CA2082310A1 - Chiral drugs - Google Patents
Chiral drugsInfo
- Publication number
- CA2082310A1 CA2082310A1 CA 2082310 CA2082310A CA2082310A1 CA 2082310 A1 CA2082310 A1 CA 2082310A1 CA 2082310 CA2082310 CA 2082310 CA 2082310 A CA2082310 A CA 2082310A CA 2082310 A1 CA2082310 A1 CA 2082310A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- set forth
- chiral drug
- ratio
- enantiomeric
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
Abstract
"CHIRAL DRUGS"
ABSTRACT OF THE DISCLOSURE
Chiral drug compounds are provided wherein the enantiomeric ratios are pre-selected so as to provide the desired rate and distribution of the compound into a human. More specifically, the correct enantiomeric ratio of the compound is determined by means of its partition coefficient.
ABSTRACT OF THE DISCLOSURE
Chiral drug compounds are provided wherein the enantiomeric ratios are pre-selected so as to provide the desired rate and distribution of the compound into a human. More specifically, the correct enantiomeric ratio of the compound is determined by means of its partition coefficient.
Description
FIELD OF THE INVENTION
The present invention relates to chlral drugs and to methods of use therefor. More speciflcally,the chiral drugs are utllized in the form of their eutectic compounds.
BACKGROUND OF_THE INVEN~ION
There are at present many known chiral drugs. Typically, such chiral drugs have heretofore, been synthesized and used as the racemlc compound or mixture.
It has been determined that often the enantiomers of a racemic drug will differ in their pharmacodynamic and/or pharmacokinetic properties from one another as a consequence of their stereoselective interaction with optically active biological macromolecules.
In a paper entitled "Enantloselectlve Aspects of Drug Action and Disposition: Therapeutic Pitfalls" by F. Jamali et al. J. Pharm Sci. 78: 695-715, 1989 certain aspects concerning properties of enantiomers were discussed in further detail.
Recent studies have focused on the separation of enantiomers with the intention of determining the single isomer having the most desired pharmacodynamic or pharmacokinetia properties. The drug is then produced as a single active moiety. For example one of the more popular drugs, ibuprofen has been patented as a single isomer and disclosed for example in U.S. Patent number 4,851,444 issued to A. Sunshine et al., and U.S. Patent number 4,877,620 issued to D.
Loew et al. It had been believed prior to these disclosures that the stereochemically pure components were merely a refined form of their respective racemates, whilst the inactive, or less active enantiomer was considered to be an isomeric "ballast".
It is also known that the physicochemical properties of many chiral compounds are dependent upon the relative proportions of one enantiomer to another, namely the S:R ratio or conversely the R:S
ratio.
Furthermore, it has recently been learned that when the two enantiomers are present in a specific ratio, what is termed a 23~0 chlral eutectic compound ls formed. A eutectic compound 18 one which is at its least thermodynamically stable state. In such eutectlc compounds, the absorptlon of the drug ls enhanced and lts dlstrlbutlon in the body altered. Stated otherwlse, the physlochemlcal properties of these eutectlc compounds differ from both the enantiomers and the racemate.
For example, it has been shown ln "Ibuprofen: A Racemate Mlxture or Compound" S. K. Dwivedi et al. Pharm. Res., 7(Suppl):
140,1990,that for ibuprofen, the melting point of the racemate ls 75C whereas for the slngle isomers it is 49C. However, at a speciflc ratio namely S:R 83%:17~ the melting point ls 44C. Thls comprises the eutectlc state for thls particular drug.
Additionally, not only has it been determlned that the meltlng point ~8 lowered, but enhancement of the saturable solubility takes place. ~;
SUMMARY OF THE_INVENTION
The present invention is founded on the discovery that there exists a correlative relatlonshlp between the partitlon coefficient, the melting point, and the enantiomerlc ratlo of certain chiral drug compounds.
