Topical formulations

The invention relates to topically administrable pharmaceutical preparations containing pharmaceutically acceptable methanediphosphonic acid derivatives of formula ##STR1## and their salts, wherein R.sub.1 and R.sub.2 are hydrogen or C.sub.1 -C.sub.3 alkyl.

It is known that representatives of a class of synthetic 
methanediphosphonic acid derivatives are used, for example, in the 
treatment of osteolytic bone metastases and hypercalcaemia, since they are 
able to inhibit the growth and decomposition of hydroxyapatite. These 
compounds thus prevent bone resorption by binding spontaneously to the 
hydroxyapatite of the bone, so that osteoclasts, for example, are unable 
to cleave further hydroxyapatite crystals. Compounds of this class of 
substances are described, for example, in DE-OS 2,405,254. 
It is known that corresponding methanediphosphonic acid derivatives are 
absorbed to only a small extent following oral administration, especially 
if food is given at the same time. In order to achieve the desired 
therapeutic effect, correspondingly higher doses must be administered. 
Because of the importance of this class of substances in the treatment of, 
for example, osteoporosis, Paget's disease, Bechterew's disease and the 
formation of bone metastases, many attempts are being made to provide a 
pharmaceutical form of administration from which the active ingredients 
can readily be absorbed irrespective of whether food is given. 
The methanediphosphonic acid derivatives used in accordance with the 
invention, which contain two dissociable acid groups and a basic centre, 
are known to exist in ionic form. F. N. Marzulli et al., The Journal of 
Investigative Dermatology 44, 339-344 (1965), studied the penetration of 
radioactively labelled organic phosphoric acid esters and phosphoric acid 
in vitro through human Stratum corneum and found that ionised phosphoric 
acid is able to pass through the skin to only an extraordinarily small 
extent. The conclusion drawn from these studies was that neutral molecules 
pass through the barrier of the Stratum corneum relatively easily, while 
ionic forms are able to penetrate only to a very small extent and with 
great difficulty. This view is shared by R. J. Scheuplein, Physiological 
Reviews 51, 16-23 (1971), who concludes that ionisation drastically 
reduces skin permeation. 
Even more surprising is the discovery that pharmaceutically acceptable 
methanediphosphonic acid derivatives, especially those of formula I below, 
are readily conveyed through the skin and can thus immediately act 
systemically. These unexpected discoveries were made during in vitro 
studies to determine percutaneous absorption properties by the method of 
A. S. Bhatti et al., J. Pharm. Pharmacol., 40, 45 P (1988). In these 
studies, corresponding diffusion cells having a cell surface area of 1.27 
cm.sup.2 and pig skin as the membrane were used as a model for human skin. 
The studies showed that significant therapeutic amounts of active 
ingredient diffused through the membrane. These results were confirmed in 
studies of the in vitro transdermal absorption of bisphosphonates. 
Experiments were carried out on guinea pigs using .sup.14 C-labelled 
active ingredient. 6 mg of cold bisphosphonate active ingredient and 
approximately 10.sup.6 dpm of .sup.14 C-labelled bisphosphonate in 200 
.mu.l of 2% Klucel in distilled water having a pH of 7.5 were applied to a 
shaved area of 3.times.5 cm, and the area was covered with an occlusive 
dressing. The radioactive material in the excreted urine was measured 
after 1, 2 and 3 days. 
The present invention relates to topically administrable pharmaceutical 
preparations containing pharmaceutically acceptable methanediphosphonic 
acid derivatives or salts thereof, to their manufacture and use. 
Suitable methanediphosphonic acid derivatives having pharmaceutical 
activity are, for example, compounds of formula 
##STR2## 
and their salts, wherein R.sub.1 and R.sub.2 are hydrogen or C.sub.1 
-C.sub.3 alkyl. 
Salts of compounds of formula I are especially their salts with bases, such 
as metal salts derived from groups Ia, Ib, IIa and IIb of the Periodic 
Table of Elements, for example alkali metal salts, especially sodium or 
potassium salts, alkaline earth metal salts, especially calcium or 
magnesium salts, and also ammonium salts with ammonia or organic amines. 
C.sub.1 -C.sub.3 alkyl is methyl, ethyl, n-propyl and isopropyl. 
The compounds of formula I and their salts are described, for example, in 
DE-OS 2,405,254. 
The methanediphosphonic acid derivatives of formula I have valuable 
pharmacological properties. In particular, they have a pronounced 
regulatory effect on the calcium metabolism of warm-blooded animals. They 
also bring about a marked inhibition of bone resorption in rats, which can 
be demonstrated both in the test arrangement according to Acta Endocrinol. 
78, 613-24 (1975) and in the TPTX (thyroparathyroidectomised) rat model by 
means of experimental hypercalcaemia induced by vitamin D.sub.3. Likewise, 
tumour hypercalcaemia induced by Walker-256 tumours is inhibited following 
peroral administration. Furthermore, in adjuvant arthritis in rats they 
exhibit a pronounced inhibition of the progress of chronic-arthritic 
processes in the test arrangement according to Newbould, Brit. J. 
Pharmacology 21, 127 (1963) and according to Kaibara et al., J. Exp. Med. 
159, 1388-96 (1984). They are therefore excellently suitable as active 
ingredients in medicaments for the treatment of diseases that can be 
associated with disorders of the calcium metabolism, for example 
inflammatory processes in joints and degenerative processes in articular 
cartilage, and osteoporosis, periodontitis, hyperparathyroidism and 
calcium deposits in blood vessels or on prosthetic implants. They have a 
favourable effect both on diseases in which abnormal deposition of 
difficultly soluble calcium salts is observed, such as diseases of the 
arthritis type, for example Bechterew's disease, neuritis, bursitis, 
periodontitis and tendinitis, fibrodysplasia, osteoarthritis or 
arteriosclerosis, and on diseases involving abnormal degeneration of hard 
body tissue, such as hereditary hypophosphatasia, degenerative processes 
in articular cartilage, osteoporoses of various origins, Paget's disease 
and Osteodystrophia fibrosa, as well as osteolytic processes caused by 
tumours, and hypercalcaemia. 
