AU647674B2 - Pharmaceutical compositions containing triazole derivatives for rectal administration - Google Patents
Pharmaceutical compositions containing triazole derivatives for rectal administration Download PDFInfo
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- AU647674B2 AU647674B2 AU27010/92A AU2701092A AU647674B2 AU 647674 B2 AU647674 B2 AU 647674B2 AU 27010/92 A AU27010/92 A AU 27010/92A AU 2701092 A AU2701092 A AU 2701092A AU 647674 B2 AU647674 B2 AU 647674B2
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- Prior art keywords
- pharmaceutical composition
- semi
- weight
- rectal administration
- pharmaceutical
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F3/00—Biological treatment of water, waste water, or sewage
- C02F3/02—Aerobic processes
- C02F3/12—Activated sludge processes
- C02F3/1205—Particular type of activated sludge processes
- C02F3/1221—Particular type of activated sludge processes comprising treatment of the recirculated sludge
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F3/00—Biological treatment of water, waste water, or sewage
- C02F3/006—Regulation methods for biological treatment
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F3/00—Biological treatment of water, waste water, or sewage
- C02F3/02—Aerobic processes
- C02F3/12—Activated sludge processes
- C02F3/14—Activated sludge processes using surface aeration
- C02F3/18—Activated sludge processes using surface aeration the aerator having a horizontal axis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
- Y02W10/00—Technologies for wastewater treatment
- Y02W10/10—Biological treatment of water, waste water, or sewage
Description
64 7 74 S F Ref: 220962
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFCATION FOR A STANDARD PATENT
ORIGINAL
a a a. a a Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Heinrich Mack Nachf.
Heinrich-Mack-Str. 7918 Illertissen
GERMANY
Walter Fries, Gunther Pfaff, Jorg Pfitzner and Gerhard Simon Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Pharmaceutical Compositions Containing Triazole Derivatives for Rectal Administration The following statement is a full description of this invention, including 'he best method of performing it known to me/us:- 5845/7 PC8010A -1- PHARMACEUTICAL COMPOSITIONS CONTAINING TRIAZOLE DERIVATIVES FOR RECTAL ADMINISTRATION Background of the Invention A problem with therapeutically active substances is that these compounds cannot be administered by every administration route at the same dosage level with the same resulting activity. Various substances which can be injected show a considerable loss of activity on oral administration. Other substances, which can be orally administered, lose bioavailability to a considerable extent if they are rectally administered.
Oral administration forms are particularly problematical in those patients who tend to vomit. This problem is apparent with therapies such as immunosuppression or candidiasis of the oesophagus.
Administration in the form of injections is not appropriate in many cases. Many people have a fear of frequent injections and with cachectic patients injection is difficult.
The present invention is therefore intended to provide rectally administered pharmaceutical compositions which have approximately the same bioavailability of active component as oral administration forms.
•In order to achieve the same high blood level values as after an oral dose, approximately a 1.5 to 3 to fold amount of the oral dose must be incorporated in the suppository Sucker, P. Fuchs and R. Speiser, Pharmazeutishe Technologie (Pharmaceutical Technology), Georg Thieme Verlag, Stuttgart 1978). The problem of incorporating a substantially higher amount of the active compound is that absorption can differ greatly from person to person and in the case of good absorption a blood level value is achieved which is clearly above the optimum blood level value.
It is therefore the object of the present invention to make available a pharmaceutical composition for rectal administration which has approximately the same bioavailability as an oral administration form.
