GB2090738A - Suppository containing active ingredient - cyclodextrin complex - Google Patents
Suppository containing active ingredient - cyclodextrin complex Download PDFInfo
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- GB2090738A GB2090738A GB8138240A GB8138240A GB2090738A GB 2090738 A GB2090738 A GB 2090738A GB 8138240 A GB8138240 A GB 8138240A GB 8138240 A GB8138240 A GB 8138240A GB 2090738 A GB2090738 A GB 2090738A
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- Prior art keywords
- suppository
- active ingredient
- cyclodextrin
- suppositories
- complex
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
Abstract
A suppository comprises a suppository base and an active ingredient in the form of a complex ??? or beta gamma -cyclodextrin, said active ingredient being volatile and/or liable to decomposition in the uncomplexed state. The active ingredient is e.g. an essential oil.
Description
SPECIFICATION
Improvements in suppositories
The present invention relates to stable suppositories, specifically those comprising an active ingredient which is volatile and/or liable to decomposition, and a process for the preparation thereof.
One fundamental problem in the manufacturing of rectal suppositories, mainly used in pediatrics, resides in the fact that the active ingredient (i.e. the pharmaceutical, generally an essential oil) decreases the melting point of the suppository base to a significant extent. For this reason, on storage the suppository softens and in use melts prematurely. In order to eliminate this drawback various auxiliary agents have been suggested and used. It is known to add to the suppository base colloidal silicon dioxide or a lipid having a higher melting point which is well-miscible with the suppository base (e.g. cetyl stearate, stearin or paraffin wax).
However this was not a fully satisfactory solution, because so much colloidal silicon dioxide had to be added that it caused gelling of the composition, and this made the uniform moulding of the suppository base difficult if not impossible.
A further difficulty is that the active ingredient, e.g. the essential oil, dispersed in the suppository mass is often unstable and decomposes or escapes within a short period of time.
For the reasons outline above there is no satisfactory process for the industrial scale manufacture of ointments comprising such active ingredients, because the storage life is unsatisfactory. These are not proprietary but so-called magistral compositions. Such compositions are prepared in pharmacies by manual methods and can be stored only for very short periods of time. This manual activity could be replaced by industrial scale manufacture if suppositories or ointments of suitable strength and storage life could be prepared using active ingredients compatible with the suppository base.
In the case of pharmaceuticals which are volatile and/or well-soluble in the fatty suppository base, mainly essential oils, active ingredient must be used in an amount of several times the actual desired dosage, because the essential oils are highly soluble in the suppository base and their absorption by the patient is therefore limited.
There are also known water-soluble suppository bases of non-fatty character, e.g. the Massa polyoxyaethene (a mixture of polyethylene glycols) according to the 6th Hungarian Pharmacopoiea. The melting point of these substances is however so high (about 50"C) that their admixture with essential oils is accompanied by considerable losses. In order to obtain a mouldable mixture it is necessary to heat these bases to a temperature at least 1 00C higher than the melting point and at such temperatures, substantial evaporation of the essential oils or other volatile ingredients take place.
In Hungarian Patent Specification No. 174,699 the preparation of inclusion complexes of aromatic materials and essential oils formed with cyclodextrins and the use thereof for the flavouring of foodstuffs is disclosed.
It would be desirable to provide suppositories which comprise one or more volatile and/or unstable active ingredient(s) but are free of the disadvantages of the known compositions, i.e. they could be stored for prolonged periods of time, would not decompose, would not lose their active ingredient content on storage, would possess desirable mechanical properties and which on use would readily liberate the active ingredient.
It would also be desirable to provide a process for the manufacture of such suppositories which would be applicable on an industrial scale, as in the case of other pharmaceutical compositions. The present invention is intended to achieve these objectives, at least to some extent.
We have found surprising by that when an active ingredient, especially one which is volatile and/or liable to decomposition, is used in the form of an inclusion complex formed with a-, ss-, or y-cyclodextrin improved suppositories can be prepared.