The invention relates especially to topically administrable pharmaceutical 
preparations that contain a pharmaceutically effective methanediphosphonic 
acid selected from the following compounds of formula I: 
3-amino-1-hydroxypropane-1,1-diphosphonic acid, 
3-dimethylamino-1-hydroxypropane-1,1-diphosphonic acid and 
3-(N-methyl-N-n-propylamino)-1-hydroxypropane-1,1-diphosphonic acid, or a 
pharmaceutically acceptable salt thereof. 
The invention relates also to a process for the manufacture of the 
topically administrable pharmaceutical preparations according to the 
invention, which process may be carried out in accordance with methods 
known per se and comprises processing a pharmaceutically acceptable 
methane diphosphonate derivative with customary pharmaceutically 
acceptable adjuncts and additives. 
The invention relates further to a method of increasing the absorption of 
pharmaceutically acceptable methanediphosphonic acid derivatives, 
especially of compounds of formula I, which comprises incorporating a 
compound of formula I or a salt thereof into a pharmaceutical composition 
for topical administration. 
The invention relates specifically to the pharmaceutical preparations 
described in the Examples and to processes for the manufacture thereof. 
Depending on the starting materials and procedures chosen, the compounds of 
formula I may be in the form of one of the possible isomers or in the form 
of a mixture thereof, for example in the form of optical isomers, such as 
enantiomers or diastereoisomers, or geometrical isomers, such as cis-trans 
isomers. The optical isomers are in the form of the pure antipodes and/or 
of racemates. 
The compounds of formula I may also be employed in the form of their 
hydrates or include other solvents used for crystallisation. 
The topically administrable pharmaceutical preparations according to the 
invention contain the pharmaceutically acceptable compounds of formula I, 
for example, in a pharmacologically effective amount, together with a 
pharmaceutically acceptable additive or adjunct. The daily dose of active 
ingredient depends on age and individual condition and on the method of 
administration. 
Pharmaceutical preparations suitable for topical administration are 
especially creams, ointments and gels and also pastes, foams, tinctures 
and solutions that contain from approximately 0.5 to approximately 5% 
active ingredient. 
Creams or lotions are oil-in-water emulsions that contain more than 50% 
water. As oily base there are used especially fatty alcohols, especially 
those containing from 12 to 18 carbon atoms, for example lauryl, cetyl or 
stearyl alcohol, fatty acids, especially those containing from 10 to 18 
carbon atoms, for example palmitic or stearic acid, liquid to solid waxes, 
for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, 
especially liquid, semi-solid or solid substances or mixtures thereof, for 
example petroleum jelly (petrolatum) or paraffin oil. Suitable emulsifiers 
are surface-active substances having predominantly hydrophilic properties, 
such as corresponding non-ionic emulsifiers, for example fatty acid esters 
of polyalcohols or ethylene oxide adducts thereof, especially 
corresponding fatty acid esters with (poly)ethylene glycol, 
(poly)propylene glycol or sorbitol, the fatty acid moiety containing 
especially from 10 to 18 carbon atoms, especially partial glycerol fatty 
acid esters or partial fatty acid esters of polyhydroxyethylene sorbitan, 
such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty 
acid esters (Tweens), and also polyoxyethylene fatty alcohol ethers or 
fatty acid esters, the fatty alcohol moiety containing especially from 12 
to 18 carbon atoms and the fatty acid moiety especially from 10 to 18 
carbon atoms, especially those having approximately from 2 to 23 ethylene 
glycol or ethylene oxide units, such as polyhydroxyethylenecetylstearyl 
ether (for example Cetomacrogol), polyhydroxyethylene-(4)-lauryl ether and 
polyhydroxyethyleneglycerol fatty acid ester (for example Tagat S), or 
corresponding ionic emulsifiers, such as alkali metal salts of fatty 
alcohol sulfates, especially having from 12 to 18 carbon atoms in the 
fatty alcohol moiety, for example sodium lauryl sulfate, sodium cetyl 
sulfate or sodium stearyl sulfate, which are usually used in the presence 
of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives 
to the aqueous phase are, inter alia, agents that prevent the creams from 
drying out, for example humectants, such as polyalcohols, such as 
glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and also 
preservatives, perfumes, etc. 
Ointments or lotions are water-in-oil emulsions that contain up to 70%, but 
preferably from approximately 20% to approximately 50%, water or aqueous 
phase. Suitable as fatty phase are especially hydrocarbons, for example 
petroleum jelly, paraffin oil and/or hard paraffins, which, in order to 
improve the water-binding capacity, preferably contain suitable hydroxy 
compounds, such as fatty alcohols or esters thereof, for example cetyl 
alcohol or wool wax alcohols, or wool wax. Emulsifiers are corresponding 
lipophilic substances, such as sorbitan fatty acid esters (Spans), for 
example sorbitan oleate and/or sorbitan isostearate. Additives to the 
aqueous phase are, inter alia, humectants, such as polyalcohols, for 
example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, 
and also preservatives, perfumes, etc. 
Microemulsions are isotropic systems based on the following four 
components: water, an emulsifier, for example of the type indicated above, 
such as a surfactant, for example emulgin, a lipid, such as a non-polar 
oil, for example paraffin oil, and an alcohol containing a lipophilic 
group, for example 2-octyldodecanol. If desired, other additives may be 
added to the microemulsions. 
Fatty ointments are water-free and contain as base especially hydrocarbons, 
for example paraffin, petroleum jelly and/or liquid paraffins, also 
natural or partially synthetic fat, such as fatty acid esters of glycerol, 
for example coconut fatty acid triglyceride, or preferably hardened oils, 
for example hydrogenated groundnut oil or castor oil, also fatty acid 
partial esters of glycerol, for example glycerol mono- and di-stearate, 
and also, for example, the fatty alcohols increasing the water-absorption 
capacity, emulsifiers and/or additives mentioned in connection with the 
ointments. 