From a pharmokinetlc vlewpolnt, two lnter-related physicochemlcal properties are of importance, namely the dissolution rate and the partition coefficient. The partition coefflcient determines the rate of absorption and extent of the di#tribution of the compounds into the body. Thus by determinatlon of the partition coefficient, derivation of the correct enantiomerlc ratlo to produce the compound which will give the desired rate of absorption and distributlon lnto a human $s posslble. More speclflcally, when the partition coefficlent is at its lowest value at the eutectic point, then the enantiomeric ratio produaing the compound gives the optimum rate of absorptlon ~u~
dlstribution rate. It wlll be evident, therefore, that for the compounds claimed in the instant invention the partition coefflclent and melting polnt wlll be at there lowest value colncldentally wlth the eutectic state.
As a result of practlslng the present lnvention lt will be evldent to one skilled ln the art that it ls posslble not only to determlne the enantlomerlc ratlo whlch wlll accelerate dissolution of the drug in the body, but also to determlne a ratio at which dissolutlon may be slowed down.
In accordance with the present lnventlon there 18 provided a chiral drug adapted for introduction into a human sub~ect which comprises a compound formed of two enantlomers ln a ratio such as to exhibit a predetermlned partition coefflcient whereby the absorptlon and distrlbutlon sald drug takes place at a preselected rate.
In a second broad aspect a chiral drug adapted for introduction lnto a human ls provided whlch comprises a compound formed of two enantlomers in a speciflc ratlo so as to provide a eutetic compound, the ratio of said enantiomers havlng been p~edetermined by selecting a partition coefficient value indicative of the composition of said eutectic compound, said eutetic compound being fun¢tional to be absorbed and distributed into the human at ~ p r ~~ . : .
a~grese~ected rate.
Thirdly~the invention provides a method for controlling the >~
dissolution of a chiral drug into a human sub~ect which comprises determining the partition coefficient whereby the absorption and ~
distrlbutlon of said drug takes place at a preselected rate into a ~;-human; from the partition coefficient determination, extrapolating to obtain the enantiomeric ratio required: and administering a compound formed of this enantiomeric ratio composition to said human in a sultable dosage form.
DESCRIPTION OF THE DRAWINGS
Figure 1 is a plot of melting point versus the % of S enantiomers for ketoprofen.
Flgure 2 ls a plot of meltlng polnt versus the ~ of S enantiomers for etodolac.
' ~08231~
Figure 3 is a plot of meltlng polnt versus the % of S enantlomers for propranolol.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The chiral drugs applicable to the present lnventlon would be those havlng one or more single asymmetric carbon atoms in their structure.
These chiral drugs usefully could be selected from non-steroidal anti-inflammatory drugs, hypotensive B-blockers, calcium channel blockers, antiarryhyth~ics and the like.
More specifically, such drugs could include propranolol, ibuprofen, etodolac or ketoprofen.
The partltion coefficient yielding the desired rate and extent of distributlon may be determlned by conventlonal methods known to one skllled ln the art.
The specific enantiomerlc ratio required is determined by progresslvely adding one enantiomer to another and measuring the melting point of the mixed and fused powder.
The compounds of this invention are useful ln the treatment of lnflammatory conditlons and hypotension. Humans suffering from these allments may be treated with the appropriate type of drug by administering to the patient a pharmaceutically effective amount of one or more of the present compounds optionally, but preferably in the presence of a pharmaceutically acceptable carrler or diluent.
There may also be lncluded a pharmaceutlcally compatible binding agent, and/or ad~uvant materials. The actlve materials can also be mixed with other active materials which do not impalr the desired action and/or supplement the desired action. The above materials according to the present invention can be administered by any route, for example, orally, parentally, intravenously, intradermally, sub-cutaneously or topically in solid or liquid form.
The solid form preparation includes powders, tablet, dispensable granules, capsules, cachets, suppositories and 2~82310 olntments. A solld carrler can be one or more substances whlch may also act as dlluents, flavourlng agents, solublllzers, lubrlcants, suspendlng agents, blnders, or tablet dlslntegrating agent~, namely magnesium carbonate, magneslum stearate, talc, su~ar, lactose, pectln, dextrln, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low meltlng wax, cocoa butter and the llke.
. . ...