Summary of the Invention A pharmaceutical composition for rectal administration is therefore disclosed which comprises the following constituents: a) at least one therapeutically active triazole compound of the general formula: X R 2 N N-CH 2 C C N (I) N R, R 3
\N
wherein R, is phenyl optionally substituted with from one to three substituents independently selected from the group consisting of F, CI, Br, I, CF 3
(C,-C
4 )alkyl, S 10 C 4 )alkoxy, and 5-chloropyrid-2-yl; X is OH, F, CI or Br;
R
2 is H, CH, or F; and R 3 is H or F; and wherein the triazole derivative being employed comprises an amount of 0.1 15 to 25 percent by weight, preferably 1 to 10 percent by weight, relative to the total weight of the composition, and b) semi-synthetic glycerides, composed of saturated fatty acid glycerides having a chain length of C, to Cg, and having a melting range of 320-440C, preferably in the range of 35 0 -39 0 C, and wherein the semi-synthetic glycerides comprise between 20 80 to 99.9 percent by weight, relative to the total weight of the pharmaceutical composition, and c) a mixture of solid, purified, saturated hydrocarbons having a solidification point of 400-70°C, in particular of 50 0 -62'C, wherein the hydrocarbons comprise between 0 to 8 percent by weight, relative to the total weight of the pharmaceutical composition.
The composition may, moreover, contain auxiliaries customary in suppositories u a small extent.
The therapeutically active constituents of the above pharmaceutical compositions are triazole derivatives which have antimycotic activity. Compounds of formula I and methods for their syntheses are described in United States Patent 4,404,216, which is hereby incorporated by reference in its entirety.
In a preferred embodiment, the triazole derivatives of formula I have the general formula (II):
X
N N-CH C H N N (II)
SR
1
N
in which R 1 is phenyl optionally substituted with from 1 to 3 substituents independently selected from the group consisting of F, Cl, Br, I and CF3, and wherein X is OH, F, Cl or Br.
In particularly preferred embodiments, the triazole derivative of formula I is 1,3- S 10 bis(1 H-1,2,4-triazol-1-yl)-2-bromo-2-(2,4-dichlorophenyl)propane, 1,3-bis(1 H-1,2,4-triazoli" 1-yl)-2-chloro-2-(2,4-dichlorophenyl)propane or 1,3-bis(1 H-1,2,4-triazol-1 iodophenyl)-propan-2-ol The most preferred triazole derivative is 2,4-difluoro-a,u-bis(1H-1,2,4-triazol-1ylmethyl)benzyl alcohol (fluconazole).
15 Detailed Description of the Invention One or more different triazole derivatives can be incorporated into the pharmaceutical compositions claimed.
A therapuetically effective dose of 25-400 mg of the triazole derivative of formula I per individual administration form (suppository) is preferably employed. This active compound is only soluble to a very small extent in the rectal fluid, which is customarily about 1-3 ml.
Quantitatively, the main constituent of the pharmaceutical compositions according to the invention is the semi-synthetic glycerides The semi-synthetic glycerides employed according to the invention are composed of saturated fatty acid glycerides having a chain length of the fatty acids of 6 to 20 carbon atoms. In a preferred embodiment, the chains of the fatty acids have 8 to 18 carbon atoms.
The iodine number of the semi-synthetic glycerides is preferably below 3 and particularly preferably below 2.
The hydroxyl number of the semi-synthetic glycerides is preferably below 20 and particularly preferably below 6.
In particularly preferred embodiment, semi-synthetic glycerides are employed which have been prepared by transesterification (interesterification). As a result of this preparation process, lower molecular weight fatty acids are also obtained, which contribute to the "softener" properties. In mixed products of suitable esters and alcohols and also in semi-synthetic glycerides which have been prepared by esterification and not by transesterification, these low molecular weight fatty acids are not present.
The semi-synthetic glycerides as used according to the invention can be produced by an interesterification of refined hydrogenated vegetable oils at high temperature using an alkaline reacting catalyst. Then the alkali soaps can be removedby rinsing and the product can be decolorised, deodorised and finally dried.
It was found that the semi-synthetic glycerides obtained by interesterification show in the differential scanning calorimeter a melting diagramme which is more continuous than the diagramme obtained by using materials as described in the prior art (Gstirner, Einfthrung in die Verfahrenstechnik der Arzneiformung, Wissenschaftliche S Verlagsgesellschaft mbH Stuttgart, 1973 152-155)). The diagramme of the semi-synthetic glycerides obtained by interesterification shows only one broad peak whereas the S.material as used in the prior art shows at least two separate peaks.
