 to 4.9% by weight, have dissolution rates of at least 85% after 30 minutes, and the rates do not change even after weeks of exposure to temperatures of 40-50° C. This applies both to low and to high contents of active substance in the form of administration.
Less than 5% by weight stearic acid in the outer phase, relative to the total weight of the form of administration, results on the one hand in a sufficient lubricant effect, so that the tablet or capsule filler does not stick to the processing machines, and on the other hand the granulated active substance does not become water-repellent.
This aspect of the invention therefore relates to solid pharmaceutical dosage forms in which the active substance is a diphosphonic acid or a physiologically compatible salt thereof, wherein the active substance in granulate form, optionally together with pharmaceutical adjuvants, is present in the inner phase and the outer phase contains a lubricant in the form of stearic acid in proportions of less than 5% by weight relative to the total weight of the form of administration.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, the outer phase of the pharmaceutical form of administration contains a lubricant in the form of stearic acid in proportions of less than 5% by weight relative to the total weight of the form of administration. Preferably, the form of administration contains stearic acid in a proportion of 0.1 to 3%, particularly 0.9 to 3% by weight, relative to the total weight of the form of administration. Particularly, preferably stearic acid is added in a proportion of 1.5 to 2.7% by weight relative to the total weight of the form of administration, in which case the rate of release will be at least 90% (determined by the Paddle method after the USP).
The granulated active substance can contain pharmaceutically acceptable adjuvants and/or additives such as lactose, starch, glucose, mannitol, microcrystalline cellulose, hydroxypropyl methyl cellulose or other substances known for this purpose in the art.
The form of administration according to the invention can also contain other pharmaceutical adjuvants in the outer phase, more particularly a disintegrating agent, all known disintegrating agents being usable. More particularly cross-linked polyvinyl pyrrolidone (Crospovidone USPNF) is a preferred disintegrating agent for the purposes of the invention.
The following bisphosphonates are active substances which can be used according to the invention in the form of free acids or pharmaceutically compatible salts or hydrates, particularly sodium salts:
(4-amino-1-hydroxybutylidene)bis-phosphonate (alendron
Gabel Rolf-Dieter
Preis Walter
Woog Heinrich
Hoffmann-La Roche Inc.
Johnston George W.
Lau Bernard
Page Thurman K.
Pulliam Amy E
LandOfFree
Pharmaceutical composition containing diphosphonic acid or... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical composition containing diphosphonic acid or..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical composition containing diphosphonic acid or... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3038693