According to the present invention there is provided a suppository comprising a suppository base and an active ingredient in the form of a complex with a, ss or y-cyclodextrin, said active ingredient being volatile and/or liable to decomposition in the uncomplexed state.
The suppository may e.g. comprise 0.05-020% by weight of inclusion complex and 99.95-80% by weight of suppository base.
It has been found that the inclusion complexes of active ingredients which are volatile and/or liable to decomposition, formed with cyclodextrins, can be efficiently homogenised with suppository bases of both the lipid and hydrophilic types (Massa polyoxyaethene). They do not substantially decrease the melting point of lipid-type suppository bases and losses of the active ingredient from Massapolyoxyaethene base at the moulding temperature is much reduced.
The present invention is based further on the surprising discovery that when a cyclodextrin inclusion complex is dispersed in a fatty base the liberation and absorption of the active ingredient is higher by several orders of magnitude than when the active ingredient is uncomplexed.
This unexpected and therapeutically valuable effect on absorption renders the invention particularly useful for active ingredients which are not only excessively volatile or liable to decompose but also are poorly absorbed from typical suppositories bases, especially of the lipid type.
For the preparation of the suppositories according to the present invention, therapeutic active ingredients which are volatile and/or liable to decomposition can be used. By way of illustration, the following substances can be mentioned: sweet fennel oil, eucalyptus oil, camphor, methol, Camilla oil, azulene, etc.
The inclusion complexes can be prepared as described in Hungarian Patent Specification No. 174,699.
For use in the present invention one may employ conventional or well-known suppository bases, both of the fatty type (e.g. cocoa butter, Adeps solidus, etc) or of water-soluble type (e.g. polyethylene glycols of various molecular weights, etc.). The suppositories can also contain various conventional formulating adjuvants.
The suppositories are preferably prepared by melting the suppository base (e.g. on a water bath) and adding the finely powdered inclusion complex of the active ingredient and cyclodextrin and optionally any adjuvants under constant stirring. The mixture is then homogenised and cast into suitable moulds of the desired dimensions; it is preferred to use pre-cooled conical moulds. The casting operation can be performed by suitable machinery.
The softening point of the suppositories of the present invention does not substantially differ from that of the suppository base used; the active ingredient content of the suppositories is not set free on standing and the active ingredient content has less tendency to undergo undesired changes during storage. In many cases the absorption of the active ingredient from the complex is much more efficient than that of the uncomplexed material and hence the same therapeutic effect may be attainable using a smaller dosage of active ingredient.
A further advantage of the process of the present invention is that it can be used on an industrial scale and operated with existing processing machinery, as with other forms of phamaceutical composition.
Further detals of the present invention are to be found in the following Examples, which are given for illustraction only.
Example 1
10 g. of ss-cyclodextrin are dissolved in 100 ml. of water whereupon a solution of 1.30 g. of sweet fennel oil (Aetheroleum foeniculi) in 10 ml. of 96 % ethanol is added at 60 OC. The mixture is cooled to room temperature under intensive stirring within 4.5-5 hours and thereafter allowed to stand at 12 hours under ice cooling in order to promote complete crystallization. The precipitated product is filtered through a sintered glass filter and dried at room temperature in air. Thus 10.58 g. of the complex are obtained, active ingredient content 8.2 %.
Example2 10 g. of ss-cyclodextrin are dissolved in 100 ml. of a 1:2 mixture of ethanol and water at 50 "C, whereupon a solution of 0.60 g. of sweet fennel oil in 5 ml. of 96 % ethanol is added. The reaction mixture is cooled to room temperature under intensive stirring within 4 hours, whereupon it is allowed to stand for 12 hours under ice cooling. The precipitated crystalline inclusion complex of sweet fennel oil and ss-cyclodextrin is washed twice with 10 ml. of cold diethylether each and dried. Thus 10.2 g of the white inclusion complex of sweet fennel oil and ss-cyclodextrin are obtained. The sweet fennel oil content amounts to 4.0 % (according to photometrical analysis).