With gels, a distinction is made between aqueous gels, water-free gels and 
gels having a low water content, which gels consist of swellable, 
gel-forming materials. There are used especially transparent hydrogels 
based on inorganic or organic macromolecules. High molecular weight 
inorganic components having gel-forming properties are predominantly 
water-containing silicates, such as aluminium silicates, for example 
bentonite, magnesium aluminium silicates, for example Veegum, or colloidal 
silicic acid, for example Aerosil. As high molecular weight organic 
substances there are used, for example, natural, semi-synthetic or 
synthetic macromolecules. Natural and semi-synthetic polymers are derived, 
for example, from polysaccharides containing a great variety of 
carbohydrate components, such as celluloses, starches, tragacanth, gum 
arabic and agar-agar, and gelatin, alginic acid and salts thereof, for 
example sodium alginate, and derivatives thereof, such as lower 
alkylcelluloses, for example methyl- or ethyl-cellulose, carboxy- or 
hydroxy-lower alkylcelluloses, for example carboxymethyl- or 
hydroxyethyl-cellulose. The components of synthetic gel-forming 
macromolecules are, for example, suitably substituted unsaturated 
aliphatic compounds such as vinyl alcohol, vinylpyrrolidine, acrylic or 
methacrylic acid. Examples of such polymers are polyvinyl alcohol 
derivatives, such as polyviol, polyvinylpyrrolidines, such as collidone, 
polyacrylates and polymethacrylates, especially having a molecular weight 
of from approximately 80000 to approximately 1 million, or salts thereof, 
such as Rohagit S, Eudispert or Carbopol. Customary additives, such as 
preservatives or perfumes, may be added to the gels. 
Foams are administered, for example, from pressurised containers and are 
liquid oil-in-water emulsions in aerosol form; unsubstituted or 
halogenated hydrocarbons, such as alkanes, for example propane or butane, 
or chlorofluoro-lower alkanes, for example dichlorodifluoromethane and 
dichlorotetrafluoroethane, are used as propellant. As oil phase there are 
used, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, 
for example cetyl alcohol, fatty acid esters, for example isopropyl 
myristate, and/or other waxes. As emulsifiers there are used, inter alia, 
mixtures of emulsifiers having predominantly hydrophilic properties, such 
as polyoxyethylene sorbitan fatty acid esters (Tweens), and emulsifiers 
having predominantly lipophilic properties, such as sorbitan fatty acid 
esters (Spans). The customary additives, such as preservatives, etc., are 
also added. 
Tinctures and solutions generally have an ethanolic base, to which water 
may be added and to which there are added, inter alia, polyalcohols, for 
example glycerol, glycols and/or polyethylene glycol, as humectants for 
reducing evaporation, and fat-restoring substances, such as fatty acid 
esters with low molecular weight polyethylene glycols, that is to say 
lipophilic substances that are soluble in the aqueous mixture, as a 
replacement for the fatty substances removed from the skin by the ethanol, 
and, if necessary, other adjuncts and additives. Suitable tinctures or 
solutions may also be applied in spray form by means of suitable devices. 
The manufacture of the topically administrable pharmaceutical preparations 
is effected in a manner known per se, for example by dissolving or 
suspending the active ingredient in the base or, if necessary, in a 
portion thereof. When the active ingredient is administered in the form of 
a solution, it is generally dissolved in one of the two phases before 
emulsification; when the active ingredient is administered in the form of 
a suspension, it is mixed with a portion of the base after emulsification 
and then added to the remainder of the formulation. 
The present invention relates especially to multi-layered therapeutic 
systems for the transdermal administration of pharmaceutically acceptable 
methanediphosphonic acid derivatives, especially those of formula I, and 
their salts, which contain essentially the following constituents: 
(1) a closed backing foil which is impermeable to the subsequent layers of 
the constituents of the active ingredient formulation, 
(2) a reservoir for the active ingredient, next to the backing foil, 
provided that the active ingredient is not already present in the adhesive 
foil, 
(3) an adhesive layer and 
(4) a peel-off protecting foil. 
The therapeutic system according to the invention for the transdermal 
administration of methanediphosphonic acid derivatives of formula I is 
preferably in the form of a plaster having a base surface that is at least 
as large in area as the area of the skin envisaged for the administration 
and at least as is large as is required for it to stay firmly in place 
over the entire period of treatment. The base surface must be large enough 
for sufficient quantities of the active constituents of the active 
ingredient formulation (for example, active ingredient and the agents for 
enhancing percutaneous absorption, hereinafter "penetration enhancers") to 
be absorbed by the skin. Although, in theory, very large areas of skin are 
available for taking the plaster, for reasons of comfort the wanted 
surface area of the base surface of the plaster is about 200 cm.sup.2, in 
the first line about 20 to about 30 cm.sup.2. 
The plaster may be of any geometrical shape, e.g. may be oval, elliptical, 
circular, rectangular, optionally with rounded corners, oblong or 
rectangular with one or two rounded tabs. Other shapes are also possible. 
The backing foil (1) consists of a material or of a combination of 
materials that must be impermeable to the constituents of the formulation 
contained in the reservoir (2). It serves as a protecting and supporting 
layer. To produce the backing foil, it is possible to use high or low 
pressure polymers such as polyethylene, polypropylene, polyvinyl chloride, 
polyethylene terephthalate or also cellulose acetate or vinyl 
acetate/vinyl chloride copolymers and combinations, especially composite 
foils thereof. An impermeable, flexible backing foil that conforms to the 
shape of the part of the body to which the plaster is applied and that 
consists of materials suitable for the manufacture of hot form-sealed 
systems is preferred. 
The reservoir (2) for the active ingredient is situated between the backing 
foil (1) and the adhesive layer (3), which in turn is arranged on the 
peel-off protecting foil (4), and contains all essential constituents of 
the active ingredient formulation. The reservoir serves to hold the active 
ingredient in a limited space for release to the skin. It may contain a 
liquid, semi-solid or solid active ingredient formulation or may formed as 
homogeneous or inhomogeneous polymer matrix containing itself the active 
ingredients. Preferably, the reservoir layer containing the active 
ingredient is formed as adhesive matrix which in case of a monolith system 
needs no additional adhesive layer. In an other preferred embodiment as 
reservoir a liquid or semi-solid composition which contains the active 
ingredient and which may melt a skin temperature is embedded in a 
non-woven fabric or in a polymeric foam. 
However, if the reservoir is not itself the adhesive matrix or is 
incorporated in an adhesive layer, it can be bonded to an adhesive layer, 
which in turn can be bonded to the peel-off layer. Furthermore, a porous 
or permeable membrane may be arranged between the reservoir and an 
adhesive layer which in turn is arranged on a peel-off layer (4). 
For example, an arrangement in which the reservoir is in firm contact with 
the skin is known per se and is described, for example, in British Patent 
Application 2,021,950. The area of the backing foil (1) is greater than 
the area occupied by the reservoir (2) and, therefore, the backing foil 
projects beyond the reservoir, the projecting portion of the backing foil 
(1) being provided with an adhesive layer and adhering to the skin. The 
peel-off protective layer (4) lies over the adhesive layer (3) and over 
the reservoir (2), it being possible for the latter also to be limited by 
an additional membrane. 
