Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2000-11-27
2004-03-02
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S484000, C424S485000, C424S486000, C424S487000, C424S488000
Reexamination Certificate
active
06699498
ABSTRACT:
Disregarding a few fairly uncommon special forms, transdermal therapeutic systems (TTS) may be differentiated into two basic groups, those known as matrix systems and those known as reservoir systems. In the case of those known as matrix systems, in the simplest case the active substance is dissolved in a self-adhesive layer or in some cases only suspended in the form of crystals. Reservoir systems represent a type of pouch comprising an inert backing layer and an active substance permeable membrane, the active substance being located in a liquid preparation within this pouch. Usually, the membrane is provided with a layer of adhesive which serves to anchor the system on the skin.
Irrespective of specific embodiments of the transdermal system, the active substance is delivered to the skin by diffusion during use and is therefore required to be present, at least in part, in dissolved form.
In this form, the active substance is particularly sensitive to reactions with constituents of the formulation which may lead to an impairment of the stability. Examples of such reactions include:
a) the bonding of the active substance via an amide or ester bond to carboxyl groups or ester groups of the polymers or permeation enhancers used;
b) the reaction of a carboxyl group or ester group of the active substance with alcoholic groups of tackifying resins or permeation enhancers;
c) the hydrolysis or alcoholysis of ester groups by water or alcohols, respectively.
Such reactions, which may be inferred directly from the functional groups of the active substance and of the auxiliaries, are no surprise to the skilled worker. Corresponding risks to stability are therefore usually discovered very quickly by means of appropriate compatibility studies at elevated temperature and can then be avoided by means of appropriate reformulations of adverse active substance/auxiliary combinations.
Furthermore, the stability of the active substance and of the auxiliaries may be put at risk by reaction with active oxygen. Such active oxygen is, naturally, the oxygen of the air. An effective means of protecting the active substance present in the TTS against this oxygen is to package the TTS under a nitrogen atmosphere and/or to insert antioxidants into the packaging as well.
Despite these precautionary measures, however, it has to date been necessary to accept quite often a greater or lesser decrease in the amount of active substance when a TTS comprising oxidation sensitive active substances is stored for prolonged periods. The causes of this were not previously known.
It has now surprisingly been found that raw materials used to produce TTS may to a considerable extent comprise active oxygen in another form, namely in the form of hydroperoxides.
These hydroperoxides may form by the following mechanism in accordance with the autoxidation reactions described in the literature:
In the first step, known as the induction phase, free radicals are formed by exposure to heat and/or light, promoted by trace amounts of heavy metals and accompanied by the loss of a hydrogen atom. In the second step, known as the propagation phase, these radicals react with oxygen to form peroxy radicals. These peroxy radicals then attack further molecules, forming hydroperoxides and a new free radical. Thus a chain reaction has begun which continues until this chain is terminated by the reaction of two radicals with one another, as shown for example in the equation below.
Owing to its relatively low reactivity, the peroxide radical, functioning as a chain transfer agent, attacks particularly those sites which lead to a low-energy radical on the substrate. Preferred sites of this kind are C—H bonds in benzyl or allyl position, tertiary C—H bonds, and C—H bonds in the vicinity of ether oxygens. As a result, raw materials possessing such groups are especially susceptible to the formation of hydroperoxides.
The antioxidants or stabilizers which are used to protect oxidation sensitive active substances may intervene in this reaction chain. Antioxidants may be differentiated into free-radical scavengers and oxygen scavengers. Free-radical scavengers such as tocopherol and its derivatives, for example, remove or inactivate free radicals and so interrupt the chain mechanism of autoxidation. Oxygen scavengers, such as ascorbyl palmitate, for example, react directly with the oxidative agent and so prevent the chain reaction starting.
The addition of antioxidants/stabilizers only makes sense, however, if the starting materials themselves do not comprise hydroperoxides with an oxidative action and if the drug form is protected against the ingress of oxygen by the packaging.
Surprisingly, it has been found that in all classes of raw material used to produce transdermal therapeutic systems, with the exception of materials in film form, there are representatives which on supply or after brief storage are already loaded with considerable amounts of hydroperoxides. Specifically, this means that polymers, tackifying resins, permeation enhancers and solvents or solubilizers may have a hydroperoxide content which can to a considerable extent impair the stability of an oxidation sensitive active substance.
The peroxide content is commonly expressed by means of the so-called peroxide number PON, which indicates the amount of milliequivalents of active oxygen per kg of substance. There are various methods of determining the peroxide number. The most customary is to react a defined amount of substance in a chloroform/glacial acetic acid solution with an excess of iodide ions and then to back-titrate the resultant iodine using sodium thiosulfate. A less common method, which is restricted to aqueous solutions, is to react the substance with titanium(IV) ions and to measure the resultant peroxo complex by photometry. A semiquantitative test for peroxides which is particularly easy to implement is carried out using commercial test electrodes.
The table below lists the measured peroxide numbers of some exemplary substances used to produce reservoir and matrix systems, following approximately 6 months' storage at room temperature. The peroxide numbers were measured by the two first-mentioned methods.
Raw material
Function
PON
Hydrocarbon resin
matrix constituent
180
Collidon
matrix constituent
110
Partially hydrogenated glycerol ester
tackifier
190
of rosin
Hydrogenated glycerol ester
tackifier
80
of rosin
Poly-&bgr;-pinene
tackifier
150
Diethylene glycol
solvent/
120
monoethyl ether
permeation enhancer
Oleyl alcohol
solvent/
50
permeation enhancer
Limonene
permeation enhancer
15
The peroxide number of the finished patches may be determined by the same method. However, it is rather difficult to dissolve a sufficient amount of patch in a reasonable amount of chloroform. An easier method is to measure the peroxide loading of the individual substances and to calculate the peroxide number of the active substance component of the patches in accordance with the following formula:
∑
i
=
1
n
(
N
i
·
PON
/
100
)
n: number of formulation constituents of the active substance component of the system
N: percentage content of the formulation constituents in the active substance constituents of the system (numerical value)
PON: peroxide number of the individual constituents of the active substance component of the system
It has been found experimentally that the hydroperoxides present in the raw materials may react in diverse ways with the active substance with which they come in contact. Active substances which have been found to be particularly sensitive are those possessing one of the following substructures:
secondary or tertiary amino groups
C—C double bonds
C—H groups in allyl position
benzylic C—H groups
tertiary C—H groups
sulfide or sulfoxide groups
The corresponding reaction products are as follows:
In many cases, these reactions at the corresponding functional groups of the active substances are accompanied by follow-on reactions.
For example, it has been found that, in the case of 17-&bgr;-estradiol, initial hydroxylation in th
Frommer & Lawrence & Haug LLP
Ghali Isis
LTS Lohmann Therapie-Systeme AG
Page Thurman K.
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