Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1999-07-29
2003-01-14
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S448000, C514S570000, C604S307000
Reexamination Certificate
active
06506404
ABSTRACT:
The invention relates to the improved release of active ingredients from hot melt adhesive compositions through addition of pharmaceutical auxiliaries.
In the formulation of medicinal products for topical administration of active ingredients, the choice of the auxiliaries has crucial importance.
Thus, it is known that there is a connection between the solubility of an active ingredient in a vehicle and its release from this vehicle. Application of an active ingredient-containing vehicle to the skin results in an active ingredient partition equilibrium between vehicle and skin being set up. The position of this equilibrium is determined by the solubility in the two phases and is described by the partition coefficient P
s
.
According to Fick's 1st law, the following applies to the flux of a dissolved substance from a vehicle into the skin:
J
s
=
P
s
C
i
D
i
h
where J
s
is the flux, P
s
is the partition coefficient, C
i
is the concentration of the active ingredient in the vehicle, D
i
is the diffusion coefficient and h is the thickness of the skin.
According to Hildebrand and Scott, the following equation applies to the solubility of a polymer in a solvent:
&Dgr;H
m
=V
m
&phgr;
1
&phgr;
2
(&dgr;
1
−&dgr;
2
)
2
with &Dgr;H
m
enthalpy of mixing, V
m
total volume of the mixture, &PHgr; volume content of the components and &dgr; solubility parameter,
where the solubility is good when the parameters are close to identical and thus the term (&dgr;
1
−&dgr;
2
) is small.
A difference of &dgr;
1
−&dgr;
1
<2 indicates expected solubility.
Hildebrand's solubility parameter is defined as the total of all the intramolecular attractive forces for a substance and can be measured by various methods. A general discussion of the solubility parameter concept can be read in a number of publications; as an example, Vaughan, C. D., Journal of the Society of Cosmetic Chemists 36, 319-333 (1985) may be mentioned here.
It is possible to derive from these equations according to Sloan, K. B. et al, Journal of Pharmaceutical Sciences, 75, 744 (1986) the following expression for the partition equilibrium of an active ingredient between vehicle and skin:
ln
P
s
=
(
δ
i
-
δ
v
)
2
V
i
φ
v
2
RT
-
(
δ
i
-
δ
s
)
2
V
i
φ
s
2
RT
=
ln
C
i
skin
C
i
vehicle
V
i
molar volume of the active ingredient
&dgr;
i
active ingredient solubility parameter
&dgr;
v
vehicle solubility parameter
&dgr;
s
skin solubility parameter
The release of a low molecular weight substance from a polymeric matrix is determined by complex interplay of specific interactions of all the components. According to the above equation, the concentration of active ingredient in the skin is high when the solubility in the skin is high and the solubility in the vehicle is low. Accordingly, it is possible to alter the release of an active ingredient from a vehicle by adjusting the solubility parameter &dgr;
v
of this vehicle.
Since Hildebrand's solubility parameter &dgr; is a material constant, it further follows from this equation that a specific modification of the vehicle is necessary for each active ingredient. It is not possible to draw conclusions by analogy within a group of chemical substances or family of active ingredients because of the significant differences in the &dgr; values. This is made clear for example by the values for chemically closely related auxiliaries such as cetyl alcohol (&dgr;=8.94), lauryl alcohol (&dgr;=9.51) and capryl alcohol (&dgr;=10.09) or else ethylene glycol (&dgr;=14.50), diethylene glycol (&dgr;=13.61) and triethylene glycol (&dgr;=12.21).
As is evident, inter alia from U.S. Pat. No. 4,555,524, the beneficial use of auxiliaries for distinctly improved release of an active ingredient is known for topical administration forms such as creams or ointments. This achieves, by dissolving ibuprofen in a combination of pharmaceutical auxiliaries, increased release of the active ingredient compared with formulations containing the undissolved active ingredient. Deliberate adjustment of the solubility parameter &dgr;
v
of the vehicle for optimal release of ibuprofen is not described therein. In addition, the amounts of auxiliary employed are so large that it is not possible to produce adhesive administration forms with them.
The strategy described above is used only in a few cases of so-called drug-in adhesive systems, that is to say active ingredient-containing plasters containing the medicinal substance in the adhesive composition.
Hot melt adhesive compositions make it possible to avoid the disadvantages associated with the use of solvents which is necessary in conventional active ingredient-containing adhesive compositions. Mention should here be made of the harmfulness of most organic solvents, high industrial expenditures for extraction and recovery, high costs for the required high-purity solvents and, in particular, very high expenditure for removing solvent residues from the matrix.
The advantages of hot melt adhesive compositions for producing active ingredient-containing adhesive compositions have been described in the patent literature for some years now (see, for example, EP 0 305 757 A1).
The targeted optimization of the solubility of an active ingredient in a matrix is not known for hot melt adhesive compositions based on polystyrene block copolymers.
U.S. Pat. No. 5,527,536 describes active ingredient-containing hot melt adhesive compositions based on polystyrene block copolymers, especially polystyrene block copoly(ethylene/butylene) block polystyrene (SEBS). These compositions contain besides SEBS tackifiers and antioxidants. The use and benefits of added pharmaceutical auxiliaries is not described.
For hot melt adhesive compositions based on ethylene/vinyl acetate copolymers, optimization of release of active ingredients is described in U.S. Pat. No. 4,837,025. Fatty acid esters with polyalcohols are used here.
WO 93/00058 describes the optimization of active ingredient-containing adhesive compositions by application of the principles described above, with the solubility parameter &dgr;
v
being altered by mixing two polymeric adhesive compositions with different solubility parameters, preferably a silicone adhesive composition and an acrylate adhesive composition. Low molecular weight auxiliaries are not employed to adjust the &dgr;
v
.
U.S. Pat. No. 5,702,720 describes an active ingredient-containing plaster which contains flurbiprofen dissolved in an acrylate adhesive composition. Isopropyl myristate which is likewise present acts as promoter which enhances penetration of the active ingredient through the skin. This low molecular weight auxiliary is evidently not employed to optimize the solubility in the vehicle.
WO 94/23713 describes anti-inflammatory medicinal products based on phenylpropionic acids and phenylacetic acids for topical administration which contain combinations of lipophilic and hydrophilic auxiliaries. No statements are made about the mode of action and function of these auxiliaries.
Adjustment of the solubility parameter &dgr;
v
of the vehicle by adding lipophilic and hydrophilic auxiliaries is evidently not intended and would be complicated and laborious. In addition, the effects of the different auxiliaries on &dgr;
v
would be in contrary directions and would cancel each other out.
EP 0 827 741 A2 discloses that the release of ketoprofen from adhesive vehicles can be improved by adding auxiliaries. For example, polyisobutylenes dissolved in hexane/toluene are described as the basis for the adhesive composition.
Ibuprofen is (±)-2-(4-isobutylphenyl)propionic acid (C
13
H
18
O
2
; M
R
206.28; melting point 75 to 77° C.) with the general formula
(according to Römpp Lexikon Chemie, version 1.3, Stuttgart/New York: Georg Thieme Verlag 1997). Ibuprofen is a known active ingredient with analgesic and anti-inflammatory properties and is therefore employed for soft-tissue rheumatism and inflammatory joint
Mayan Robert
Philipp Peter
Wasner Matthias
Beiersdorf AG
Hartley Michael G.
Norris & McLaughlin & Marcus
Williamson Michael A.
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