An example of a system in which the reservoir (2) is, for example, in firm 
contact with the adhesive layer (3), it being possible for the active 
ingredient base to be present both in the reservoir and in the adhesive 
layer, is described in U.S. Pat. No. 4,597,961. The backing foil (1) is 
also larger in area than the area occupied by the reservoir (2) and 
projects beyond the latter. The adhesive layer (3) covers both the 
reservoir (2) and the projecting portion of the backing foil (1). The 
peel-off protective layer (4) lies on top of the adhesive layer. 
The matrix used for immobilising drug compositions which are liquid or 
semi-solid or which melt at skin temperature essentially consists of, for 
example, natural or synthetic polymers, such as cotton, cellulose, 
regenerated cellulose, polyamides, polyester, polyurethane or cellulose 
derivatives, for example those of the type described below, viscose or 
polypropylene. In particular, such fibrous structures are used in the form 
of a non-woven fabric or in form of woven and mitted fabrics and also 
foams. 
The reservoir (2) can also contain liquid polymeric material in which the 
active ingredient formulation or constituents thereof are homogeneously 
dispersed. Such polymeric materials are, for example, silicone rubber 
(silicones), e.g. linear organosiloxanes in which every silicon atom in 
the siloxane chain is substituted by two identical or different alkyl, 
e.g. methyl or ethyl, aryl, e.g. phenyl, alkenyl, e.g. vinyl or allyl, 
alkylaryl, e.g. tolyl or xylyl, or aralkyl, e.g. benzyl, radicals, and 
every terminal silicon atom is substituted by three of the mentioned 
organic radicals. The preparation of these silicones is described in U.S. 
Pat. Nos. 2,541,137, 2,723,966, 2,863,846, 2,890,188, 2,927,907, 3,002,951 
and 3,035,016. 
In addition to the liquid polymeric material and the active ingredient 
formulation, the reservoir (2) can also contain other liquids such as 
glycerol or propylene glycol and also water and have the release 
properties described in U.S. Pat. No. 4,291,015. 
The contents of the reservoir (2) preferably consist exclusively of the 
actual active ingredient formulation which contains the penetration 
enhancer, especially ethanol, the active ingredient and, optionally, other 
auxiliaries, for example gelling agents and, optionally, 
viscosity-increasing adjuncts, such as polyvinyl alcohol, 
polyvinylpyrrolidone, cellulose derivatives, e.g. those of the type 
mentioned, and gelatin. 
The reservoir (2) can, in addition, be provided with a permeable layer of 
the required permeability to the active ingredient and the penetration 
enhancer. This layer controls the rate of release of the penetration 
enhancer and/or of the active ingredient from the system to the skin and 
is also called a control or regulating membrane. 
The materials that can be used in the therapeutic systems of the invention 
for producing the permeable layer are known per se. Such membrane 
materials may be homogeneous (diffusion membranes) or macrostructured 
(porous membranes). The latter may be regarded as being a sponge-like 
structure having a skeleton of polymeric material with interconnected 
voids and pores dispersed therein. Membrane materials that control the 
rate of release may consist of isotropic material with a homogeneous 
structure or of anisotropic material with a non-homogeneous structure. 
Such materials are commercially available and can be produced in various 
ways, for example as described by R. E. Kesting, Synthetic Polymer 
Membranes, McGraw Hill, Chapters 4 and 5, 1971, J. D. Ferry, 
Ultrafiltration Membranes, Chemical Review, Vol. 18, page 373, 1984. 
Membrane materials having from 5 to 95% by volume voids and an effective 
pore diameter of approximately from 1.0.times.10.sup.-9 m to 
1.0.times.10.sup.-4 m are especially suitable. More especially suitable 
are membrane materials having pore diameters of less than approximately 
5.0.times.10.sup.-9 m and molecular diffusion. For best results, reference 
should be made to the prior art and the known embodiments with known 
membrane materials and known shapes which ensure an optimum rate of 
release of the active ingredient. In particular, the membrane material 
must be chemically resistant to the active ingredient and to the 
penetration enhancer used. 
A list of suitable membrane materials, which should not be regarded as 
exhaustive, is given below: 
polycarbonates, e.g. linear polyesters of carbonic acid derivatives that 
contain carbonate groups in the polymer chain and can be prepared, for 
example, by reacting dihydroxy aromatic compounds with phosgene. Such 
materials are obtainable from General Electric under the trade mark 
Lexan.RTM.; 
polyvinyl chlorides, e.g. PVC, which is obtainable from Goodrich under the 
trade mark Geon.RTM. 121; 
polyamides of the polyhexamethyleneadipamide type, or polyamides known by 
the generic name "Nylon". An especially suitable material is sold under 
the trade mark Nomex.RTM. by DuPont; 
acrylic acid copolymers, e.g. those which are sold under the trade name 
Dynel.RTM. and consist of about 60% polyvinyl chloride and 40% 
acrylonitrile, and styrene/acrylic acid copolymers and the like; 
polysulfones with diphenylsulfone groups in the linear chain. Such polymers 
are sold as P-1700 by Union Carbide; 
halogenated polymers, such as polyvinylidene fluorides, that are sold, for 
example, under the trade mark Kynar.RTM. by Pennwalt; polyvinyl fluorides 
that are obtainable from DuPont under the trade mark Tedlar.RTM., and 
polyfluorohalocarbons obtainable under the trade mark Aclar.RTM. from 
Allied Chemical; 
polychloroethers that are sold by Hercules under the trade mark 
Penton.RTM., and other similar thermoplastic polymers; 
acetal polymers such as the polyformaldehyde polymers that are sold by 
DuPont under the trade mark Delrin.RTM., and the like; 
acrylic acid resinates, such as polymethyl methacrylate, poly-n-butyl 
methacrylate and the like; 
polyethylene and copolymers of ethylene, e.g. with vinyl acetate or 
acrylates. 
other polymers, such as polyurethanes, polyimides, polybenzimidazoles, 
polyvinyl acetate, aromatic and aliphatic polyethers, cellulose esters, 
for example cellulose triacetate, cellulose, Colledion.RTM. (cellulose 
nitrate with 11% nitrogen), epoxy resinates, polyolefins, e.g. 
polyethylene/polypropylene, porous rubber, polyvinylpolypyrrolidone, 
crosslinked polyvinyl alcohol, copolymers of vinylpyrrolidone and vinyl 
alcohols, polyelectrolyte structures consisting of two ionically 
associated polymers as are described in U.S. Pat. Nos. 3,549,016 and 
3,546,142, polystyrene derivatives such as polystyrene sodium sulfonates 
or polyvinylbenzyltrimethylammonium chlorides, polyhydroxyethyl 
methacrylates, polyisobutyl vinyl ether and similar polymers can also be 
used. Other copolymers that are obtainable by copolymerisation of various 
amounts of the monomers forming the basis of the mentioned polymers can 
also be used to produce the membrane material determining the rate of 
release of the active ingredient and/or the penetration enhancer. 
