Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-08-18
2001-06-12
Carr, Deborah D. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S546000, C514S549000, C514S552000, C554S110000, C554S223000, C554S224000, C554S227000
Reexamination Certificate
active
06245811
ABSTRACT:
FIELD
The specification relates to the presentation of bioactives, in which term we include a drug, essential nutrient or any other compound to be administered to the human or animal body in therapy or maintenance of health.
In particular, the specification relates to the presentation of such bioactives in a form in which they are lipophilic so that they can pass lipid barriers in the body readily, or to the presentation of two bioactives in the same molecule (where at least one of the bioactives is a fatty acid or fatty alcohol), or to the presentation of bioactives in a form which serves both aims and/or the aims of ready synthesis of such compounds without a chiral centre. From a drug regulatory viewpoint it is a great advantage to have two bioactives presented as a single molecule rather than as two separate entities. There may also be advantages in presenting known bioactives in novel ways. Those advantages include increased lipophilicity, the additive effects of two bioactives which are not normally presented together, and the sometimes synergistic effects of such bioactives.
The invention concerns the linking of bioactives (where at least one bioactive is an unsaturated fatty acid) through certain link molecules, specifically geminal dioxo and geminal amino oxo moieties considered in detail later herein, to yield geminal tripartate drugs, the synthesis of a range of compounds and their use in therapy and/or the maintenance of health.
Geminal Tripartate Mutual Prodrug Concept
Frequently simple ester mutual prodrugs of bioactives are not sufficiently labile in vivo to ensure a sufficiently high rate of conversion of the prodrug to the two desired bioactives. One reason is that for these simple ester mutual prodrugs the ester bond may be resistant to enzymatic attack for either steric or electronic reasons. One way to overcome this problem is to use the geminal tripartate mutual prodrug approach whereby the bioactives are linked via either a geminal dioxo or geminal amino oxo linkage. For example, two bioactive carboxylic acids may be linked as a diester via a geminal dioxo linkage. As outlined in Scheme 1, the first step in the hydrolysis of the general dioxo diester is enzymatic cleavage, either via enzymatic pathway 1 or pathway 2, of one of the mutual bioactive ester bonds with subsequent formation of a highly unstable hydroxymethyl ester which rapidly dissociates in vivo to the other bioactive and an aldehyde. With either pathway both bioactives are generated after only one enzymatic hydrolysis reaction.
A further advantage is the opportunity for simultaneously or approximately simultaneous delivery of two different bioactives. For example, a bioactive alcohol may be coupled to an unsaturated fatty acid as an ester/ether via a geminal dioxo linkage. As outlined in Scheme 2, ester hydrolysis leads to formation of the unsaturated fatty acid and an unstable hemiacetal derivative of the bioactive alcohol which rapidly splits into the free bioactive and an aldehyde.
Published Material
The concepts of linking unsaturated fatty acids to bioactives using the geminal dioxo or geminal amino oxo diester approach such as discussed above has received no great attention in the published patent and general literature with the exception of Terumo K.K. in EPA-0 222 155 which link 5-fluoro uracil to alpha linolenic acid, dihomo gamma linolenic acid, or eicosapentaenoic acid through a group —CH(R)-O— where R=methyl etc as, inter alia, anti-cancer agents.
Lipid Barriers
Many drugs act at the cell membrane surface by combining with cell surface receptors, or alternatively are taken into cells by specific transport systems. However, there are many drugs which, while they act within cells by modifying one of many different functions such as nucleic acid functions, the actions of intracellular enzymes, or the behaviour of systems like the lysosomes or the microtubules, are not able to penetrate cells effectively. There may be no receptors and transport systems with which they can link, or these systems may transport the drug into the cell at a less then optimum rate. Equally drugs may penetrate intracellular membranes such as mitochondrial and nuclear membranes at less than optimum rates.
There are other barriers to drug movements which are recognised as important. One of particular significance is the blood-brain barrier, which has many of the characteristics of the cell membrane. There are many drugs which have difficulty in reaching adequate concentrations in the brain because of this barrier. Another is the skin: until a few years ago drugs were applied to the skin only if their purpose was to act on the skin. However, it has been recognised that the skin can be an appropriate route for getting drugs with systemic actions into the body, and as a result more and more compounds are being administered by variations of patch technology.
All three types of barriers, the cell membrane and intracellular membranes, the blood-brain barrier and the skin have an important feature in common, they are substantially composed of lipids. What this means is that they are impermeable to primarily water-soluble drugs unless these drugs can be carried across the membrane by a receptor or transport system. In contrast, lipophilic substances are able to cross the barriers more readily without the need for any specific receptor or transport system.
Classes of Bioactives Requiring Passage Through Lipid Barriers
Drugs whose pharmacokinetic behaviour may be improved by increased lipophilicity, listed by route of entry, are as follows:
1. Cell entry: drugs particularly likely to benefit are those that act primarily intracellularly. These include:
a. All anti-inflammatory drugs, whether steroid or non-steroid
b. All cytotoxic drugs used in the management of cancer;
c. All antiviral drugs;
d. All other drugs that have to enter cells in order to achieve optimum effects, in particular drugs which act on DNA or RNA, or on enzymes located intracellularly, or on second messenger systems, or on microtubules, mitochondria, lysosomes, or any other intracellular organelle.
e. Steroid hormones and other hormones that act intracellularly, such as oestrogens, progestins, androgenic hormones and dehydroepiandrosterone.
2. Blood-brain barrier: all drugs acting on the central nervous system will have their transport improved by this technique. This includes all drugs used in psychiatry, all drugs used in cerebral infections with any organism or in cerebral cancer and all other drugs acting on nerve cells such as anti-epileptic drugs and others acting on neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's chorea and others.
3. Skin: as with the blood-brain barrier, all drugs that may be required to penetrate the skin to achieve a systemic effect will benefit from their conversion to a fatty acid derivative.
For example, the approach discussed is applicable to amino acids. Of particular interest are those which seem to play roles in the regulation of cell function as well as acting as components of proteins. Examples include tryptophan (a precursor of 5-hydroxytryptamine [5-HT], a key regular of nerve and muscle function), phenylalanine (a precursor of catecholamines) and arginine (a regulator of the synthesis of nitric oxide which also plays important roles in controlling cellular activities).
Properties Conferred Generally
Generally the compounds proposed herein have many advantages in addition to their lipophilicity. Two moieties of a given fatty acid or even a single moiety may be delivered, in a form which is readily incorporated into the body as an oral, parenteral or topical formation; which is very well tolerated with none of the side effects associated, for example, with free fatty acids; which is not too stable to be properly utilised.
When two different fatty acids are to be delivered, the advantages are as before plus the ability to administer simultaneously two materials with different biological actions in a single molecule. This avoids the regulatory p
Horrobin David Frederick
Knowles Philip
Manku Mehar
McMordie Austin
Pitt Andrea
Carr Deborah D.
Gray, Esq. Bruce D.
Kilpatrick & Stockton LLP
Scotia Holdings PLC
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