According to the invention, semi-synthetic glycerides are employed with ratty acid radicals having 8-18 carbon atoms and which were produced by interesterification.
The effect of the semi-synthetic glycerides employed according to the invention was compared with the effect of such suppository base materials usually used as adeps solidus and consisting of a mixture of mono-, di- and triglycerides of the saturated fatty acids C 1
,H
2 3 COOH to C,7H 3 sCOOH (Gstirner, "Einfuhrung in die Verfahrenstechnik der Arzneiformung", Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1973, p. 152- S 155). In this comparative test, suppositories were produced which in each case contained the same ratio of a triazole derivative to glycerides. The chain length of the fatty acid radicals of the comparative formulation was in the range between Co-Ce.
In animal experiments with rabbits the parameter AUC (area under the curve), the area under the plasma level-time curve, and Cm., the maximum plasma level concentration, were determined. The following results were obtained: Area Under the Curve Maximum Concentration Suppositories Basis (mcg x h/ml) Cm.x (mcg/ml) semi-synthetic glycerides 447.3 48.06
C
8
-C,
1 (according to the invention) semi-synthetic glycerides 378.3 37.63 Clo-C, 1 (according to Gstirner) The table above shows that by using the (Cg-Ce) semi-synthetic glycerides according to the invention, about 18% more of the effective agent was reabsorbed from the suppositories and that the maximum obtainable blood level of the effective substance of this preparation is about 27% higher than by using a mixture of mono-, di- and triglycerides wherein the chain length is between Co and C, 8 A further constituent of the pharmaceutical composition according to the invention are the solid, purified, saturated hydrocarbons which are employed in an amount of 0 to 8 percent by weight, preferably 2 to 5.5 percent by weight, relative to the total weight of the pharmaceutical composition.
These hydrocarbons have a solidification point of 40 0 -70 0 C and preferably between 500-620C. These hydrocarbons are used in the preparation as a viscosityincreasing substance to prevent sedimentation of the active compound. A relatively high viscosity of the melt would be expected to delay the partition and reduce the absorption of the active component on melting of the suppository in the rectum.
Surprisingly, this was not observed in the bioavailability investigations. In fact, rapid release of the active compound was observed.
Rapid release of an active compound from a suppository is only expected by one skilled in the art if the oil/water partition coefficient is small. Only then can acceptable bioavailability by expected. For the compound preferably employed (fluconazole), the oil/water partition coefficient has a value of 1.605 and is thus in the middle range of the customary values. Thus, good bioavailability would not be expected.
If solubility/partition values are plotted against one another, the value for 15 fluconazole is close to that for morphine, codeine and ephedrine bases. These compounds, however, do not show good bioavailability from suppository fatty bases.
A poor bioavailability therefore also has to be taken into account for a pharmaceutical composition which contains a triazole derivative.
Surprisingly, it has now been found that the triazole derivatives employed S 20 according to the invention have a bioavailability which is comparable with oral administration forms if the pharmacologically active compound having a particle size of below 150 is suspended in a solidified melt of semi-synthetic glycerides on their own or preferably with the addition of a mixture of solid, purified, saturated hydrocarbons.
In addition to the customary casting in metal moulds, the casting of the suppositories can also be carried out directly in preshaped containers made of plastic, aluminum or plastic laminate.
The present invention is further illustrated with reference to the following examples: EXAMPLE 1 kg of ground 2,4-difluoro-a,a-bis(1H-1,2,4-triazol-2-ylmethyl)benzyl alcohol (fluconazole) were added with stirring to a molten mixture of 180.12 kg of semi-synthetic glycerides and 4.88 kg of purified, saturated hydrocarbons. The suspension was homogenized and poured into the appropriate packagings in suppository form. The packagings can be prepared from plastic, aluminum or a laminated material.
EXAMPLE 2 kg of 2,4-difluoro-a,a-bis(1 H-1,2,4-triazol- -ylmethyl)benzyl alcohol were added with stirring to a molten mixture of 180.25 kg of semi-synthetic glycerides and 9.75 kg of purified, saturated hydrocarbons. The suspension was homogenized and poured into metal moulds in suppository form.