When using a permeable membrane, several arrangements are possible: the 
active ingredient formulation is arranged between the backing foil (1) and 
the membrane layer. In that arrangement, the backing foil and the membrane 
form a space which can optionally be divided into several compartments. In 
certain embodiments, the backing foil (1) and the membrane layer are 
joined, e.g. welded or glued, to each other at the very edge. In these 
embodiments, the active ingredient and the penetration enhancer are 
contained in the same reservoir. These embodiments are preferred when the 
active ingredient formulation is liquid or semi-solid. 
It is also possible, in accordance with the embodiment described in German 
Offenlegungsschrift 3,205,258, to fill the space formed by the backing 
foil (1) and the membrane only with penetration enhancer, e.g. ethanol, 
and optionally with a gelling agent or viscosity-increasing adjunct, such 
as gelatin, and to apply the active ingredient formulation to the other 
side of the membrane. In that case, the membrane would control only the 
rate of diffusion of the enhancer. The active ingredient can be present in 
a separate layer between membrane and adhesive layer (3) and optionally or 
exclusively in the adhesive layer (3). 
The reservoir (2) can, in addition, be divided into several compartments. 
This division into compartments is suitable for liquid active ingredient 
formulations and prevents the latter from sinking and becoming 
concentrated at the lowest point of the system if cavities or folds are 
formed as a result of the plaster not being stored flat. Division into 
compartments is especially advantageous if the reservoir layer occupies an 
area of more than 30 cm.sup.2. The compartments can be distributed as 
desired. For example, a radial arrangement of the partitions, extending 
from the middle point of the plaster, or vertical or horizontal 
boundaries, or oblique lines etc. are possible. 
Division of the compartments, especially by partitions or seal seams, can 
be effected by hot-welding. In this procedure, the material of the backing 
foil (1) is welded to the material of the membrane layer. 
Dermatologically acceptable adhesives are suitable for the adhesive layer 
(3). Suitable adhesives are, for example, silicone adhesives [e.g. of the 
Bio-PSA.RTM. or Silicon Adhesive 355 (Dow Corning) type], adhesive 
formulations of acrylic acid resins or methacrylic acid resins, e.g. 
polymers of acrylic acid or methacrylic acid esterified by alcohols such 
as n-butanol, n-pentanol, isopentanol, 2-methylbutanol, 1-methylbutanol, 
1-, 2- or 3-methylpentanol, 2-ethylbutanol, isooctanol, n-decanol or 
n-dodecanol, or copolymers of these acrylic acid or methacrylic acid 
esters with monomers containing ethylene groups, such as acrylic acid 
itself, methacrylic acid, acrylamide, methacrylamide, 
N-alkoxymethacrylamide, N-alkoxymethylmethacrylamide, N-tert.-butylamide, 
itaconic acid, vinyl acetate [e.g. of the Durotak.RTM. 280-2516 type 
(National Starch & Chemical B.V.)], N-branched alkylmaleic acid amide in 
which the branched alkyl group has from 10 to 24 carbon atoms, glycol 
diacrylates or mixtures thereof, polyalkenylenes, such as polyisobutylenes 
of different molecular weights, for example of from approximately 100 to 
1.5 million, e.g. polyisobutylene 300 or 35000 or 1.2 million, 
hydrogenated hydrocarbon resins, natural or synthetic rubber, such as 
styrenebutadiene, butyl ether, neoprene, polyisobutylene, polybutadiene 
and polyisoprene, polyvinyl acetate, urea/formaldehyde resinates, 
resorcinol/formaldehyde resinates, cellulose derivatives such as 
ethylcellulose, methylcellulose, nitrocellulose, cellulose acetate 
butyrate and carboxymethylcellulose, and also natural gums such as agar, 
acacia, pectin, starch, dextrin, albumin, gelatin, casein, etc. It is also 
possible to add thickeners and stabilisers and also solvents to the 
mentioned adhesives; however, they may be used without solvents in the 
form of so-called hot-melt adhesives, which are applied at higher 
temperatures to the polymeric materials in the molten state. The solvents 
in which the adhesives are dissolved are, especially, are readily volatile 
and tolerated by the skin. Examples that may be mentioned are 
corresponding hydrocarbons, such as alkanes, e.g. hexane, heptane, 
aromatic hydrocarbons, e.g. toluene, lower alkanols, such as methanol, 
ethanol or isopropanol, esters, such as lower alkanecarboxylic acid-lower 
alkyl esters, e.g. ethyl acetate, or ketones, such as acetyl acetone, or 
mixtures thereof. 
The adhesive layer (3) may be applied to some or all of the membrane. If 
the membrane is completely covered by the adhesive layer, the latter may, 
in addition to its actual function as an adhesive to the skin, act as a 
permeable membrane. The desired membrane properties, e.g. control of the 
rate of diffusion of the penetration enhancer, can be obtained by varying 
the thickness and composition of the adhesive layer (3). The adhesive 
layer (3) may, in addition, contain the total amount or, preferably, a 
portion of the active ingredient. The amount of active ingredient 
contained in the adhesive layer (3) can be used, in particular, to 
administer an initial surge dose before the continuous release, which is 
controlled by the therapeutic system, commences at the desired therapeutic 
level. 
The membrane can also be covered by the adhesive layer (3) partially and/or 
discontinuously. A covering at the edges is possible, for example an 
annular circumferential covering. The membrane can also be covered in a 
pattern, for example in a rhomboidal pattern. The membrane can be covered 
at the outer edge by a continuous band of adhesive material, for example 
in the shape of a ring, and on the inside surface with discontinuous 
bands, for example in a rhomboidal pattern. 