¦ Llquld form preparatlons lnclude solutions, suspensions and ¦ emulsions. The liquid preparation for parenteral inJection may be i~ water or water propylene glycol solution or water polyethylene glycol and the like to be acceptable to biological systems (isotoniclty, pH etc.). Aqueous solutions sultable for oral use can be prepared by dlssolving the active component in water and adding suitable colorant, flavours, stabilizing and thickening agents as desired. A~ueous suspensions sultable for oral use can be made by dispersing the flnely divlded active component in water with vlscous material, l.e. natural or synthetic gum, resins, methyl cellulose, sodium carboxymethyl cellulose and other well known suspending agents.
The quantitles of active compound ln a unit dose of preparation may be varled to the particular application and the potency of the active lngredient. Determination of the proper dosage for a partlcular situation is within the skill of art.
~, EXPERIMENTAL
The following results are illustrative of the lnvention but are not to be construed as limiting the scope thereof in any way.
Preparatlon of Compounds with Various Enantiomeric Ratios Various proportions of S and R enantiomers were accurately weighed. The resulting mixtures were then either dissolved in an appropriate solvent to give a solution of the compound, or the powder was first melted and then solidified to produce a solid ~`` 2082310 compound.
Melting Polnt Measurement Meltlng polnts were measured after the two enantlomers were melted and then solidified. This permit8 a thorough amalgamation of the two enantiomers.
Partition Coefflcients Measurement Solutlons containln~ 20 mg% of stereochemically pure (>95%) S-ibuprofen, racemic and eutectic (82%S plus 18% R) were prepared in pH 7.4 phosphate buffer. To 1 mL of the above solution was added lmL of octanol ln lOmL screw-cap test tubes. The tubes were sealed and shaken for 7 days at room temperature. The ibuprofen content of both aqueous and octanol layers were measured on the seventh day. The partltion coefflcient was calculated as the ratio of the concentratlon found in the octanol phase over that found in the aqueous layer.
Bulk Dissolution Method Into a ~acketed flask was transferred 600 mL of pH 1.5 phosphate buffer. Thirty mg racemate, S-ibuprofen, or the eutectlc compound were placed in a rotating basket. The basket was immersed in the buffer. The contents were stirred constantly at 600 r.p.m.
(equivalent to 159 r.p.m. USP model). Using a pipet equipped with a filter, samples were taken at 0, 20, 40, 60 and 80 minutes after addltlon of the compounds and analyzed for lbuprofen.
AssaY of IbuDrofen The assay was made accord$ng to the methods described earlier in the following: Liquid Chromatographic Assay of Ibuprofen Enantiomers in Plasma', R. Mehvar, F. Jamali ~ F. M. Pasutto. Clin.
Chem. 34.493-496, 1988.
: - `
i- 20~23~0 Table 1 Some Physlcochemlcal Properties of Ibuprofen Powders wlth Dlfferent S:R Ratlo.
Compound M.P.Solubllltyl po/~2 Dlssolution3 ~-C g/mL tsos S4 49 300 1.83 22 (97.5+23.o) Racemate 75 156 3.00 44 (61.5+25.8)6 - ~
Eutectlc' 43 320 1.25 16 (98.2+21.9)6 ~-1. Solublllty @ pH 1.5 @ 35C.
2. Partitlon coefflcient (octanol/water pH, 7.4) at room temperature.
The present invention relates to chlral drugs and to methods of use therefor. More speciflcally,the chiral drugs are utllized in the form of their eutectic compounds.
BACKGROUND OF_THE INVEN~ION
There are at present many known chiral drugs. Typically, such chiral drugs have heretofore, been synthesized and used as the racemlc compound or mixture.
It has been determined that often the enantiomers of a racemic drug will differ in their pharmacodynamic and/or pharmacokinetic properties from one another as a consequence of their stereoselective interaction with optically active biological macromolecules.
In a paper entitled "Enantloselectlve Aspects of Drug Action and Disposition: Therapeutic Pitfalls" by F. Jamali et al. J. Pharm Sci. 78: 695-715, 1989 certain aspects concerning properties of enantiomers were discussed in further detail.