EXAMPLE 3 10 kg of 2,4-difluoro-a,a-bis(1H-1,2,4-triazol-1-ylmethyl)benzyl alcohol were o S 10 added with stirring to a melt of 360 kg of semi-synthetic glycerides. After homogenization, the suspension was poured into metal moulds.
EXAMPLE 4 kg of 2,4-difluoro-a,a-bis(1H-1,2,4-triazol-1-ylmethyl)benzyl alcohol were added with stirring to a molten mixture of 92.56 kg of semi-synthetic glycerides and 15 2.44 kg of purified, saturated hydrocarbons. The suspension was homogenized and poured into suppository moulds.
EXAMPLE kg of 2,4-difluoro-a,a-bis(1H-1,2,4-triazol-1-ylmethyl)benzyl alcohol were added with stirring to a molten mixture of 170.1 kg of semi-synthetic glycerides and 20 4.9 kg of purified, saturated hydrocarbons. The suspension was homogenized and poured into suppository moulds.
EXAMPLE 6 (comparison example) The pharmacokinetics of suspension and suppositories were compared in a cross-over test in humans.
As active compound, fluconazole was employed in an amount of 25 mg once as suppositories (prepared according to Example 4) and once as suspension. The suspension employed for the comparison contained the following constituents in addition to the active compound: sucrose, colloidal silice., xanthan gum, buffer substances, preservative, colorant and flavoring. The parameters "area under the curve" and Cm,, were determined. The bioavailability -f the pharmaceutical forms is assessed with reference to the parameters AUC (area under the curve area under the
D
plasma level-time curve) and C, (maximum plasma level concentration). The following results were obtained here: PARAMETER SUPPOSITORY SUSPENSION Area under the curve 0-96 h (mcg x h/ml) 19.87 3.2 18.58 3.03 Cm (mcg/ml) 0.451 0.062 0.544 0.101 EXAMPLE 7 (comparative example) The comparison tests according to Example 6 were also carried out using a higher fluconazole concentration. In this case, 200 mg of the active compound were incorporated firstly into the suppositories according to the invention (prepared according to Example 5) and on the other hand incorporated into capsules for oral administration. In addition to the active compound, the comparatively tested capsules contained the following further constituents: lactose, maize starch, colloidal silica, magnesium stearate and sodium lauryl sulphate. The following results were obtained in this case: PARAMETER SUPPOSITORY CAPSULES Area under the curve 0-96 h (mcg x h/ml) 151.3 31 163 26 Cma 3.4 0.5 3.9 t/2 32.0 6.8 33.0 7.8 The comparison experiments show that the pharmaceutical preparations according to the invention for rectal administration have the same bioavailability as oral administration forms which have the same concentration of active compound as the suppositories.
1*..r
Claims (8)
1. A pharmaceutical composition for rectal administration that comprises the following constituents: a) at least one therapeutically active triazole compound of the formula: X R 2 N N-CH C N (I) R K wherein R, is phenyl radical optionally substituted with one to three substituents independently selected from the group consisting of F, CI, Br, I, CF 3 (C,-C,)alkyl, C 4 )pakoxy, and 5-chloropyrid-2-yl; X is OH, F, Cl or Br; R 2 is H, CH 3 or F; R3 is H or F; and wherein the compound of formula I comprises an amount of 0.1 to 25 percent by weight, relative to the total weight of the composition, and b) semi-synthetic glycerides produced by interesterification, consisting of saturated fatty acid glycerides having a chain length of Ca to C,i and having a melting 20 range of 320-44°C, wherein the semi-synthetic glycerides comprise between 80 to 99.9 percent by weight, relative to the *otal weight of the pharmaceutical composition, and c) a mixture of solid, purified, saturated hydrocarbons having a solidification point of 400-70 0 C, wherein the hydrocarbons comprise between 0 to 8 percent by weight, relative to the total weight of the pharmaceutical composition.