Example 3
10 g. of ss-cyclodextrin are dissolved in 100 ml. of distilled water at 60 "C. Afterthe solution has become clear a solution of 1.70 g. of eucalyptus oil and 15 ml. of 96 % ethanol is added under stirring. The mixture is cooled to room temperature under intensive stirring within 4.5-5 hours and thereafter allowed to stand under ice cooling for 12 hours in order to promote complete crystallization. The precipitated product is filtered off through sintered glass filter and dried at room temperature in the air. The weight of the complex amounts to 10.70 g., active ingredient content 9.6 %.
Example 4
10 g. of ss-cyclodextrin are dissolved in 100 ml. of distilled water at 60 C, whereupon a solution of 1.5 g. of camphor and 15 ml. of 96 % ethanol is added under constant stirring. The mixture is cooled to room temperature under intensive stirring within 4.5-5 hours and allowed to stand under ice cooling for 12 hours in order to promote complete crystallization. The precipitated crystals are filtered through a sintered glass filter and dried in the air at room temperature. The weight of the complex amounts to 11.0 g., active ingredient content 10.2 %.
Example 5
10 g. of ss-cyclodextrin are dissolved in 100 ml. of distilled water at 60 "C whereupon a solution of 1.48 g. of methanol and 10 ml. of 96 % ethanol is added. The mixture is cooled to room temperature under intensive stirring within 4.5-5 hours and allowed to stand under ice cooling for 12 hours in order to enhance complete crystallization. The precipitated product is filtered through a sintered glass filter and dried in the air at room temperature. The weight of the complex amounts to 10.75 g., active ingredient content 9.60 %.
Example 6
95 g. of a solid fat (Adeps solidus, Ph.Hg. VI) are melted on a water bath. The melted mass is allowed to cool to 35-38 C, whereupon 5 g. of the inclusion complex of sweet fennel oil and ss-cyclodextrin prepared according to Example 1 and previously sieved through a sieve No. VI (Ph.Hg. VI) are added under stirring.
The mixture is subjected to thorough stirring whereupon it is poured into conical moulds pre-cooled to 34 "C.
Thus suppositories having an average weight of 1.025 g. are obtained.
For the sake of compaison conventional suppositories are prepared according to the above method by melting 95 g. of Adeps solidus (Ph.Hg. VI.) as described above, adding 5 g. of sweet fennel oil (Ph.Hg. VI.) under stirring and preparing suppositories of an average weight of 1 g.
Example 7
One proceeds according to Example 6 except that the inclusion complex of sweet fennel oil and ss-cyclodextrin is replaced by an inclusion complex of eucalyptus oil and ss-cyclodextrin.
Example 8
One proceeds according to Example 6 except that the inclusion complex of sweet fennel oil and p-cyclodextrin is replaced by an inclusion complex of canphor and (3-cyclodextrin.
Example 9
One proceeds according to Example 6 except that an inclusion complex of menthol and ss-cyclodextrin is used.
Example 10
23.4 g. of Massa polyoxyaetheni (Ph.Hg. VI.) are melted on a water bath at a temperature of 60 to 70 C. To the melt cooled to 50 "C 2 g. of an inclusion complex of sweet fennel oil and ss-cyclodextrin are added under stirring and the mixture is poured into cooled forms weighing 1 g. and coated with paraffin. The average weight of the suppositories amounts to 1.35 g.
For the sake of comparison we tried to prepare suppositories containing only sweet fennel oil in the place of the inclusion complex. We have failed however to prepare the suppositories because at the moulding temperature of about 50 "C a very strong evaporation of the essential oil took place.
Example 11
One proceeds according to Example 10 except that the inclusion complex of sweet fennel oil and ss-cylodextrin is replaced by the inclusion complex of eucalyptus oil and ss-cyclodextrin.
Example 12 One proceeds according to Example 10 except that an inclusion complex of camphor and ss-cyclodextrin n is used.
Example 13
One proceeds according to Example 10 except that an inclusion complex of menthol and ss-cyclodextrine is used.
