Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
1999-04-01
2002-12-24
Travers, Russell (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C424S400000, C514S212080, C514S316000, C514S376000, C514S378000, C514S424000
Reexamination Certificate
active
06497886
ABSTRACT:
The present invention relates to 1,3-bis-(N-lactamyl)propanes and their use as solvents in pharmaceutical and cosmetic compositions.
A priority requirement in the development of an optimal administration form for a drug is that the bioavailability be good. As a rule, the most favorable conditions for this are provided by solutions of the active ingredient used, irrespective of whether a product for injection, a liquid oral drug form or, for example, a soft gelatin capsule preparation is concerned.
However, the solubility of many drugs in water is too low for them to be administered parenterally in the form of an aqueous solution, for example. Recourse is therefore frequently had to other solvents, for example organic, aqueous/organic or oily solvents.
It is important in the selection of suitable solvents to ensure that certain requirements are met. The solvent which is used must not be toxic, nor must it increase the toxicity of the active ingredient dissolved therein. It is, of course, necessary for the solvent to be compatible with the active ingredient, and it must not lead to inactivation or decomposition. Furthermore, the solvent must not induce irritation, sensitization or an allergic reaction either, and it should also be suitable for heat sterilization. For parenteral purposes, the viscosity should be low enough for injection with a relatively thin needle to be possible.
In addition, miscibility with other solvents, such as physiological saline or an infusion solution for preparing a product for injection or the oily vehicle in a soft gelatin capsule preparation, is important.
Besides water, well-known solvents are, for example, low molecular weight polyethylene glycols, 1,2-propylene glycol, ethanol, glycerol, benzyl alcohol, dimethylacetamide or neutral oils such as paraffin, castor oil or mixtures of triglycerides of saturated vegetable fatty acids.
However, the properties of the abovementioned solvents are not always satisfactory. Thus, the miscibility with other solvents may be limited, or the volume of solvents required to dissolve the active ingredient is so large that physiological tolerability is no longer ensured. For example, the widely used propylene glycol is immiscible with fixed oils. Benzyl alcohol has the disadvantage that its solubility in water is only 4%. Although glycerol is miscible with water, it is not soluble in fixed oils. In addition, the maximum glycerol concentration which can be used is limited to about 5% for tolerability reasons. Dimethyl-acetamide has very good dissolving properties but the tolerability is relatively poor so that use in humans does not appear acceptable.
The use of pyrrolidone derivatives such as 2-pyrrolidone, N-methylpyrrolidone and hydroxyethylpyrrolidone as solvents or cosolvents is known.
For example, EP-A 271 374 describes aqueous antibiotics compositions for veterinary use in which a tetracycline is dissolved in N-(hydroxyethyl)-2-pyrrolidone.
EP-A 626 171 discloses injection solutions for intravenous or intramuscular administration of oxytetracycline or doxycycline, the solvent phase being formed by N-methylpyrrolidone and/or 2-pyrrolidone.
A mixture of 2-pyrrolidone and N-methyl-2-pyrrolidone comprises the pharmaceutical vehicle of a composition for the cosmetic and therapeutic treatment of human beings and animals which is described in DE 26 15 140.
Although the formulations based on pyrrolidone derivatives described above have good solubility properties, they do not meet the strict requirements to be met by drugs, because the physiological tolerability is unsatisfactory. Furthermore, the absorption times are relatively long, and the serum levels achieved therewith are in need of improvement.
Nor do the bis- or poly-(N-pyrrolidonyl)alkanes described in the prior art sufficiently comply with the strict requirements to be met by pharmaceutical solvents. Thus, the asymmetric polypyrrolidonyl compounds of U.S. Pat. No. 3,989,815 are not at all intended for use as solvents; on the contrary they are used only as dispersants. The bis(N-pyrrolidonyl)alkanes described in U.S. Pat. No. 5,326,880 as vehicles for pharmaceutical compositions administered topically dissolve many active ingredients to only a limited extent. They are therefore unsuitable for pharmaceutical preparations where good solubility of the active ingredient matters.
