Instant granules and process for their formulation

Details Instant granules and process for their formulation Instant granules and process for their formulation

2001-06-05

2003-11-11

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S489000, C424S493000, C424S497000, C424S400000

Reexamination Certificate

active

06645529

ABSTRACT:

The invention relates to a pharmaceutical formulation in the form of instant granules according to the precharacterizing clause of claim 1. Such a formulation is described, for example, in EP-B1-232,277. Said publication discusses the fact that, according to the invention, an amino acid (e.g. tryptophane in Example 1) can be processed as an active substance or a plurality of active substances (e.g. vitamins and mineral salts in Example 2, applied to a carrier material comprising acid, which presents a problem for kidney patients) can be processed, it also being stated that a plurality of layers can be applied to the granular carrier material of soluble carbohydrate by means of a binder solution, for anchoring relatively large amounts of active substance.
This last proposal is subject to limits in practice, especially in the case of amino acids, unless special measures are taken. In particular, it has been found that, for amounts of active substance which are greater than the amounts occurring in the examples mentioned in EP-B1-232,277 and for active substances which are very bulky, the active substances on the carbohydrate carriers cannot be sufficiently anchored by the binder layer alone and too much active substance remains free, with the result that neither the desired suspension property nor the flowability of the product can be satisfactorily achieved.
In the case of amounts of active substance of from 60 to 100 parts by weight—based on 100 parts by weight of carrier—undesired agglomerations of the active substance occur when the binder is applied repeatedly, so that, on introduction into water, the desired suspension is no longer achievable and the particles sink to the bottom or remain on the surface of the water.
It is therefore one object of the invention to improve the formulation described in EP-B1-232,277 and its preparation in such a way that instant granules and a process for their preparation are provided, by means of which it is possible easily to accommodate even very large amounts of even different—in particular insoluble or slightly soluble—active substances, in particular a plurality of amino acids, analgesics, antioxidants, such as, for example, paracetamol, beta-carotene, etc, After introduction into water, the pharmaceutical formulation should be suspended within an appropriately short time by stirring, should have a pleasant taste and should furthermore remain in suspension for an appropriately long time.
This requirement is particularly applicable to amino acids because they have to be administered in large amounts per dose, both when used as a food supplement and particularly as a preparation for kidney patients who have to survive on a low protein diet and require a large supply of amino acids. By supplying essential amino acids, the deficit can be satisfactorily compensated, with the result that adverse symptoms can be prevented and the necessity of a dialysis can in certain circumstances be postponed.
There are on the market a number of amino acid-containing products with essential amino acids in tablet or capsule form, but, for example, kidney patients have to take 5 units of these, 3 times a day, which presents considerable problems for the patient or consumer, all the more so since this group of—mostly elderly—patients usually also has to take a number of other medicaments, generally in tablet form. A dosage form which can be administered in liquid form in order to facilitate the intake for the patient was therefore desirable for this amino acid medication.
A further object of the invention was therefore to develop an instant formulation comprising a high dose of active substance and small amounts of excipients, which formulation can be readily suspended in a small amount of water, say from 50 to 100 ml, and is readily accepted by the patient with regard to taste. Consequently, consumption by the patient should be substantially facilitated.
The difficulty of developing such a product which is suspendable in water was associated with the weight ratios and volume ratios of carrier material to active substance. Granulation of the active substances alone did not achieve the object since this resulted, on the one hand, in agglomerates of the active substances which did not disintegrate into their individual particles within the distribution time in water, therefore were insufficiently suspendable and sank to the bottom of the glass, on the other hand the active substance partially did not granulate at all and was therefore floating to the surface and no proper suspension could be achieved (see negative Example 1).
A similar, slightly better, effect occurred when excipients were granulated together with the active substances, since in this case, on the one hand, the addition of solution caused the easily soluble carrier materials to agglomerate and, in another case, the resulting granulation of the particles of active substance was insufficient for achieving a flowable product (see also negative example 2).
The application of a phospholipid (Epikuron®) solution as a surfactant to the granulated active substances well as to excipients granulated together improved the suspension of the active substances, but coarser particles still remained in the suspension and a part of the active compound was still floating to the surface (see negative examples 1a and 2a).
When a corresponding amount of binder was added to the solution, the result was an undesired coarse-particle agglomeration of the active substances and/or of the active substances with the carrier material, which, in spite of milling to the desired particle size, exhibited reduced suspension properties and settled on the bottom when stirred into water.
All these problems have been overcome according to the invention by anchoring only a part of the active substances on a first, preferably compact and/or crystalline, carrier material having a bulk density of between 58 and 100, preferably between 60 and 95 g/100 ml, while the excess of the active substances not anchored to the surface of the first carrier material is granulated by means of the introduction of a second, voluminous, e.g. spray dried, carrier material which is selected from carrier materials having a bulk density of between 30 to 55, preferably between 33 and 50 g/100 ml and thereby are usually more easily and/or quickly soluble than the first carrier material. Preferred carrier materials are listed in Table 1.
The bulk density of conventional products available on the market is not directly depending on the grain size distribution which may widely differ.
Advantageous embodiments, further developments and improvements of the invention are described in the dependent claims.
TABLE 1
grain size distribution of conventional
bulk
products
density
>0.5 mm
0.2-
carrier
(g/
(% by
0.5 mm
<0.2 mm
material
100 ml)
weight)
(% by weight)
(% by weight)
First carrier
materials
sorbitol
58
0
58
42
mannitol
63
0
92
8
lactose
69
0
36
64
saccharose (fine
81
0
71
29
grain)
saccharose
88
28
68
4
(coarse grain)
hydrogenated
90
99
1
0
maltose
trisodiumcitrate.
95
22
70
8
2H
2
O
monocalcium
82
0
8
92
phosphate.H
2
O
second carrier
materials
maltodextrine
33
16
39
45
(spray-dried or-
granulated)
sorbitol (spray
45
19
77
4
dried)
mannitol (spray
45
0
20
80
dried)
glucose syrup
50
0
3
97
(dried)
instant sugar
50
9
36
55
This invention was based on the consideration that, in cases where small amounts of excipients are desired, either on the basis of dietary or medical indication or for economic reasons, it is necessary to find a procedure which makes it possible to combine bulky insoluble or slightly soluble active substances in a weight ratio of from 60 to 100 parts by weight—with 100 parts by weight of the total carrier material.
This is possible by introducing the carriers in two or more stages. In the first step, a part of the total carrier materials—consisting of at least 80, preferably at least 100% by weight of the first carrier material—is initially taken; the surface is then wet by adding water, ethanol, an ethanol/water mixture and/or a binder so

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