Determination of the in vitro release of the active ingredient
The in vitro release of the active ingredient content of the suppositories is determined according to the method of Mühlemann [Pharm. Acta. Helv. 31, 305 (1956)]. A cellulose membrane is used as dialyzing memberane [Medicell International Ltd., London, diameter of pores 2.4 nm, thickness (dry) 25 mJ. Diffusion takes place through a surface of 8.5 cm2 at 37+5 "C. On one side of the membrane a suppository is placed into 10 ml. of distilled water, while on the other side of the membrane there are 30 ml. of distilled water.In 5 dialyzing cells suppositories containing only Adeps solidus, in 5 cells an inclusion complex of sweet fennel oil and ss-cyclodextrin (50 mg. of a complex having an essential oil content of 4 % pro suppository) dispersed in a base of Adeps solidus (suppository "a") and in 5 cells sweet fennel oil (50 mg. of essential oil pro suppository) dispersed in a suppository base ofAdeps solidus (suppository "b") are placed. The suppository containing only the Adeps solidus base is tested because of the presence of contaminations which cause ultraviolet absorption.From time to time samples are taken from that side of the membrane where originally pure distilled water was present and the ultraviolet absorption is measured as a wave length of 259 nm (The sweet fennel oil contains 50-60 % of anethol which shows an absorption maximum of 259 nm.). A calibration curve is taken with various dilutions of sweet fennel oil at 259 nm. The results are shown in Table I.
It can be seen from Table I that the release of active ingredient release from the suppository comprising the inclusion complex is 110-150 times better than that from the conventional fatty suppositories containing only the essential oil. It is a pre-condition of the absorption of the essential oil into the human organism that the active ingredient should get into the aqueous phase.
The in vitro release of the active ingredient from the suppository prepared according to Example 9 was tested in a similar manner. The results are disclosed in Table II.
TABLE I
Diffusion Suppository "b" Suppository "a" Increase of delivery
time achieved with the complex
(hours) mg % mg % (times, x)
1 0.029 0.058 0.173 8.64 150
2 0.051 0.104 0.311 15.56 149
3 0.072 0.145 0.413 20.655 142
5 0.109 0.219 0.562 28.08 129
8 0.159 0.318 0.706 35.28 111
TABLE II
Diffusion Amount of essential oil diffused out from Improvement of delivery
time 108 mg. of complex (=4.24 mg. of sweet as compared to essential oil
(hours) fennel oil pro suppository (times, x)
mg.
1 1.39 32.9 571
2 1.87 44.2 425
3 1.99 47.1 325
4 2.19 51.6 236
It appears from the Table that when the ss-cylodextrin complex of the essential oil is dispersed in Massa polyoxyaethenithe release of the active ingredient is quick and significant and is 230-570 times higher than that of the essential oil dispersed in Adeps solidus in the conventional manner.
Determination of the physical characteristics of the suppositories
The solidification points, disintegration times and breaking strength of the following suppositories are compared: suppository prepared from Adeps solidus; suppository prepared from Adeps solidus and containing essential oil; suppository prepared from Adeps solidus and containing an inclusion complex of essential oil and cyclodextrin; suppository prepared from Massa polyoxyetheni; suppository prepared from Massapolyoxyaetheniand containing an essential oil; suppository prepared from Massa polyoxyaetheni and containing an inclusion complex of the essential oil and cyclodestrin.
The suppositories are prepared as follows:
Suppository "A" Adeps solidus suppository, average weight 1 9.
Suppository "B"
Sweet fennel oil 0.05g.
Camphor 0.05g.
Eucalyptus oil 0.10 g.
Colloidal silicon dioxide 0.05g.
Solid fat (Adeps solidus) 1.75g.
(Preparation No. 200 according to Formulae Normales V.
Suppository "C"
Sweet fennel oil 0.05g.
Camphor 0.05g.
Eucalyptus oil-ss-cyclodextrin complex
according to Example 3 1.04g.
Colloidal silicon dioxide 0.05g.
Solid fat (Adeps solidus) 0.81 g.