2. A pharmaceutical composition according to claim 1, wherein the therapeutically active agent is a triazole derivative of the following formula (II): x N N-CHg -C---CH 2 -N N I) wherein R, is phenyl optionally substituted with from 1 to 3 substituents independently selected from a group consisting of F, CI, Br, I and CF 3 and X is OH, F, CI or Br.
3. A pharmaceutical composition according to claim 1, wherein the triazole derivative is 1,3-bis(1H-1,2,4-triazol-1-yl)-2-bromo-2-(2,4-dichlorophenyl) propane.
4. A pharmaceutical composition according to claim 1, wherein the triazole derivative is 1,3-bis(1H-1,2,4-triazoi-1-yl)-2-chloro-2-(2,4-dichlorophenyl) propane.
5. A pharmaceutical composition according to claim 1, wherein the triazole derivative is 1,3-bis(1 H-1,2,4-triazol-1-yl)-2-(4-iodophenyl)propan-2-ol.
6. A pharmaceutical composition according to claim 1, wherein the trazole derivative is 2,4-difluoro-a,a-bis(1H-1,2,4-triazol-1-ylmethyl)benzyl alcohol.
7. A pharmaceutical preparation according to any one of the preceding
10. claims, wherein the pharmaceutical preparation is present in the form of a suppository for rectal administration, which contains 10-400 mg of the triazole derivative per suppository. 8. A pharmaceutical preparation according to any one of the preceding s claims, wherein the semi-synthetic glycerides have an iodine number of less than 3, and a hydroxyl number of less than 9. A pharmaceutical preparation according to any one of the preceding claims, wherein the saturated hydrocarbons are present in an amount of 2-5.5 percent by weight, relative to the total weight of the pharmaceutical composition. 10. A process for preparing a pharmaceutical composition substantially as hereinbefore described with reference to any one of the Examples. DATED 7 October, 1992 Hciiinrich Mack Nachf. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON PHARMACEUTICAL COMPOSITIONS CONTAINING TRIAZOLE DERIVATIVES FOR RECTAL ADMINISTRATION Abstract This invention relates to pharmaceutical compositions for rectal administration containing semi-synthetic glycerides produced by interesterification, and, as the active ingredient, triazole derivatives of the formula X R SN N-C H-C-C C N (I) independently selected from the group consisting of F, CI, Br, 1, CF 3 (C,-C,)alkyl, C 4 )alkoxy, and 5-chloropyrid-2-yl; X is OH, F, CI pr Br; R 2 is H2,, CH, or F; and R 3 is H 15 or F.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4134124 | 1991-10-15 | ||
DE19914134124 DE4134124A1 (en) | 1991-10-15 | 1991-10-15 | Biological sewage cleaning - has aeration units in the recirculating basin operated according to ammonia and oxygen@ content |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2701092A AU2701092A (en) | 1993-04-22 |
AU647674B2 true AU647674B2 (en) | 1994-03-24 |
Family
ID=6442728
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU27010/92A Ceased AU647674B2 (en) | 1991-10-15 | 1992-10-14 | Pharmaceutical compositions containing triazole derivatives for rectal administration |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU647674B2 (en) |
DE (1) | DE4134124A1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4304676C1 (en) * | 1993-02-16 | 1994-06-23 | Optum Umwelttech Gmbh | Process for operating a wastewater treatment plant and associated wastewater treatment plant |
EP1903010A1 (en) * | 2006-09-22 | 2008-03-26 | Holm, Niels Christian | Method for wastewater treatment in continuously charged activated sludge plants comprising upstream denitrification |
DE102009011490A1 (en) | 2008-12-11 | 2010-06-17 | Envicon Klärtechnik Verwaltungsgesellschaft mbH | Process for the load-dependent control of nitrification and denitrification in wastewater treatment plants with upstream denitrification |
-
1991
- 1991-10-15 DE DE19914134124 patent/DE4134124A1/en not_active Withdrawn
-
1992
- 1992-10-14 AU AU27010/92A patent/AU647674B2/en not_active Ceased
Also Published As
Publication number | Publication date |
---|---|
AU2701092A (en) | 1993-04-22 |
DE4134124A1 (en) | 1993-04-22 |
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