It is an object of the present invention to provide solvents for pharmaceutical preparations which, besides an excellent dissolving capacity for the active ingredient used, also provide excellent miscibility with other solvents and good physiological tolerability.
We have found that this object is achieved by certain, asymmetric 1,3-bis-(N-lactamyl)propanes which are excellent solvents for a large number of active ingredients of low solubility in water and, furthermore, can be used universally because they are miscible in any ratio with other conventional pharmaceutical solvents. The compounds according to the invention are chemically inert and show high physiological tolerability.
The present invention relates to the use of at least one 1,3-bis(N-lactamyl)propane of the formula I
where R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are, independently of one another, hydrogen, alkyl, cycloalkyl, aryl or aralkyl, and at least one of these radicals is not hydrogen, (NLac) and (NLac′) are identical or different and are N-lactamyl radicals, as solvents in pharmaceutical or cosmetic compositions.
The term “alkyl” comprises straight-chain or branched alkyl groups, preferably C
1
-C
10
-alkyl, in particular C
1
-C
6
-alkyl and, particularly preferably, C
1
-C
3
-alkyl, such as methyl, ethyl, n- and i-propyl, n-, i- or t-butyl, n-pentyl, neopentyl or n-hexyl, etc.
“Cycloalkyl” comprises cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and polycyclic radicals such as norbornyl, camphyl, pinanyl or decahydronaphthyl, it being possible for both the mono- and the polycyclic radicals to be substituted by one or more C
1
-C
4
-alkyl groups.
The term “aryl” comprises aromatic radicals, preferably naphthyl and, in particular, phenyl.
“Aralkyl” means aryl groups which are connected via a C
1
-C
4
-alkylene unit to the basic framework. “Aralkyl” is preferably benzyl.
“Alkylene” means linear or branched divalent alkyl radicals, preferably C
1
-C
6
-alkylene and, in particular, C
1
-C
4
-alkylene, such as methylene, 1,1- and 1,2-ethylene, 1,1-, 1,2-, 1,3- and 2,2-propylene, 2-methyl-1,1-propylene etc.
The term “N-lactamyl” represents N-substituted mono- or polycyclic lactams which may be substituted by C
1
-C
4
-alkyl groups, C
1
-C
4
-alkoxy groups or halogen, and/or be fused to aromatic systems, and/or contain further hetero atoms, preferably nitrogen or oxygen, in the lactam ring. Particularly preferred N-lactamyl radicals are derived from pyrrolidone, piperidone, &dgr;- or &egr;-caproactam, 4-oxazolidinone or tetrahydro-1,4-oxazin-3-one and, in particular, from pyrrolidone.
In 1,3-bis-(N-lactamyl)-propanes according to the invention which are preferably used as solvents in pharmaceutical compositions, at least one of the radicals R
1
, R
2
, R
3
, R
4
, R
5
and R
6
is alkyl, while the remainder of these radicals are hydrogen.
Particularly suitable compounds of the formula I are those where only one of R
1
, R
2
, R
3
, R
4
1
R
5
and R
6
is not hydrogen, with R
1
being preferred in this case and being, in particular, alkyl.
In a particular embodiment, 1,3-bis-(N-lactamyl)butanes are used, i.e. compounds of the formula I where R
1
is methyl.
The lactamyl groups (NLac) and (NLac′) in formula I may be identical or different, but they are preferably identical.
A particular class of compounds for use as solvents in pharmaceutical preparations are those compounds of the type described above which have no center of symmetry. Compounds of this type result when the substituted propylene unit is asymmetric per se and/or the lactamyl radicals NLac and NLac′ are different. Preferred compounds are those where the propylene unit is asymmetric and the
Breitenbach Jörg
Kratz Detlef
Lang Siegfried
BASF - Aktiengesellschaft
Berman Alysia
Keil & Weinkauf
Travers Russell
LandOfFree
1,3-bis-(N-lactamyl) propane and the pharmaceutical and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 1,3-bis-(N-lactamyl) propane and the pharmaceutical and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 1,3-bis-(N-lactamyl) propane and the pharmaceutical and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2918356