Suppository "D"
Adeps solidus suppository, average weight 2 g.
Suppository "E"
Menthol 0.05g.
Camphor 0.10 g.
Eucalyptus oil 0.30 g.
Colloidal silicon dioxide 0.10 g.
Solid fat (Adeps solidus) 3.45g.
(Preparation No. 201 according to Formulae Normales V.)
Suppository "F"
Menthol 0.05g.
Camphor 0.10 g.
Complex of eucalyptus oil and ss-cyclodextrin according to Example 3 3.13g.
Colloidal silicon dioxide 0.10g.
Solid fat (Adeps solidus) 0.62 g.
Suppository "G"
Massa polyoxyaetheni suppository, average weight 1 g.
Suppository "H"
Identical with Suppository "C" except that the same amount of Massa polyoxyaetheni (polyethylene glycol) is used as basic suppository base instead of Adeps solidus.
Suppository "I"
Massa polyoxyaetheni suppository, average weight 2 g.
Suppository "J"
Identical with Suppository "F" except that the same amount of Massa polyoxyaetheni is used as
suppository base in the place ofAdeps solidus.
The following measurements are carried out:
Solidification point: This is measured according to the standard "rotating thermometer" method disclosed in the Hung. Pharmacopoiea VI. The data disclosed in the Table are the average values of three parallel experiments.
Disintegration time: The melting and dissolving of the suppositories are determined with the.aid of the standard apparatus and method disclosed in Hungarian Pharmacopoiea VI. The results disclosed in the
Table are average values of five parallel experiments.
Breaking strength: This test is carried out on suppositories thermostated to 15 "C by using an Erveka or
Schleuniger type table breaking strength measuring apparatus respectively. The results disclosed in the
Table are the average values of twenty parallel experiments.
It can be seen from Table Ill that while the solidification point ofAdeps solidus based suppositories is decreased by the essential oil, it is even slightly increased by the inclusion complex of the essential oil and cyclodextrin. The use of the inclusion complex manifests itself first of all in the improvement of the disintegration time and breaking strength. When an essential oil is dispersed in the suppository the disintegration time is reduced to one-third of the original value; however when the essential oil is dispersed in the form of its cyclodextrin complex the disintegration time remains substantially the same. As a result of the dispersed essential oil the breaking strength is reduced by a factor of 4-17: when the inclusion complex of the essential oil and cyclodextrin is used the breaking strength remains the same or becomes even somewhat higher.In the case ofMassapolyoxyaethenisuppositoriesthe inclusion complex of the essential oil and cyclodextrin does not increase the disintegration time and the breaking strength.
The above data prove unambiguously that when the essential oils are used in the form of their ss-cyclodextrin complexes the physical properties and characteristics of the suppositories are improved to a significant extent.
TABLE Ill
Physical characteristics of the suppositories
Solidification Dis- Breaking
Suppository point integration strength
"C time kg.
"A" (Adeps s., 1 g.) 28.6 5'25" 6.50
"B" (Adeps s. + essential
oil) 26.7 1 '40" 0.88
"C" (Adeps s. + complex) 30.0 5'37" 6.50 "D" (Adeps s.,2 9.) 28.6 9'15" 10.30
"E" (Adeps s. + essential
oil) 26.6 3'56" 2.50 "F"(Adepss. +complex) 30.0 10'35" 11.00 "G" (Massa p., 1 g.) - 24'51" 9.20
"H" (Massa p. + complex) - 26'52" 12.50
"I" (Massa p., 2 g.) - 31'37" 13.60
"J" (Massa p. + complex - 45'50" 14.50
Determination of satability of the suppository - active ingredient
Suppositories containing sweet fennel oil and the ss-cyclodextrin complex thereof respectively are prepared according to Exampls 6 and 10 respectively. The composition of the suppositories is as follows:
Suppository "K"
Sweet fennel oil 0.005 9.
Solid fat (Adeps solidus) 0.995 9.
Suppository "L"
Sweet fennel oil-ss-cyclodextrin complex
according to Example 1 0.024 g.