Recent studies have focused on the separation of enantiomers with the intention of determining the single isomer having the most desired pharmacodynamic or pharmacokinetia properties. The drug is then produced as a single active moiety. For example one of the more popular drugs, ibuprofen has been patented as a single isomer and disclosed for example in U.S. Patent number 4,851,444 issued to A. Sunshine et al., and U.S. Patent number 4,877,620 issued to D.
Loew et al. It had been believed prior to these disclosures that the stereochemically pure components were merely a refined form of their respective racemates, whilst the inactive, or less active enantiomer was considered to be an isomeric "ballast".
It is also known that the physicochemical properties of many chiral compounds are dependent upon the relative proportions of one enantiomer to another, namely the S:R ratio or conversely the R:S
ratio.
Furthermore, it has recently been learned that when the two enantiomers are present in a specific ratio, what is termed a 23~0 chlral eutectic compound ls formed. A eutectic compound 18 one which is at its least thermodynamically stable state. In such eutectlc compounds, the absorptlon of the drug ls enhanced and lts dlstrlbutlon in the body altered. Stated otherwlse, the physlochemlcal properties of these eutectlc compounds differ from both the enantiomers and the racemate.
For example, it has been shown ln "Ibuprofen: A Racemate Mlxture or Compound" S. K. Dwivedi et al. Pharm. Res., 7(Suppl):
140,1990,that for ibuprofen, the melting point of the racemate ls 75C whereas for the slngle isomers it is 49C. However, at a speciflc ratio namely S:R 83%:17~ the melting point ls 44C. Thls comprises the eutectlc state for thls particular drug.
Additionally, not only has it been determlned that the meltlng point ~8 lowered, but enhancement of the saturable solubility takes place. ~;
SUMMARY OF THE_INVENTION
The present invention is founded on the discovery that there exists a correlative relatlonshlp between the partitlon coefficient, the melting point, and the enantiomerlc ratlo of certain chiral drug compounds.
From a pharmokinetlc vlewpolnt, two lnter-related physicochemlcal properties are of importance, namely the dissolution rate and the partition coefficient. The partition coefflcient determines the rate of absorption and extent of the di#tribution of the compounds into the body. Thus by determinatlon of the partition coefficient, derivation of the correct enantiomerlc ratlo to produce the compound which will give the desired rate of absorption and distributlon lnto a human $s posslble. More speclflcally, when the partition coefficlent is at its lowest value at the eutectic point, then the enantiomeric ratio produaing the compound gives the optimum rate of absorptlon ~u~
dlstribution rate. It wlll be evident, therefore, that for the compounds claimed in the instant invention the partition coefflclent and melting polnt wlll be at there lowest value colncldentally wlth the eutectic state.
As a result of practlslng the present lnvention lt will be evldent to one skilled ln the art that it ls posslble not only to determlne the enantlomerlc ratlo whlch wlll accelerate dissolution of the drug in the body, but also to determlne a ratio at which dissolutlon may be slowed down.
In accordance with the present lnventlon there 18 provided a chiral drug adapted for introduction into a human sub~ect which comprises a compound formed of two enantlomers ln a ratio such as to exhibit a predetermlned partition coefflcient whereby the absorptlon and distrlbutlon sald drug takes place at a preselected rate.
In a second broad aspect a chiral drug adapted for introduction lnto a human ls provided whlch comprises a compound formed of two enantlomers in a speciflc ratlo so as to provide a eutetic compound, the ratio of said enantiomers havlng been p~edetermined by selecting a partition coefficient value indicative of the composition of said eutectic compound, said eutetic compound being fun¢tional to be absorbed and distributed into the human at ~ p r ~~ . : .
a~grese~ected rate.
Thirdly~the invention provides a method for controlling the >~
dissolution of a chiral drug into a human sub~ect which comprises determining the partition coefficient whereby the absorption and ~
distrlbutlon of said drug takes place at a preselected rate into a ~;-human; from the partition coefficient determination, extrapolating to obtain the enantiomeric ratio required: and administering a compound formed of this enantiomeric ratio composition to said human in a sultable dosage form.
DESCRIPTION OF THE DRAWINGS
Figure 1 is a plot of melting point versus the % of S enantiomers for ketoprofen.
Flgure 2 ls a plot of meltlng polnt versus the ~ of S enantiomers for etodolac.