The protective layer (4) is removed before application. It consists of 
materials that are impermeable to the constituents of the reservoir layer 
(2). It is possible to use the same materials as those used for producing 
the backing foil (1), and also metal foils, for example thin aluminium 
foil. Organic polymers are rendered capable of being peeled off the 
adhesive layer, for example, by suitable surface treatment, for example 
silicone treatment. 
The active ingredient formulation contained in the transdermal therapeutic 
system of the invention, especially in the reservoir (2), contains as 
adjunct an agent that enhances percutaneous absorption (penetration 
enhancer--"flux-enhancer") which increases the flux of the active 
ingredients of formula I through the skin, so that a greater quantity of 
active ingredients is absorbed by the skin per unit of application area 
and per unit of time. The penetration enhancer can, in addition, 
accelerate the flow of the active ingredient through the permeable 
membrane layer in membrane systems. In particular, the use of a suitable 
penetration enhancer results in the administration through the skin of 
that dosage of active ingredients which is required per unit of time to 
maintain the therapeutic level. Suitable penetration enhancers have a 
higher flux through the skin than do the active ingredients whose 
absorption is to be enhanced and can be mixed with other pharmaceutically 
acceptable adjuncts. 
Suitable penetration enhancers are preferably monovalent, saturated or 
unsaturated aliphatic, cycloaliphatic or aromatic alcohols having from 4 
to 12 carbon atoms, e.g. n-hexanol or cyclohexanol, aliphatic, 
cycloaliphatic or aromatic hydrocarbons having from 5 to 12 carbon atoms, 
e.g. hexane, cyclohexane, isopropylbenzene and the like, cycloaliphatic or 
aromatic aldehydes and ketones having from 4 to 10 carbon atoms, such as 
cyclohexanone, acetamide, N,N-di-lower alkylacetamides such as 
N,N-dimethylacetamide or N,N-diethylacetamide, C.sub.10 -C.sub.20 
alkanoylamides, e.g. N,N-dimethyllauroylamide, 1-n-C.sub.10 -C.sub.20 
alkylazacycloheptan-2-one, e.g. 1-n-dodecylazacycloheptan-2-one 
(Azone.RTM., Nelson), pyrrolidones, such as N-methylpyrrolidone, 
polyalkylene glycol laureates, e.g. polyethylene glycol monolaureate or 
N-2-hydroxyethylacetamide, and known vehicles and/or penetration enhancers 
such as aliphatic, cycloaliphatic and aromatic esters, N,N-di-lower alkyl 
sulfoxide, unsaturated oils, halogenated or nitrated aliphatic or 
cycloaliphatic hydrocarbons, salicylates, polyalkylene glycol silicates, 
and mixtures thereof. 
C.sub.2 -C.sub.4 alkanols, e.g. isopropanol or isobutanol and, especially, 
ethanol, are especially preferred as penetration enhancers. 
The amount of active ingredient, present in the therapeutic system, that is 
required to achieve a therapeutic effect depends on many factors: inter 
alia the minimum necessary dosage, the permeability of the membrane 
material, which determines the flux, and of the adhesive layer, and the 
period for which the plaster will be fixed to the skin or the mucous 
membranes. Since the active ingredient is to be released over a period of 
more than one day, there is, in fact, no upper limit to the maximum 
amounts of active ingredient present in the plaster. The minimum amount of 
active ingredient is determined by the requirement that sufficient, for 
example therapeutically effective, quantities of active ingredient must be 
present in the plaster to maintain the desired rate of release over the 
given period. 
Adjuncts can be added to the active ingredients. Suitable adjuncts are 
water, isotonic aqueous sodium chloride solution, dextrose in water or 
sodium chloride solution, liquid glyceryl triesters with low molecular 
weight fatty acids, lower alkanols, natural oils such as corn oil, 
groundnut oil, sesame oil, castor oil and condensation products thereof 
with ethylene oxide, and the like, hydrocarbons such as pharmaceutical 
grade mineral oil, silicones, emulsifiers such as monoglycerides or 
diglycerides of fatty acids, phospholipic acid derivatives such as 
lecithin or cephalin, polyalkylene glycols such as polyethylene glycol, 
aqueous phases to which a swelling agent such as sodium 
carboxymethylcellulose, sodium alginate, polyvinylpolypyrrolidone, etc. 
has been added and to which, in addition, dispersion agents or emulsifiers 
such as lecithin may be added, polyoxyethylene and the like. The adjuncts 
may, in addition, contain additives such as preservatives, stabilisers, 
wetting agents, emulsifiers, etc. 
If C.sub.2 -C.sub.4 alkanols such as ethanol are used as penetration 
enhancers, gelling agents such as gelatin or swelling agents such as 
cellulose ethers, e.g. hydroxypropylcellulose, are preferably added as 
adjuncts to the active ingredient formulation. 
The transdermal therapeutic systems of the invention are prepared in a 
manner known per se, for example as follows: the adhesive layer (3) is 
applied to a base layer (peel-off protective layer (4)), e.g. foil or 
film. The constituents of the active ingredient reservoir, for example 
membrane layer and active ingredient formulation, can also be applied to 
the base layer, and the impermeable backing foil can be placed on top. The 
plaster is then punched out of the master. The reservoir is optionally 
bonded to the backing foil with additional adhesive. The reservoir can 
also be hot-welded to the membrane or to the adhesive. In liquid-filled 
systems, the membrane layer is applied to the adhesive layer and the 
active ingredient formulation is placed on the membrane. 
The preparation processes are described in U.S. Pat. No. 3,797,494, 
preferably in DE-A-26 04 718 and DE-A-32 05 258 and in U.S. Pat. Nos. 
4,031,894 and 4,262,003 or in the publication by H. Asche in Schweiz. 
Rundschau Med. (Praxis) 74, No. 11,257-260 (1985), but the use according 
to the invention is not limited to the transdermal therapeutic systems 
described in those publications. The preferred transdermal therapeutic 
system described in DE-A 32 05 258 is a therapeutic system in the form of 
a plaster-like patch that releases the active ingredient transdermally, 
avoiding side-effects, and delivers it through the skin so that the active 
ingredient content of the plasma remains approximately constant. 