Adeps solidus 0.976 g.
Suppository "M"
Sweet fennel oil 0.05g.
Massa polyoxyaetheni 1.20 g.
Suppository "N"
Sweet fennel oil + ss-cyclodextrin complex according to Example 1 0.024 9.
Massa polyoxyaetheni 1.226 9.
The suppositories "K" and "L" are moulded at 34-36 "C and the suppositories "M" and "N" at a temperature of 50-55 "C. The essential oil content of suppository "M" is much larger, because at the higher temperture of 50-55 "C it could be expected that a part of the essential oil escapes. It appears from the following Tables that after moulding, the essential oil content of the suppository is but 31.45 mg/suppository. Thus during the 30 minutes period of mouling 37 % of the essential oil content is lost, so this method is unsuitable for the production of suppositories.
The suppositories are stored in a refrigerator for a week, thereafter 25 suppositories of each group are stored a 40 "C and 60 "C in Petri dishes in a thermostat. Samples using both types of suppository base in equal numbers are stored in the same thermostat.
Samples are taken at the point of time indicated in Table IV and are analysed. The Adeps solidus based suppositories are dissolved in 5 ml. of chloroform and diluted to 25 ml. with dimethyl-formamide (to dissolve the compixes). A enfold dilution is prepared with 96 % ethanol. The Massa polyoxyaetheni based suppositories are dissolved in 25 ml. of a 1:2 volume mixture of water and 96 % ethanol and a tenfold dilution is prepared with 96 % ethanol. The extinction of the clear solution thus obtained is determined at 259 nm. As control, solutions of thermally treated Adeps solidus and Massa polyoxyaetheni respectively of the same concentration are used.
In the case of suppositories containing the free essential oil not only the extinction measured at 259 nm decreased, but at 244,273 and 291 nm further new peaks appeared (decomposition products of the active ingredient).
The suppositories containing the inclusion complex of the essential oil showed no substantial decrease of the maximum at 259 nm and no further peaks appeared, thus no decomposition could be detected.
TABLE IV
Thermal stability measurements
Time of heating Supp. "K" Sup. "L"
at 40 C
After moulding 1.725 mg. = 100% 1.984 mg = 100% 31.450 mg. = 100% 1.808 mg = 100% 1 day 1.469 mg. = 85.2 % 2.009 mg = 101.2 24.230 mg = 77.0 1.711 mg = 94.6 3 days 1.203 mg. = 69.7 1.791 mg = 96.2 15.851 mg = 50.4 1.730 mg = 95.7 8 days 0.572 mg. = 33.2 1.875 mg = 94.5 ~x 1.573 mg = 87.0 14 days 0.166 mg. = 6.7 1.929 mg = 97.2 ~x 1.646 mg = 91.0 21 days 0 0 1.936 mg = 97.6 ~x 1.646 mg = 91.0
at 60 C
After moulding 1.725 mg. = 100% 1.984 mg = 100% 31.450 mg = 100% 1.808 mg = 100% 1 daq 0 = 0 1.793 mg = 90.4 6.519 mg = 20.7 1.551 mg = 85.8 4 days 0 = 0 1.549 mg = 78.1 0.339 mg = 1.1 1.525 mg = 84.3
Remarks : Massa polyoxyaetheni and suppositories prepared therefrom do notmelt at 40 C.
~x = no experiment was made
The mg data given in each column indicate the amount of the sweet fennel oil pro capsule.
The stability of the active ingredient content is determined as follows:
Suppositories weighing 1 g. and containing 51.7 mg. of the sweet fennel oil p-cyclodextrin complex according to Example 1 are prepared using Adeps solidus as the suppository base. The suppositories are prepared as described in Example 6, whereupon they are packed in the cold one-by-one into aluminium foils and stored in a cold place. The active ingredient content of the suppositories is measured after 5 months. No decrease could be detected in comparison with the original active ingredient content (4.24 mg. and 4.29 mg of sweet fennel oil included in the complex per capsule; this difference is within the measuring error and is a standard deviation; +0.08 and +0.07 mg. respectively).