' ~08231~
Figure 3 is a plot of meltlng polnt versus the % of S enantlomers for propranolol.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The chiral drugs applicable to the present lnventlon would be those havlng one or more single asymmetric carbon atoms in their structure.
These chiral drugs usefully could be selected from non-steroidal anti-inflammatory drugs, hypotensive B-blockers, calcium channel blockers, antiarryhyth~ics and the like.
More specifically, such drugs could include propranolol, ibuprofen, etodolac or ketoprofen.
The partltion coefficient yielding the desired rate and extent of distributlon may be determlned by conventlonal methods known to one skllled ln the art.
The specific enantiomerlc ratio required is determined by progresslvely adding one enantiomer to another and measuring the melting point of the mixed and fused powder.
The compounds of this invention are useful ln the treatment of lnflammatory conditlons and hypotension. Humans suffering from these allments may be treated with the appropriate type of drug by administering to the patient a pharmaceutically effective amount of one or more of the present compounds optionally, but preferably in the presence of a pharmaceutically acceptable carrler or diluent.
There may also be lncluded a pharmaceutlcally compatible binding agent, and/or ad~uvant materials. The actlve materials can also be mixed with other active materials which do not impalr the desired action and/or supplement the desired action. The above materials according to the present invention can be administered by any route, for example, orally, parentally, intravenously, intradermally, sub-cutaneously or topically in solid or liquid form.
The solid form preparation includes powders, tablet, dispensable granules, capsules, cachets, suppositories and 2~82310 olntments. A solld carrler can be one or more substances whlch may also act as dlluents, flavourlng agents, solublllzers, lubrlcants, suspendlng agents, blnders, or tablet dlslntegrating agent~, namely magnesium carbonate, magneslum stearate, talc, su~ar, lactose, pectln, dextrln, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low meltlng wax, cocoa butter and the llke.
. . ...
¦ Llquld form preparatlons lnclude solutions, suspensions and ¦ emulsions. The liquid preparation for parenteral inJection may be i~ water or water propylene glycol solution or water polyethylene glycol and the like to be acceptable to biological systems (isotoniclty, pH etc.). Aqueous solutions sultable for oral use can be prepared by dlssolving the active component in water and adding suitable colorant, flavours, stabilizing and thickening agents as desired. A~ueous suspensions sultable for oral use can be made by dispersing the flnely divlded active component in water with vlscous material, l.e. natural or synthetic gum, resins, methyl cellulose, sodium carboxymethyl cellulose and other well known suspending agents.
The quantitles of active compound ln a unit dose of preparation may be varled to the particular application and the potency of the active lngredient. Determination of the proper dosage for a partlcular situation is within the skill of art.
~, EXPERIMENTAL
The following results are illustrative of the lnvention but are not to be construed as limiting the scope thereof in any way.
Preparatlon of Compounds with Various Enantiomeric Ratios Various proportions of S and R enantiomers were accurately weighed. The resulting mixtures were then either dissolved in an appropriate solvent to give a solution of the compound, or the powder was first melted and then solidified to produce a solid ~`` 2082310 compound.
Melting Polnt Measurement Meltlng polnts were measured after the two enantlomers were melted and then solidified. This permit8 a thorough amalgamation of the two enantiomers.
Partition Coefflcients Measurement Solutlons containln~ 20 mg% of stereochemically pure (>95%) S-ibuprofen, racemic and eutectic (82%S plus 18% R) were prepared in pH 7.4 phosphate buffer. To 1 mL of the above solution was added lmL of octanol ln lOmL screw-cap test tubes. The tubes were sealed and shaken for 7 days at room temperature. The ibuprofen content of both aqueous and octanol layers were measured on the seventh day. The partltion coefflcient was calculated as the ratio of the concentratlon found in the octanol phase over that found in the aqueous layer.
Bulk Dissolution Method Into a ~acketed flask was transferred 600 mL of pH 1.5 phosphate buffer. Thirty mg racemate, S-ibuprofen, or the eutectlc compound were placed in a rotating basket. The basket was immersed in the buffer. The contents were stirred constantly at 600 r.p.m.