The daily dose of active ingredient for a patient weighing about 70 kg is 
estimated to be from approximately 50 .mu.g to approximately 150 .mu.g, 
depending on the potency of the particular active ingredient used.

The following Examples illustrate the invention described above, but they 
do not limit the scope thereof in any way. 
EXAMPLE 1 
Gel, containing as active ingredient, for example, 
3-amino-1-hydroxypropane-1,1-diphosphonic acid, having the following 
composition: 
______________________________________ 
active ingredient 1.0 g 
Carbopol 934 P 1.0 g 
glycerol 3.0 g 
isopropanol 25.0 g 
Softigen 767 0.2 g 
demin. water q.s. ad 
100.0 g 
______________________________________ 
EXAMPLE 2 
Solution, containing as active ingredient, for example, 
3-amino-1-hydroxypropane-1,1-diphosphonic acid, having the following 
composition: 
______________________________________ 
active ingredient 1.0 g 
isopropanol 60.0 g 
propylene glycol 10.0 g 
demin. water q.s. ad 
100.0 g 
______________________________________ 
EXAMPLE 3 
Microemulsion, containing as active ingredient, for example, 
3-amino-1-hydroxypropane-1,1-diphosphonic acid, having the following 
composition: 
______________________________________ 
active ingredient 1.0 g 
Labrasol* 32.9 g 
Plurolisostearate** 
13.2 g 
isostearyl isostearate 
41.9 g 
demin. water q.s. ad 
100.0 g 
______________________________________ 
EXAMPLE 4 
Cream (W/O), containing as active ingredient, for example, 
3-amino-1-hydroxypropane-1,1-diphosphonic acid, having the following 
composition: 
______________________________________ 
active ingredient 1.0 g 
cetyl alcohol 6.5 g 
cetyl palmitate 5.0 g 
stearyl alcohol 6.5 g 
petroleum jelly 5.0 g 
glycerol 12.5 g 
sodium laurylsulfate 1.0 g 
methylparaben 0.18 g 
propylparaben 0.05 g 
demin. water q.s. ad 100.0 g 
______________________________________ 
EXAMPLE 5 
Ointment (O/W emulsion), containing as active ingredient, for example, 
3-amino-1-hydroxypropane-1,1-diphosphonic acid, having the following 
composition: 
______________________________________ 
active ingredient 1.0 g 
cetyl alcohol 3.0 g 
glycerol 6.0 g 
methylparaben 0.18 g 
propylparaben 0.05 g 
Arlacel 60 0.6 g 
Tween 60 4.4 g 
stearic acid 9.0 g 
isopropyl palmitate 2.0 g 
paraffin oil, viscous 10.0 g 
demin. water q.s. ad 100.0 g 
______________________________________ 
EXAMPLE 6 
Anhydrous ointment, containing as active ingredient, for example, 
3-amino-1-hydroxypropane-1,1-diphosphonic acid, having the following 
composition: 
______________________________________ 
active ingredient 1.0 g 
petroleum jelly 35.0 g 
paraffin oil, viscous 
35.0 g 
Lanette N 30.0 g 
______________________________________ 
EXAMPLE 7 
Lotion, containing as active ingredient, for example, 
3-amino-1-hydroxypropane-1,1-diphosphonic acid, having the following 
composition: 
______________________________________ 
active ingredient 1.0 g 
cetyl alcohol 1.9 g 
glycerol 4.3 g 
sodium laurylsulfate 1.0 g 
methylparaben 0.18 g 
propylparaben 0.05 g 
paraffin oil, viscous 2.5 g 
demin. water q.s. ad 100.0 g 
______________________________________ 
EXAMPLE 8 
Foam, containing as active ingredient, for example, 
3-amino-1-hydroxypropane-1,1-diphosphonic acid, having the following 
composition: 
______________________________________ 
active ingredient 1.0 g 
cetyl alcohol 1.7 g 
glycerol 5.0 g 
methylparaben 0.18 g 
propylparaben 0.05 g 
isopropyl palmitate 2.0 g 
Arlacel 83 1.5 g 
Cetomacrogol 1000 2.4 g 
paraffin oil, viscous 1.0 g 
demin. water q.s. ad 100.0 g 
______________________________________ 
EXAMPLE 9 
Monolith adhesive transdermal system, containing as active ingredient, for 
example, 3-amino-1-hydroxypropane-1,1-diphosphonic acid 
______________________________________ 
Composition: 
______________________________________ 
polyisobutylene (PIB) 300 
5.0 g 
(Oppanol B1, BASF) 
PIB 35000 3.0 g 
(Oppanol B10, BASF) 
PIB 1200000 9.0 g 
(Oppanol B100, BASF) 
hydrogenated hydrocarbon resin 
43.0 g 
(Escorez 5320, Exxon) 
1-dodecylazacycloheptan-2-one 
20.0 g 
(Azone, Nelson Res., Irvine CA) 
active ingredient 20.0 g 
Total 100.0 g 
______________________________________ 
Preparation 
The above components are together dissolved in 150 g of special boiling 
point petroleum fraction 100-125 by rolling on a roller gear bed. The 
solution is applied to a polyester film (Hostaphan, Kalle) by means of a 
spreading device using a 300 .mu.m doctor blade, giving a coating of about 
75 g/m.sup.2. After drying (15 minutes at 60.degree. C.), a 
silicone-treated polyester film (thickness 75 .mu.m, Laufenberg) is 
applied as the peel-off film. The finished systems are punched out in 
sizes in the wanted form of from 5 to 30 cm.sup.2 using a punching tool. 
The complete systems are sealed individually in sachets of aluminised 
paper. 
EXAMPLE 10 
Matrix transdermal system with adhesive coating at the edge only, 
containing as active ingredient, for example, 
3-amino-1-hydroxypropane-1,1-diphosphonic acid 
______________________________________ 
Composition: 
______________________________________ 
active ingredient 10.0 g 
hydroxypropylcellulose 
1.0 g 
(Klucel HF) 
polyethylene glycol monolaurate 
5.0 g 
demineralised water 84.0 g 
______________________________________ 
Preparation 
The constituents are dissolved in water, with stirring. A polyester film 
(Hostaphan, Kalle) is coated with silicone adhesive (Silicon Adhesive 355, 
Dow Corning, 55% solid dissolved in special boiling point petroleum 
fraction 100-120) using a spreading device and a 150 .mu.m doctor blade, 
and is then dried (15 minutes, 60.degree. C.). 