The above experimental data show that the suppositories according to the present invention can be stored for a long time without any decrease of the active ingredient content.
Claims (11)
1. A suppository comprising a suppository base and an active ingredient in the form of a complex with a, p or y-cyclodextrin, said active ingredient being volatile and/or liable to decomposition in the uncomplexed state.
2. A suppository according to claim 1 wherein said suppository base is of fatty character.
3. A suppository according to claim 2 wherein said suppository base is a solid fat (Adeps solidus).
4. A suppository according to claim 1 wherein said suppository base is water-soluble.
5. A suppository according to claim 4 wherein said water soluble base comprises a mixture of polyethylene glycols.
6. A suppository according to any of the preceding claims wherein said active ingredient comprises an essential oil.
7. A suppository according to claim 6 comprising as active ingredient an inclusion complex of sweet fennel oil and p-cyclodextrin.
8. A suppository according to claim 6 according as active ingredient an inclusion complex of eucalyptus oil and p-cyclodextrin.
9. A suppository according to any of the preceding claims comprising 0.05-20% by weight of said complex.
10. A suppository according to claim 1, substantially as described herein.
11. A suppository according to claim 1, substantially as illustrated in any one of Examples 6-11 herein.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU80803050A HU180183B (en) | 1980-12-19 | 1980-12-19 | Process for preparing stable suppository compositions containing volatile and/or labile active substances |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2090738A true GB2090738A (en) | 1982-07-21 |
| GB2090738B GB2090738B (en) | 1985-02-27 |
Family
ID=10962287
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8138240A Expired GB2090738B (en) | 1980-12-19 | 1981-12-18 | Suppository containing active ingredientcyclodextrin complex |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS57123114A (en) |
| FR (1) | FR2496460B1 (en) |
| GB (1) | GB2090738B (en) |
| HU (1) | HU180183B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0094157A1 (en) * | 1982-04-30 | 1983-11-16 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its use |
| JPS5921613A (en) * | 1982-07-28 | 1984-02-03 | Takeda Chem Ind Ltd | Pharmaceutical preparation for rectum administration |
| US4659696A (en) * | 1982-04-30 | 1987-04-21 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its nasal or vaginal use |
| EP0334218A1 (en) * | 1988-03-23 | 1989-09-27 | HEXAL-PHARMA GMBH & CO. KG | Solid, especially suited for oral and rectal adiministration, etofenamate-containing preparations |
| WO1993000078A1 (en) * | 1991-06-28 | 1993-01-07 | The Government Of The United States Of America, Represented By The Department Of Health And Human Services | Molecular encapsulation and delivery of alkanes to living mammalian cells for risk assessment and pharmaceutical application |
| US5221669A (en) * | 1991-04-19 | 1993-06-22 | The United States Of America As Represented By The Department Of Health And Human Services | Antiviral compositions containing α-cyclodextrin sulfates alone and in combination with other known antiviral agents and glucocorticoids and methods of treating viral infections |
| US6071496A (en) * | 1988-02-05 | 2000-06-06 | Scharing Aktiengesellschaft | Polyalkylcyanoacrylate agents and methods for enhancing contrast in ultrasound imaging |
| WO2000062739A1 (en) * | 1999-04-16 | 2000-10-26 | Unilever Plc | Breath freshening lipstick containing menthol and cyclodextrine |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59148717A (en) * | 1983-02-11 | 1984-08-25 | Takeda Chem Ind Ltd | Drug for vaginal application |
| GB8613688D0 (en) * | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| FR2711530B1 (en) * | 1993-10-29 | 1995-12-01 | Oreal | Water in oil emulsion containing polyols and its use in cosmetology. |