(equivalent to 159 r.p.m. USP model). Using a pipet equipped with a filter, samples were taken at 0, 20, 40, 60 and 80 minutes after addltlon of the compounds and analyzed for lbuprofen.
AssaY of IbuDrofen The assay was made accord$ng to the methods described earlier in the following: Liquid Chromatographic Assay of Ibuprofen Enantiomers in Plasma', R. Mehvar, F. Jamali ~ F. M. Pasutto. Clin.
Chem. 34.493-496, 1988.
: - `
i- 20~23~0 Table 1 Some Physlcochemlcal Properties of Ibuprofen Powders wlth Dlfferent S:R Ratlo.
Compound M.P.Solubllltyl po/~2 Dlssolution3 ~-C g/mL tsos S4 49 300 1.83 22 (97.5+23.o) Racemate 75 156 3.00 44 (61.5+25.8)6 - ~
Eutectlc' 43 320 1.25 16 (98.2+21.9)6 ~-1. Solublllty @ pH 1.5 @ 35C.
2. Partitlon coefflcient (octanol/water pH, 7.4) at room temperature.
3. Dissolution rate (mlnutes to dissolve 50%), bulk @ 37C,pH, ~
1.5. ~ , 4. Purity of our stereochemically "pure" compounds is approximately 96%. Hence the gap between truly pure enantiomers and the eutectic compound is even greater then reflected above.
1.5. ~ , 4. Purity of our stereochemically "pure" compounds is approximately 96%. Hence the gap between truly pure enantiomers and the eutectic compound is even greater then reflected above.
5. S:R ratlo approxlmately 83/17.
6. Particle size (mean+SD). Note that the racemate dissolves more 810wly despite lts smaller surface area.
All the observed differences are statlstlcally signiflcant @
~ 0.05 ~` 2~2310 Table 2 glven herebelow provides the partltlon coefflclent of some chiral drugs determined using octanol and water at pH 7.4.
Table 2 Ibuprofen Ketoprofen Etodolac Propranolol Racemate 2.99 0.17 1.77 0.08 3.53 0.20 3.40 0.22 R - 1.31 0.04 3.48 0.17 S 1.83 0.09 1.33 0.05 - 2.78 0.08 Eutectic 1.25 0.03 1.16 0.03 2.48 0.31 2.53 0.15 S:R Ratio of Eutectlc 83/17 95/5 75/25 95/5 _ The phase diagrams of ibuprofen, ketoprofen, etodolac and propranolol, given herein, indicate that for all these chiral drugs the melting polnt depends upon the enantlomerlc ratlo, and there exlsts an eutectlc state at which the lowest melting point is seen.
Thus, for lbuprofen, ketoprofen, etodolac and propranolol, the value of the partitlon coefficlent follows the same trend as that of the melting point, with the eutectic having the lowest and the racemlc the highest meltlng point and partition coefflcient, respectlvely.
All the observed differences are statlstlcally signiflcant @
~ 0.05 ~` 2~2310 Table 2 glven herebelow provides the partltlon coefflclent of some chiral drugs determined using octanol and water at pH 7.4.
Table 2 Ibuprofen Ketoprofen Etodolac Propranolol Racemate 2.99 0.17 1.77 0.08 3.53 0.20 3.40 0.22 R - 1.31 0.04 3.48 0.17 S 1.83 0.09 1.33 0.05 - 2.78 0.08 Eutectic 1.25 0.03 1.16 0.03 2.48 0.31 2.53 0.15 S:R Ratio of Eutectlc 83/17 95/5 75/25 95/5 _ The phase diagrams of ibuprofen, ketoprofen, etodolac and propranolol, given herein, indicate that for all these chiral drugs the melting polnt depends upon the enantlomerlc ratlo, and there exlsts an eutectlc state at which the lowest melting point is seen.
Thus, for lbuprofen, ketoprofen, etodolac and propranolol, the value of the partitlon coefficlent follows the same trend as that of the melting point, with the eutectic having the lowest and the racemlc the highest meltlng point and partition coefflcient, respectlvely.