Discs having a diameter of 2.5 cm (corresponding to a surface area of 5 
cm.sup.2) are punched out of a non-woven fabric of viscose, polyamide and 
polypropylene (Vilmed type M 1539, Freudenberg) having a thickness of 
about 2.7 mm. After these discs have been bonded to the coated side of the 
polyester film, the above solution is metered onto the fabric discs in an 
amount of 450 mg per system by means of a micro-metering system. The discs 
are then covered with a silicone-treated polyester film. The individual 
systems are punched out using a tool having a diameter of 5 cm, care being 
taken to ensure that the fabric disc charged with the active ingredient 
solution is located in the centre of the system. The finished systems are 
packed individually as described in Example 9. 
EXAMPLE 11 
Membrane transdermal system, closed by means of a seal seam at the edge and 
containing as active ingredient, for example, 
3-amino-1-hydroxypropane-1,1-diphosphonic acid 
______________________________________ 
Composition: 
______________________________________ 
active ingredient 10.0 g 
hydroxypropylcellulose 
1.0 g 
(Klucel HF) 
polyethylene glycol monolaurate 
5.0 g 
demineralised water 84.0 g 
______________________________________ 
Preparation 
The adhesive layer (silicone adhesive, see Example 10 is applied to a 
fluorine-treated polyester film by means of a screen printing process and 
dried. Application of a heatsealable non-woven fabric of cellulose and 
polyester (Sontara Vlies 8412, DuPont) to form a laminate consisting of 
the peel-off film, the adhesive layer and the fabric. The solution is 
applied by means of a micro-metering system to the above laminate (fabric 
on top) in an amount of 300 mg for a 5 cm.sup.2 system, a cover film of a 
heat-sealable polyester/ethyl vinyl acetate composite foil (Scotchpack 
1220, 3M) is drawn over the laminate (ethyl vinyl acetate side towards the 
solution or fabric), and the system is sealed using a suitable 
heat-sealing tool (inside diameter 2.5 cm, outside diameter 3.5 cm; 
sealing conditions: 0.5 sec, 170.degree. C.) and then punched out and 
packed individually as described in Example 9. 
EXAMPLE 12 
System analogous to Example 11 
______________________________________ 
Composition: 
______________________________________ 
active ingredient 10.0 g 
hydroxypropylcellulose 
3.0 g 
(Klucel HF) 
1-dodecylazacycloheptan-2-one 
5.0 g 
(Azone, Nelson Res., Irvine CA) 
ethanol 50% 84.0 g 
______________________________________ 
Preparation 
The constituents are dissolved by stirring. Preparation and packing of the 
systems analogously to Example 11. 
In a manner analogous to that described in any one of the above Examples, 
it is possible to incorporate into the base layers other active 
ingredients of formula I, for example selected from 
3-amino-1-hydroxypropane-1,1-diphosphonic acid, 
3-dimethylamino-1-hydroxypropane-1,1-diphosphonic acid and 
3-(N-methyl-N-n-propylamino)-1-hydroxypropane-1,1-diphosphonic acid, or a 
pharmaceutically acceptable salt thereof. 
EXAMPLE 13 
Matrix transdermal system consisting of two layers and containing as active 
ingredient, for example, 3-amino-1-hydroxypropane-1,1-diphosphonic acid 
Layer 1: 
Identical to the matrix of Example 9, the matrix being applied by means of 
a 150-250 .mu.m doctor blade (rate of application 30-60 g/m.sup.2) to a 
silicone-treated polyester film (for specifications see Example 9) and 
covered with a silicone-treated paper foil (temporary covering). 
Layer 2: 
A suitable amount of flux enhancer (e.g. 5-25% 
1-dodecylazacycloheptan-2-one, Azone) is dissolved in the adhesive 
compound specified in Example 9 (dissolved in benzine) or in another 
suitable adhesive (e.g. copolymer based on acrylate esters and vinyl 
acetate, Durotak 280-2516, National Starch & Chemical BV, Zutphen/NL) 
without the active ingredient. The adhesive is laminated by means of a 
150-300 .mu.m doctor blade and the intermediate layer is removed 
continously and discarded. Further processing as in Example 9. 
EXAMPLE 14 
Matrix transdermal system consisting of two layers and containing as active 
ingredient, for example, 3-amino-1-hydroxypropane-1,1-diphosphonic acid 
Layer 1: 
As Example 13. 
Layer 2: 
A suitable amount of flux enhancer is introduced into a customary hot-melt 
adhesive (e.g. acrylate adhesive Durotak 089-1526). A polyester film is 
applied with an aluminium foil by means of a hot-melt applicator at about 
140.degree.-160.degree. C. The further processing of layers 1 and 2 is 
carried out as in Example 13. 
EXAMPLE 15 
Reservoir-type membrane transdermal system, containing as active 
ingredient, for example, 3-amino-1-hydroxypropane-1,1-diphosphonic acid 
Composition analogous to Example 11. 
Onto the membrane side of a laminate consisting of peel-off film 
(polyester, silicone-treated on one side, thickness about 75 .mu.m;) 
adhesive (e.g. suitable mixture of polyisobutylene 1200000, 
polyisobutylene 35000 and polyisobutylene 1200; rate of application 40-60 
g/m.sup.2); regulation membrane (ethyl vinyl acetate containing 6-25% 
vinyl acetate, preferably 12-18%, thickness about 50 .mu.m) an amount of 
about 100-600 mg, depending on the system area provided, of the reservoir 
formulation according to Example 18 is metered on a suitable apparatus. 
Alternatively, the active ingredient, or a portion thereof, can be 
dissolved or suspended in the adhesive layer. In that case, the active 
ingredient contained in the adhesive layer would act as the initial dose 
and that in the reservoir as the maintenance dose. 
In a manner analogous to that described in any one of the above Examples, 
it is possible to incorporate into the base layers other active 
ingredients of formula I, for example selected from 
3-amino-1-hydroxypropane-1,1-diphosphonic acid, 
3-dimethylamino-1-hydroxypropane-1,1-diphosphonic acid and 
3-(N-methyl-N-n-propylamino)-1-hydroxypropane-1,1-diphosphonic acid, or a 
pharmaceutically acceptable salt thereof.