Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1999-06-10
2001-09-18
Bawa, Raj (Department: 1619)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C424S043000, C424S489000
Reexamination Certificate
active
06290931
ABSTRACT:
This application is a 371 of PCT/DE97/02915 filed Dec. 15, 1997
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to homogeneous preformulations containing high concentration of steroids, for producing low-dose solid and semi-solid pharmaceutical preparations having a concentration content of 0.001 to 1 weight percent of steroid.
2. Prior Art
The invention also relates to a method for producing the homogeneous preformulations, containing steroids in high concentration, for the claimed low-dose solid and semi-solid pharmaceutical preparation.
It is known that the homogeneous distribution of active ingredients is an essential prerequisite for the reliable effect of a medication.
The problem of homogeneous active ingredient distribution arises especially in single-dose solid and semi-solid forms of preparation in which the active ingredient is not in dissolved form, such as in tablets, lozenges, capsules and suppositories.
The prerequisite for the homogeneous distribution of active ingredients in the single-dose forms of medication is on the one hand a uniform distribution of the active ingredient in the basic mixture or preformulation and on the other the preservation of this distribution during further processing. Nonhomogeneities in the mixture of active ingredients and adjuvants and inaccuracies in further processing are added together and lead to fluctuations in dosage in solid and semi-solid single dose forms of medication.
In high-dose preparations, as a rule no serious mixing nonhomogeneities occur.
In low-dose forms of medication, the primary problem is to furnish a sufficiently homogeneous distribution, which is stable against demixing, of the very low mass of active ingredient in proportion to the mass of the pharmaceutical adjuvants.
From the professional and patent literature, low-dose solid and semi-solid preparations containing steroids are known; the preformulations are produced by means of dry and moist granulation technologies or dry mixing processes.
M. Dittgen, H. Kala et. al., for instance, in “Zur pharmazeutischen Technologie der Granulierung” [On the pharmaceutical technology of granulation], Pharmazie 35, 4, pages 237 to 249, 1980, describe such granulation technologies.
It is problematic by means of the mixing process to achieve good content uniformity while avoiding demixing and sizing effects, for instance from defluidizing and outgassing of fine active ingredient particles from the fluidized bed.
Formulations produced by these technologies have the disadvantages of
the use of micronized active ingredients and the attendant necessity of one additional process step;
derived from this the possibility of recrystallization and clumping by way of the active surfaces of the active ingredient particles and the attendant negative effects on homogeneity and release properties.
In a special form of the fluidized bed-spray granulation process, the use of micronized active ingredients is circumvented by dissolving the active ingredient in an organic solvent at high dilution and spraying it onto a large-particle adjuvant moving in a fluidized bed and granulating it by building on that structure.
The disadvantages of the formulations produced by this method are:
the occurrence of deviations from the desired steroid content by outgassing of fine steroidal abrasion from the fluidized bed;
the fact that because of the long dwell times in the production process, undesired decomposition processes can occur in thermally unstable active ingredients.
One disadvantage of the method that should not be underestimated is that large quantities of solvent are in the final steps of the galenic preparation, which requires major effort and expense for equipment and safety technology (explosion proofing together with rendering nitrogen inert).
In European patent disclosure EP 0 503 521, it is described that a direct-tabletable pharmaceutical preparation is attained by dry mixing of micronized steroids with certain excipients (spray-dried lactose).
This proves to have the following disadvantages:
Only selected excipients have the requisite adsorptive properties;
The loading capacity of the surfaces is only very limited;
once again, micronized active ingredients are used, which have the disadvantage of recrystallization and clumping along the active surfaces of the active ingredient particles and the attendant negative effects on homogeneity and release properties.
M. Dekker, in “The spray drying of pharmaceuticals”, Drug Development and Industrial Pharmacy”, 18 (11 & 12) pages 1169 through 1206, 1992, and
E. Nürnberg, in “Darstellung und Eigenschaften pharmazeutisch relevanter Sprühtrocknungsprodukte” [Characterization and properties of pharmaceutically relevant spray drying products], Acta Pharmazeutica Technologica, 26(1), pages 40 to 67, 1980 describe the use of spray drying technology for the galenic formulation of pharmaceutical active ingredients, including steroids.
With the spray drying, primarily retardant effects or effects that improve solubility and stability are attained by way of active ingredient imbedding or microencapsulations (for instance in polymeric adjuvants) or inclusion complexes (in cyclodextrins).
According to J. Cooper and J. E. Rees, “Tableting research and technology” J. Pharm. Sci. 61 (1972) pages 1551 to 1555, the spray drying can be used
for coating medication particles with protective casings and for modifying the physical properties of the active ingredients and adjuvants, with the goal of making their further processing (such as tablets) easier.
According to H. Kala et.al., “The use of spray drying in pharmacy”, Pharmazie, 34, No. 12 (1979) pages 779 to 784, the use of spray drying for attaining certain properties in active ingredients and adjuvants that go beyond simple drying and simultaneous micronization is fundamentally known.
For example, metastable medication modifications or amorphous active ingredients can be produced in standardized fashion, in order to improve the speed of dissolution or to preclude uncertainty factors dictated by the existence of various crystal modifications.
In this connection, spray imbedding in various adjuvants and spray drying of suspensions of a solution of medication and insoluble adjuvant (celluloses) are mentioned in particular.
H. Kala et.al. also mention that spray products (adjuvants as dry binders, active ingredients, and combinations) in the form of spherical, free-flowing particles have already been used for direct tableting.
M. Dekker, in “The spray drying of pharmaceuticals”, Drug Development and Industrial Pharmacy, 18 (11 & 12) pages 1169 through 1206, 1992, mentions that fine, free-flowing adjuvant granulates (fillers, binders, explosives, pigments) for direct tableting can be produced by spray drying.
The goal of this spray granulation process is to attain more favorable processing properties, which however as a rule are associated with an increased particle size, for direct tableting.
The disadvantage of these technologies with a view to direct production of low-dose pharmaceutical preparations is as follows:
because of the large particle size of these granulates, the requisite content uniformity does not always exist through subsequent mixing;
the spray granulation of the necessarily highly dilute steroid solutions or suspensions is very complicated and expensive, because of the large volumes involved.
SUMMARY OF THE INVENTION
Homogeneous preformulations containing high concentration of steroids, for producing low-dose solid and semi-solid pharmaceutical preparations having a concentration content of 0.001 to 1 weight percent of steroids and the production of a homogeneous preformulation, containing steroids in high concentration, for low-dose solid and semi-solid pharmaceutical preparation with a concentration content of 0.001 to one weight percent of steroid by means of spray drying, in which in a conventional dry mixing process while avoiding the above disadvantages the preformulation can be processed into a direct-tabletable pharmaceutical preparati
Dittgen Michael
Grawe Detlef
Hoesel Peter
Matthey Klaus
Moellmann Peter
Bawa Raj
JENAPHARM GmbH & Co. KG
Striker Michael J.
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