Claims (14)
1. A chiral drug adapted for introduction into a human subject which comprises:
a compound formed of two enantiomers in a ratio such as to exhibit a predetermined partition coefficient whereby the absorption and distribution of said drug takes place at a preselected rate.
a compound formed of two enantiomers in a ratio such as to exhibit a predetermined partition coefficient whereby the absorption and distribution of said drug takes place at a preselected rate.
2. A chiral drug adapted for introduction into a human which comprises:
a compound formed of two enantiomers in a specific ratio so as to provide a eutetic compound, the ratio of said enantiomers having been predetermined by selecting a partition coefficient value indicative of the composition of said eutectic compound, said eutetic compound being functional to be absorbed and distributed into the human at a preselected rate.
a compound formed of two enantiomers in a specific ratio so as to provide a eutetic compound, the ratio of said enantiomers having been predetermined by selecting a partition coefficient value indicative of the composition of said eutectic compound, said eutetic compound being functional to be absorbed and distributed into the human at a preselected rate.
3. A compound as set forth in claim 2 selected from non-steroidal anti inflammatory and hypotensive drugs.
4. A compound as set forth in claim 2 which is selected from the group comprising ibuprofen, ketoprofen, etodolac or propranolol.
5. A compound as set forth in claim 2 wherein said chiral drug comprises ibuprofen and wherein the S:R enantiomeric ration is about 83:17% respectively.
6. A compound as set forth in claim 2 wherein said chiral drug comprises ketoprofen and wherein the S:R enantiomeric ratio is about 95:5% respectively.
7. A compound as set forth in claim 2 wherein said chiral drug comprises etodolac and wherein the S:R enantiomeric ration is about 75:25% respectively.
8. The compound as set forth in claim 2 wherein said chiral drug comprises propranolol and wherein the S:R enantiomeric ratio is about 95:5% respectively.
9. A method for controlling the rate of absorption and distribution of a chiral drug into a human subject which comprises determining the partition coefficient whereby the absorption and distribution of said drug takes place at a preselected rate into a human: from the partition coefficient determination, extrapolating to obtain the enantiomeric ratio required, and administering a compound formed of this enantiomeric ratio composition to said human in a suitable dosage form.
10. The method as set forth in claim 9 wherein said chiral drug is selected from ibuprofen, ketoprofen, etodolac or proranolol.
11. The method as set forth in claim 9 wherein said chiral drug comprises ibuprofen and wherein the S:R: enantiomeric ratio is about 83:17% respectively.
12. The method as set forth in claim 9 wherein said chiral drug comprises ketoprofen and wherein the S:R enantiomeric ratio is about 95:5% respectively.
13. The method as set forth in claim wherein said chiral drug comprises Etodolac and wherein the S:R: enantiomeric ratio is about 75:25% respectively.
14. The method as set forth in claim 9 wherein said chiral drug comprises propranolol and wherein the S:R enantiomeric ratio is about 95:5% respectively.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2082310 CA2082310A1 (en) | 1992-11-06 | 1992-11-06 | Chiral drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2082310 CA2082310A1 (en) | 1992-11-06 | 1992-11-06 | Chiral drugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2082310A1 true CA2082310A1 (en) | 1994-05-07 |
Family
ID=4150655
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2082310 Abandoned CA2082310A1 (en) | 1992-11-06 | 1992-11-06 | Chiral drugs |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2082310A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6368618B1 (en) | 1999-07-01 | 2002-04-09 | The University Of Georgia Research Foundation, Inc. | Composition and method for enhanced transdermal absorption of nonsteroidal anti-inflammatory drugs |
| WO2019090141A1 (en) * | 2017-11-02 | 2019-05-09 | Vicus Therapeutics, Llc | Combination drug therapies for cancer and methods of making and using them |
-
1992
- 1992-11-06 CA CA 2082310 patent/CA2082310A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6368618B1 (en) | 1999-07-01 | 2002-04-09 | The University Of Georgia Research Foundation, Inc. | Composition and method for enhanced transdermal absorption of nonsteroidal anti-inflammatory drugs |
| WO2019090141A1 (en) * | 2017-11-02 | 2019-05-09 | Vicus Therapeutics, Llc | Combination drug therapies for cancer and methods of making and using them |
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