| CN103156924A (en) * | 2013-04-01 | 2013-06-19 | 金华牧之家动物药业有限公司 | Chinese medicinal suppository for treating mammal endometritis and preparation method thereof |
| RU2752588C2 (en) * | 2019-10-02 | 2021-07-29 | Общество с ограниченной ответственностью "Самсон-Мед" | Preparation for treatment of prostatic gland diseases made in form of a suppository |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2260536C3 (en) * | 1972-12-11 | 1975-07-10 | Fa. H. Trommsdorff, 5100 Aachen | Molecular inclusion compounds of a silver alkanolamine complex and beta-cycloheptaamylose, processes for their preparation and pharmaceuticals containing these compounds |
| HU174699B (en) * | 1977-07-01 | 1980-03-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing cyclodextrin inclusion complexes of natural and synthetic spices, aromatic and flavoring materials |
| EP0006724B1 (en) * | 1978-06-16 | 1982-12-01 | Phares Pharmaceutical Research N.V. | Pharmaceutical compositions containing urea |
| HU176217B (en) * | 1978-11-20 | 1981-01-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing a cyclodextrin-chamomille inclusion complex and compositions containing thereof |
| JPS5592312A (en) * | 1978-12-29 | 1980-07-12 | Yamanouchi Pharmaceut Co Ltd | Suppository containing bronchodilating compound |
-
1980
- 1980-12-19 HU HU80803050A patent/HU180183B/en not_active IP Right Cessation
-
1981
- 1981-12-17 FR FR8123594A patent/FR2496460B1/en not_active Expired
- 1981-12-18 JP JP56203779A patent/JPS57123114A/en active Pending
- 1981-12-18 GB GB8138240A patent/GB2090738B/en not_active Expired
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4659696A (en) * | 1982-04-30 | 1987-04-21 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its nasal or vaginal use |
| EP0094157A1 (en) * | 1982-04-30 | 1983-11-16 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its use |
| JPH0524130B2 (en) * | 1982-07-28 | 1993-04-06 | Takeda Chemical Industries Ltd | |
| US4670419A (en) * | 1982-07-28 | 1987-06-02 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its rectal use |
| JPS5921613A (en) * | 1982-07-28 | 1984-02-03 | Takeda Chem Ind Ltd | Pharmaceutical preparation for rectum administration |
| US6071496A (en) * | 1988-02-05 | 2000-06-06 | Scharing Aktiengesellschaft | Polyalkylcyanoacrylate agents and methods for enhancing contrast in ultrasound imaging |
| US6177062B1 (en) | 1988-02-05 | 2001-01-23 | Schering Aktiengesellschaft | Agents and methods for enhancing contrast in ultrasound imaging |
| EP0334218A1 (en) * | 1988-03-23 | 1989-09-27 | HEXAL-PHARMA GMBH & CO. KG | Solid, especially suited for oral and rectal adiministration, etofenamate-containing preparations |
| US5221669A (en) * | 1991-04-19 | 1993-06-22 | The United States Of America As Represented By The Department Of Health And Human Services | Antiviral compositions containing α-cyclodextrin sulfates alone and in combination with other known antiviral agents and glucocorticoids and methods of treating viral infections |
| WO1993000078A1 (en) * | 1991-06-28 | 1993-01-07 | The Government Of The United States Of America, Represented By The Department Of Health And Human Services | Molecular encapsulation and delivery of alkanes to living mammalian cells for risk assessment and pharmaceutical application |
| US5321014A (en) * | 1991-06-28 | 1994-06-14 | The United States Of America As Represented By The Department Of Health And Human Services | Molecular encapsulation and delivery of alkenes alkynes and long chain alkanes, to living mammalian cells |
| WO2000062739A1 (en) * | 1999-04-16 | 2000-10-26 | Unilever Plc | Breath freshening lipstick containing menthol and cyclodextrine |
| US6383475B1 (en) | 1999-04-16 | 2002-05-07 | Fd Management, Inc. | Breath freshening lipstick |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2496460B1 (en) | 1985-06-28 |
| JPS57123114A (en) | 1982-07-31 |
| GB2090738B (en) | 1985-02-27 |
| FR2496460A1 (en) | 1982-06-25 |
| HU180183B (en) | 1983-02-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |