CA2161143A1 - New pharmaceutical preparations comprising cyclosporin for oral administration - Google Patents
New pharmaceutical preparations comprising cyclosporin for oral administrationInfo
- Publication number
- CA2161143A1 CA2161143A1 CA002161143A CA2161143A CA2161143A1 CA 2161143 A1 CA2161143 A1 CA 2161143A1 CA 002161143 A CA002161143 A CA 002161143A CA 2161143 A CA2161143 A CA 2161143A CA 2161143 A1 CA2161143 A1 CA 2161143A1
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- Prior art keywords
- alkylene
- preparation according
- pharmaceutical preparation
- cyclosporin
- component
- Prior art date
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- Life Sciences & Earth Sciences (AREA)
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Transplantation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to new cyclosporin-comprising oral pharmaceutical preparations. The new pharmaceutical pre-parations can be produced more easily and have a good bio-availability. In addition to cyclosporin as active ingre-dient the preparations contain an alkylene-polyether or alkylene-polyester. Optionally, an alkylene-polyole, an alkylene-glycole, a polyalkylene-glycole, an alkyldiether or paxtial ether of a lower monooxyalkandiole or polyoxyal-kandiole and/or a vegetable oil or its hydrated or hydrolysed product may be contained.
Description
New Pharmac~uti~al Prepaxation5 Compri3ing Cy~lo~porin fox Oral Admini~ration The invention relates to new pharmaceutical preparations comprising cycloRporin as active ingredien~ for oral admi-nistration.
Cyclosporins are a class of peptides which are used as im-m~no~uppres~ants, in particular. Moreover, cyclosporins are known to have an~iphlogistic and antiparasitic effec~, Therefore, the use of cyclosporins is not limlted to immuno-suppre~sants only but relate~ to all phlogistic diseases in-cluding various auto-immune diseases as well as other phlo-gistic condition~, in partic~lar, phlogistic conditions ~n ~hich auto-;~ml1n~ processe~ play a xole. The above phlogis-tic ~onditions also include, in particular, arthritic di-sea~es such as rheumatoid arthritis as well as rheumatic disea6es. Cyclosporin5 can be u~ed as antiparasitic agents e.g. fox the ~reatment of protozoal infec~ions s~ch as ma-laria.
Cyclosporins are highly hydrophobic subs~zn¢es, having the consequence that it is difficult to easily process them into pha~maceutical p~ep~ration~ e~suring furthe~ suf~icient bio-~vailability. The latter aspec~ is particularl~ important, ~ecause th~ cycloRporins possess ~ephrotoxic side-effec~s of essential impo~ance. Cyclosporin-cont~;nin~ pharmaceutical prepar~ion~ proposed so far are based on the use of an ~1-cohol and/ox oils or similar vehi~le~ i~ connection with a surface-active agent. S~ch preparations are known from DE-OS
~9 07 460, for instance. The use of such liquid composi-~ions, however, is accomp~n;ed by a num~er of disadv~ntages and difficulties The use of oil~ or compar~ble vehicles on oil basis leads to imp~ir~ent of the sen~e o~ taste, in par-ticular, in the case Q~ long-time administr~tion as a con-se~uence of lon~-term t~e~p~. Since for dissolving ~he ac-ti~e ingredient a high amount of ~lcohol is ~equired, the resul~ will b~ that in addition the patient is permanently ~min; stexed alcohol and in the oa~e of evapox~tion of the alcohol during long-te~m use ~he active ingredient pre~i-pitates. T~e ~ttempt to offer su~ preparations i~ ~he for~
o~ soft gelati~ c~psules did not yield ~ satisfactory so-lution elthe~ due to the higher e~penditure conne~ted there-with.
CHS
~16I143 DE-OS 40 03 844 proposes a preparation syste~ which i~ addi-~ion to the active ing~edient contains a fatty acid sa~char-ide monoester and ~ diluent or vehicle by ~e~s of which it i~ said to be po~si~le to provide ~olid, semi-solid and li-quid prepa~tions having a content of cyclo~porin in a suf-fi~iently hi~h conce~tration, so that ~hus o~a~ adm~nis-~ration is comfortably possible ~nd an improved efficiency, for in~tance, with respect to the bio-availability prop-e~ies will be achieved. Accordingly, these forms of adm~-ni~tra~ion contain at least two ~omponents in additio~ to the active in~redient.
The applicant now has surprisingly found a preparation sys-tem for oral ~i ni stration by means of which it is possible to provide a cyclosporin-~omprising pharma~eu~ical prepara-tion for oral administration, which in addition to~the ac-tive in~redient cyclo~porin contains onl~ one vehicle com-ponent. Said component is ~n alkylene-polyether ox alkylene-polyester or any mixtu~ thereof, in which ~he vehicle sys-te~ must have an HLB of at leas~ 10. The preparations ac-cording to the invention yield a bio-avail~bili~y of the active ingredient whi~h at least is comparable with the best, known cyclosporin-containing preparations.
Ha~ing a comparably good bio-availability the pharmaceutical preparaticns according to the invention can be produced in a more economical way, ~void additives impairing the sense of taste as well as the disadvantageous alcohol contained and, in addition, lead to a ~etter patien~ compliance within the ~ense that the total weight of the formulation to ~e admi-nistered is reduced as ~o~pared ~ith known preparation~, with the active ingred.ient concen~ration staying ~he same.
Therefore, the inve~tion rela~es to pharmaceutical p~epara-tions for oral administra~ion, containing cyclosporin as ac-~i~e ing~edient and bein~ compo~ed as follo~s a) a cyclorporin as active inyr~dient, b) an alkylene-polyether or alkylene-polyester ~s vehicle or an~ mixture thereof, with ~he HLB ~eing at least 10.
Optionally, the p~eparations according to the invention may contain as further component (~) an alkylene polyole, an al-kylene glycole, a polyalkylene glycole, a C~s-al~yldie~her or partial ether of a lower ~onoo~yalkandiole or polyoxyal-kandiole having 2 ~o 15 carbon atoms and/o~ a vegetable oil or its hy~ ed or hyd~olysed produ~t.
Moreover, the preparation~ according to the inven~ion can con~ain furthe~ known, com~on and pha~maceutically accept-~1611~3 able additives (d) ~uch as are known i~ the field of theproduction of oral fox~ulations.
In pa~ts by weigh~ the prep~rations according to the in~en-tion contai~ 1 to 50 pa~ by weight of (b) and/or 0.5 to ~0 parts by weight o~ (c) per par~ by weight active in~redient, preferably S to 10 part5 by weight (b) and/or 1 to 10 parts b~ weigh~ (c) per 1 ~art acti~e ingredient and, in particu-.
lar 5 part~ by ~eigh~ (b~ and/or 1 pa~ ~y weight (c) pe~ 1 part by weight active ingredie~t In the case of component (b) it suitably pertains to C3 to C5 alkylene-triolether or C3 to Cs ~lk~lene-trioester, in particular glycerine. These also include e.g. ~ranses~erifi-c~ion product~ of the ~lkylene-triolesters with other mono-oles, dioles or polyoles as well as those subst~ces de-sc~ibed under "~omponent Csl' in DE-OS 4~ 03 84~. Saturated polyglycolised glyceride having an HL~ of at least lO are paxticularly adv~ntageous. Preferably, the satura~ed, poly- ~' glycolised glycerides known under the mark tenm Gelucire (the term Gelucire i~ a tr~e~rk of the company Gattefoss~) are u8ed and, in particular, the Gelucixe~ 35/10, 44/14, 4~/12, 50/13, 53/10 and any mixtuxes ~hereof, in which connection the ELB of the vehicle components used is at least lO.
The option~l component (c) comprise, for instance, di-ethers or partial ethers of lower (Cz.l~) mono- or polyoxyalkandi-ole~ æuch as are described in D~-OS 39 30 ~2~ in the sec~ion relating to the co~ponent 1.1. ~he optional component (c) fur~her comprises C3 s alkylene polyole~, C24 alkylene gly- -~oles, poly-(C2,-alkylene~-glycoles, and vegetable oils as well as their hydration a~d/or hydrolysis products such ~s ca~tor oil, olive oil, palm oil, coconut oil, corn oil, se-sa~e oil. The componen~ (c) may be contai~ed as single sub-stance or in any mixture~ Preferred examples of the compo-nent (c) are glycerine, p~opylene glycole and polyalkylene glycole having ~ molecular weight of up to 600, in p~rticu-lar transcutol and cas~or oil and the hydrated and hydrolys-ed products thereof.
The fu~her u~able ~dditives pertain to pharmaceutically ac-ceptable additive6 common in the field o~ oral form~ of ad-ministration. Examples thereof are the relea8e of control-ling ~u~stances, thickening agents, prese~vati~es, stabili-zers, flavorings, ~inding agents, lub~icant~ and the like.
These additi~es may amount ~o up to SO~ of t~e total co~po-sition, however, pre~erably does not exceed 25~ and, in par-ticula~, not 10~ of the total composition.
21611~3 All of the known natural and ~yn~hetic cyclo~po~ins includ-i~g their analogs and derivatives are suitable for ~he u~e in p~eparations ~ccording to the invention. Exa~ples of such cyclospo~ins are found e.g. in DE~OS 40 03 ~44 and DE-OS 40 05 190, Preferably cyclo~porin A i~ used.
The oral forms of administ~a~on include e.g. liquids, g~a-nula~es and solid forms suc~ as ta~lets and capsule~ which can be produced according to the common methods known to the per~on ~killed in ~he art.
The oral forms of adminis~ration according to the invention usually are available in ~t~n~rd dose form and contain a~out 20 ~o 200 mg, preferabl~ 50 to 100 mg acti~e ingre-dient per ~tand~d dose.
~he following example~ serve the fur~her illu~ration of the invention.
Example~
1. Co~onent~ Amount ~m~
Cyclosporin A 50.0 Gelucix 53/10 300.0 Total 350.0 2. ~yclosporin A 50.0 Gelucir 44/14 250.0 Pxopylene glycole 50 0 Total 350-0 3. ~yclo~porin A ~0.0 Gelucir 50/13 250.0 Trans~utol 75.0 Total 375 0 4. Cyclospo~in A 50.0 Gelucix 44Jl4 250.0 Total 300 0 ~1611g3 s 5. Cyclosporin A 50 0 Gelucir ~0/13 250.0 Propylene glycole 50.0 ~otal . Cyclosporin A 50 0 Gelucsr 35/10 250.0 Propylene glycole ~5 0 Total 325.0 7. Cyclo3porin ~ 50.0 Gelucir 53/10, ~2/12 27S.0 ~ranscutol 50 0 Total 375,0 8. Cy~losporin A 50.0 Gelucir 42/~2 ~o~ o Glyce~ine ~5.0 Total 375-0 9. C~closporin ~ S0.0 Gelucir 50/1~ 250.0 Castor oil 75.0 Total 375-0 Production: The composition~ of examples 1 to 9 are prod~ced in that the component ~b~ is melted ~y heati~g preferably to at lea~ 60~C and the ~tive ing~edient (a) is dissol~ed the~ein by s~irring. If desired, optio~al component (c) i~
added to the mel~ed mass.
Subseque~tly, the preparations obtained are filled, ~or in-stance, in liquid f~rm into hard-gelatin c~psules of the de-sired ~i~e in the concen~ration~ de~ired. The compositions can also be f~rther proce6~ed to tablet~ in ~he known man-ner. ~or this pu~poe, the ~elted masses are produced a~
desc~i~ed in the above~ The liquid mel~ed masses are poured out and after ~olidification diminuited by me~ns of a siev-ing ~achine. The ~ranulates produced such are mixed with ~he usual adjuvants such a~ slip agents ~nd lubricants, ~lastin~
age~ts, fillers, flavor corrige~t~ e~c. The finished mix-tures are pressed to tablets ha~ing the desired content of cyclosporin. The tablets may also be coated with a protec-tive co~er.
~io-A~allability:
R~Am~n~tion~ as to the ~io-availability of ~he ~omposi~ions accordin~ ~o the invention on dogs.
A group o~ six Be~gle dogs was used fo~ the bio-availability e~Am;nAtiorls. The test drugs were orally ap~lied to the ani-mal with an em~ty stomach ~y means of oesophayeal sounds. At defined time~ blood is taken from ~he ~ena saphena of ~he An;~?l 8 and collected in correspo~in~ plastic tubes with E~TA additive. The blood samples are sto~ed until assayin~
at -18C. Assay of the cyclosporin take~ place in ~he whole blood by means of fluorescence-polarisation ;~llnoassay (FPIA).
The areas under the cur~es (AUC~ in which the ~loo~ d~u~
concentration is applied relative ~o time were calculated accor~ing ~o the trapezoid ~ule. The aver~ge AUC values o~
compo~itioIls according to the invention are ~hown in the followin~ table in comparison to ~he commercially available sub~tances of cyclo~poxin drinking solution and cy~losporin capsules (s~ndimmllnR) which ~ere ascertained in the same in the same dosage with the same dogs.
~3xa~les AUC ( 0 -12 h) ng/rlll Exa~ple 2 gO35 + 2~34 Example 3 785~ 1 1512 Example 4 755~ ~ 1lg4 Example 5 8228 ~ 8S7 Cyclo~porin Drinking Solution 7sao 1 13ZO
C~closporin Capsules 8098 + 1$04 As the above tests on ~he bio-a~ailability show, the phar-maceutical prepa~ations according to ~he invention make it possible ~o pro~ide the ac~ive ingr~dient cyclosporin in such ~n oral form that its bio-availability at least ~o~re~-ponds to ~he preparations ~own ~o far.
Cyclosporins are a class of peptides which are used as im-m~no~uppres~ants, in particular. Moreover, cyclosporins are known to have an~iphlogistic and antiparasitic effec~, Therefore, the use of cyclosporins is not limlted to immuno-suppre~sants only but relate~ to all phlogistic diseases in-cluding various auto-immune diseases as well as other phlo-gistic condition~, in partic~lar, phlogistic conditions ~n ~hich auto-;~ml1n~ processe~ play a xole. The above phlogis-tic ~onditions also include, in particular, arthritic di-sea~es such as rheumatoid arthritis as well as rheumatic disea6es. Cyclosporin5 can be u~ed as antiparasitic agents e.g. fox the ~reatment of protozoal infec~ions s~ch as ma-laria.
Cyclosporins are highly hydrophobic subs~zn¢es, having the consequence that it is difficult to easily process them into pha~maceutical p~ep~ration~ e~suring furthe~ suf~icient bio-~vailability. The latter aspec~ is particularl~ important, ~ecause th~ cycloRporins possess ~ephrotoxic side-effec~s of essential impo~ance. Cyclosporin-cont~;nin~ pharmaceutical prepar~ion~ proposed so far are based on the use of an ~1-cohol and/ox oils or similar vehi~le~ i~ connection with a surface-active agent. S~ch preparations are known from DE-OS
~9 07 460, for instance. The use of such liquid composi-~ions, however, is accomp~n;ed by a num~er of disadv~ntages and difficulties The use of oil~ or compar~ble vehicles on oil basis leads to imp~ir~ent of the sen~e o~ taste, in par-ticular, in the case Q~ long-time administr~tion as a con-se~uence of lon~-term t~e~p~. Since for dissolving ~he ac-ti~e ingredient a high amount of ~lcohol is ~equired, the resul~ will b~ that in addition the patient is permanently ~min; stexed alcohol and in the oa~e of evapox~tion of the alcohol during long-te~m use ~he active ingredient pre~i-pitates. T~e ~ttempt to offer su~ preparations i~ ~he for~
o~ soft gelati~ c~psules did not yield ~ satisfactory so-lution elthe~ due to the higher e~penditure conne~ted there-with.
CHS
~16I143 DE-OS 40 03 844 proposes a preparation syste~ which i~ addi-~ion to the active ing~edient contains a fatty acid sa~char-ide monoester and ~ diluent or vehicle by ~e~s of which it i~ said to be po~si~le to provide ~olid, semi-solid and li-quid prepa~tions having a content of cyclo~porin in a suf-fi~iently hi~h conce~tration, so that ~hus o~a~ adm~nis-~ration is comfortably possible ~nd an improved efficiency, for in~tance, with respect to the bio-availability prop-e~ies will be achieved. Accordingly, these forms of adm~-ni~tra~ion contain at least two ~omponents in additio~ to the active in~redient.
The applicant now has surprisingly found a preparation sys-tem for oral ~i ni stration by means of which it is possible to provide a cyclosporin-~omprising pharma~eu~ical prepara-tion for oral administration, which in addition to~the ac-tive in~redient cyclo~porin contains onl~ one vehicle com-ponent. Said component is ~n alkylene-polyether ox alkylene-polyester or any mixtu~ thereof, in which ~he vehicle sys-te~ must have an HLB of at leas~ 10. The preparations ac-cording to the invention yield a bio-avail~bili~y of the active ingredient whi~h at least is comparable with the best, known cyclosporin-containing preparations.
Ha~ing a comparably good bio-availability the pharmaceutical preparaticns according to the invention can be produced in a more economical way, ~void additives impairing the sense of taste as well as the disadvantageous alcohol contained and, in addition, lead to a ~etter patien~ compliance within the ~ense that the total weight of the formulation to ~e admi-nistered is reduced as ~o~pared ~ith known preparation~, with the active ingred.ient concen~ration staying ~he same.
Therefore, the inve~tion rela~es to pharmaceutical p~epara-tions for oral administra~ion, containing cyclosporin as ac-~i~e ing~edient and bein~ compo~ed as follo~s a) a cyclorporin as active inyr~dient, b) an alkylene-polyether or alkylene-polyester ~s vehicle or an~ mixture thereof, with ~he HLB ~eing at least 10.
Optionally, the p~eparations according to the invention may contain as further component (~) an alkylene polyole, an al-kylene glycole, a polyalkylene glycole, a C~s-al~yldie~her or partial ether of a lower ~onoo~yalkandiole or polyoxyal-kandiole having 2 ~o 15 carbon atoms and/o~ a vegetable oil or its hy~ ed or hyd~olysed produ~t.
Moreover, the preparation~ according to the inven~ion can con~ain furthe~ known, com~on and pha~maceutically accept-~1611~3 able additives (d) ~uch as are known i~ the field of theproduction of oral fox~ulations.
In pa~ts by weigh~ the prep~rations according to the in~en-tion contai~ 1 to 50 pa~ by weight of (b) and/or 0.5 to ~0 parts by weight o~ (c) per par~ by weight active in~redient, preferably S to 10 part5 by weight (b) and/or 1 to 10 parts b~ weigh~ (c) per 1 ~art acti~e ingredient and, in particu-.
lar 5 part~ by ~eigh~ (b~ and/or 1 pa~ ~y weight (c) pe~ 1 part by weight active ingredie~t In the case of component (b) it suitably pertains to C3 to C5 alkylene-triolether or C3 to Cs ~lk~lene-trioester, in particular glycerine. These also include e.g. ~ranses~erifi-c~ion product~ of the ~lkylene-triolesters with other mono-oles, dioles or polyoles as well as those subst~ces de-sc~ibed under "~omponent Csl' in DE-OS 4~ 03 84~. Saturated polyglycolised glyceride having an HL~ of at least lO are paxticularly adv~ntageous. Preferably, the satura~ed, poly- ~' glycolised glycerides known under the mark tenm Gelucire (the term Gelucire i~ a tr~e~rk of the company Gattefoss~) are u8ed and, in particular, the Gelucixe~ 35/10, 44/14, 4~/12, 50/13, 53/10 and any mixtuxes ~hereof, in which connection the ELB of the vehicle components used is at least lO.
The option~l component (c) comprise, for instance, di-ethers or partial ethers of lower (Cz.l~) mono- or polyoxyalkandi-ole~ æuch as are described in D~-OS 39 30 ~2~ in the sec~ion relating to the co~ponent 1.1. ~he optional component (c) fur~her comprises C3 s alkylene polyole~, C24 alkylene gly- -~oles, poly-(C2,-alkylene~-glycoles, and vegetable oils as well as their hydration a~d/or hydrolysis products such ~s ca~tor oil, olive oil, palm oil, coconut oil, corn oil, se-sa~e oil. The componen~ (c) may be contai~ed as single sub-stance or in any mixture~ Preferred examples of the compo-nent (c) are glycerine, p~opylene glycole and polyalkylene glycole having ~ molecular weight of up to 600, in p~rticu-lar transcutol and cas~or oil and the hydrated and hydrolys-ed products thereof.
The fu~her u~able ~dditives pertain to pharmaceutically ac-ceptable additive6 common in the field o~ oral form~ of ad-ministration. Examples thereof are the relea8e of control-ling ~u~stances, thickening agents, prese~vati~es, stabili-zers, flavorings, ~inding agents, lub~icant~ and the like.
These additi~es may amount ~o up to SO~ of t~e total co~po-sition, however, pre~erably does not exceed 25~ and, in par-ticula~, not 10~ of the total composition.
21611~3 All of the known natural and ~yn~hetic cyclo~po~ins includ-i~g their analogs and derivatives are suitable for ~he u~e in p~eparations ~ccording to the invention. Exa~ples of such cyclospo~ins are found e.g. in DE~OS 40 03 ~44 and DE-OS 40 05 190, Preferably cyclo~porin A i~ used.
The oral forms of administ~a~on include e.g. liquids, g~a-nula~es and solid forms suc~ as ta~lets and capsule~ which can be produced according to the common methods known to the per~on ~killed in ~he art.
The oral forms of adminis~ration according to the invention usually are available in ~t~n~rd dose form and contain a~out 20 ~o 200 mg, preferabl~ 50 to 100 mg acti~e ingre-dient per ~tand~d dose.
~he following example~ serve the fur~her illu~ration of the invention.
Example~
1. Co~onent~ Amount ~m~
Cyclosporin A 50.0 Gelucix 53/10 300.0 Total 350.0 2. ~yclosporin A 50.0 Gelucir 44/14 250.0 Pxopylene glycole 50 0 Total 350-0 3. ~yclo~porin A ~0.0 Gelucir 50/13 250.0 Trans~utol 75.0 Total 375 0 4. Cyclospo~in A 50.0 Gelucix 44Jl4 250.0 Total 300 0 ~1611g3 s 5. Cyclosporin A 50 0 Gelucir ~0/13 250.0 Propylene glycole 50.0 ~otal . Cyclosporin A 50 0 Gelucsr 35/10 250.0 Propylene glycole ~5 0 Total 325.0 7. Cyclo3porin ~ 50.0 Gelucir 53/10, ~2/12 27S.0 ~ranscutol 50 0 Total 375,0 8. Cy~losporin A 50.0 Gelucir 42/~2 ~o~ o Glyce~ine ~5.0 Total 375-0 9. C~closporin ~ S0.0 Gelucir 50/1~ 250.0 Castor oil 75.0 Total 375-0 Production: The composition~ of examples 1 to 9 are prod~ced in that the component ~b~ is melted ~y heati~g preferably to at lea~ 60~C and the ~tive ing~edient (a) is dissol~ed the~ein by s~irring. If desired, optio~al component (c) i~
added to the mel~ed mass.
Subseque~tly, the preparations obtained are filled, ~or in-stance, in liquid f~rm into hard-gelatin c~psules of the de-sired ~i~e in the concen~ration~ de~ired. The compositions can also be f~rther proce6~ed to tablet~ in ~he known man-ner. ~or this pu~poe, the ~elted masses are produced a~
desc~i~ed in the above~ The liquid mel~ed masses are poured out and after ~olidification diminuited by me~ns of a siev-ing ~achine. The ~ranulates produced such are mixed with ~he usual adjuvants such a~ slip agents ~nd lubricants, ~lastin~
age~ts, fillers, flavor corrige~t~ e~c. The finished mix-tures are pressed to tablets ha~ing the desired content of cyclosporin. The tablets may also be coated with a protec-tive co~er.
~io-A~allability:
R~Am~n~tion~ as to the ~io-availability of ~he ~omposi~ions accordin~ ~o the invention on dogs.
A group o~ six Be~gle dogs was used fo~ the bio-availability e~Am;nAtiorls. The test drugs were orally ap~lied to the ani-mal with an em~ty stomach ~y means of oesophayeal sounds. At defined time~ blood is taken from ~he ~ena saphena of ~he An;~?l 8 and collected in correspo~in~ plastic tubes with E~TA additive. The blood samples are sto~ed until assayin~
at -18C. Assay of the cyclosporin take~ place in ~he whole blood by means of fluorescence-polarisation ;~llnoassay (FPIA).
The areas under the cur~es (AUC~ in which the ~loo~ d~u~
concentration is applied relative ~o time were calculated accor~ing ~o the trapezoid ~ule. The aver~ge AUC values o~
compo~itioIls according to the invention are ~hown in the followin~ table in comparison to ~he commercially available sub~tances of cyclo~poxin drinking solution and cy~losporin capsules (s~ndimmllnR) which ~ere ascertained in the same in the same dosage with the same dogs.
~3xa~les AUC ( 0 -12 h) ng/rlll Exa~ple 2 gO35 + 2~34 Example 3 785~ 1 1512 Example 4 755~ ~ 1lg4 Example 5 8228 ~ 8S7 Cyclo~porin Drinking Solution 7sao 1 13ZO
C~closporin Capsules 8098 + 1$04 As the above tests on ~he bio-a~ailability show, the phar-maceutical prepa~ations according to ~he invention make it possible ~o pro~ide the ac~ive ingr~dient cyclosporin in such ~n oral form that its bio-availability at least ~o~re~-ponds to ~he preparations ~own ~o far.
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Pharmaceutical preparation for oral administration containing as the only component or consisting of (a) a cyclosporin as active ingredient, and (b) an alkylene-polyether or alkylene-polyester either alone or in any mixture as vehicle, whereby the HLB of the component (b) used being at least 10.
2. Pharmaceutical preparation according to claim 1, further containing (c) an alkylene-polyole, alkylene-gly-cole, a polyalkylene-glycole, an alkyldiether or partial ether of a lower monooxyalkandiole or polyoxyalkandiole and/or a vegetable oil or its hydrated or hydrolysed product either alone or in any mixtures.
3. Preparation according to claim 1 or 2, in which the respective components (a), (b) and/or (c) are available in the following weight ratios: 1:1-50:0.5-20, preferably 1:5-10:1-10, in particular 1:5:1.
4. Preparation according to one of claims 1 to 3, in which the component (b) is chosen from among saturated poly-glycolised glycerides.
5. Pharmaceutical preparation according to the previous claim 4, in which the component (b) is chosen from among the Gelucires GelucirR 35/10, 44/14, 42/12, 50/13, 53/10 and any mixtures thereof.
6. Pharmaceutical preparation according to claim 2, in which the additional component (c) is chosen from among gly-cerine, propylene glycole, PEG with MG up to approx. 600, transcutol and castor oil.
7. Pharmaceutical preparation according to one of the previous claims in the form of hard-gelatin capsules or in the form of a tablet.
8. Pharmaceutical preparation according to one of the previous claims, characterized in that the active ingredient concentration is 20 to 200 mg, preferably 50 to 100 mg per dose unit.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4312728 | 1993-04-20 | ||
| DEP4312728.2 | 1993-04-20 | ||
| DE4412201A DE4412201A1 (en) | 1993-04-20 | 1994-04-08 | New pharmaceutical preparations for oral administration containing cyclosporin |
| DEP4412201.2 | 1994-04-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2161143A1 true CA2161143A1 (en) | 1994-10-27 |
Family
ID=25925049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002161143A Abandoned CA2161143A1 (en) | 1993-04-20 | 1994-04-20 | New pharmaceutical preparations comprising cyclosporin for oral administration |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0697881B2 (en) |
| JP (2) | JP3862273B2 (en) |
| AT (1) | ATE218878T1 (en) |
| CA (1) | CA2161143A1 (en) |
| CZ (1) | CZ291237B6 (en) |
| DK (1) | DK0697881T3 (en) |
| ES (1) | ES2178653T3 (en) |
| FI (1) | FI116120B (en) |
| HU (1) | HUT72738A (en) |
| NO (1) | NO321076B1 (en) |
| PT (1) | PT697881E (en) |
| SK (1) | SK283442B6 (en) |
| WO (1) | WO1994023733A1 (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5834017A (en) * | 1995-08-25 | 1998-11-10 | Sangstat Medical Corporation | Oral cyclopsporin formulations |
| US5962019A (en) * | 1995-08-25 | 1999-10-05 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| US5766629A (en) * | 1995-08-25 | 1998-06-16 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| US5827822A (en) * | 1996-03-25 | 1998-10-27 | Sangstat Medical Corporation | Cyclosporin a formulations as nanoparticles |
| DE19545043A1 (en) * | 1995-12-02 | 1997-06-05 | Scherer Gmbh R P | Pharmaceutical preparations for oral use and process for their preparation |
| ES2229473T3 (en) * | 1997-01-30 | 2005-04-16 | Novartis Ag | PHARMACEUTICAL COMPOSITIONS WITHOUT OIL CONTAINING CYCLOSPORINE A. |
| CA2284000C (en) * | 1997-03-12 | 2012-01-03 | Abbott Laboratories | Hydrophilic binary systems for the administration of cyclosporine |
| US6187747B1 (en) | 1997-09-08 | 2001-02-13 | Panacea Biotech Limited | Pharmaceutical composition comprising cyclosporin |
| US6346511B1 (en) | 1997-09-08 | 2002-02-12 | Panacea Biotec Limited | Pharmaceutical composition comprising cyclosporin |
| US6008191A (en) * | 1997-09-08 | 1999-12-28 | Panacea Biotec Limited | Pharmaceutical compositions containing cyclosporin |
| DE69842121D1 (en) | 1997-12-10 | 2011-03-17 | Cyclosporine Therapeutics Ltd | OMEGA-3 FATTY ACID PHARMACEUTICAL COMPOSITIONS |
| US6207179B1 (en) | 2000-05-18 | 2001-03-27 | Phoenix Scientific, Inc. | Parasiticidal formulation for animals and a method of making this formulation |
| US6998385B2 (en) | 2001-10-19 | 2006-02-14 | Isotechnika Inc. | Cyclosporine analogue mixtures and their use as immunomodulating agents |
| US6979672B2 (en) | 2002-12-20 | 2005-12-27 | Polichem, S.A. | Cyclosporin-based pharmaceutical compositions |
| US7682433B2 (en) | 2007-05-11 | 2010-03-23 | Canon Kabushiki Kaisha | Ink set, ink jet recording method, ink cartridge, recording unit, and ink jet recording apparatus |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH641356A5 (en) * | 1979-02-27 | 1984-02-29 | Sandoz Ag | Pharmaceutical compositions containing cyclosporin |
| GB8903804D0 (en) † | 1989-02-20 | 1989-04-05 | Sandoz Ltd | Improvements in or relating to organic compounds |
| DE3580717D1 (en) * | 1984-08-02 | 1991-01-10 | Sandoz Ag | PHARMACEUTICAL APPLICATION OF (NVA) 2-CYCLOSPORINE. |
| DE68900991D1 (en) † | 1988-01-29 | 1992-04-23 | Sankyo Co | CYCLOSPORIN COMPOSITIONS. |
| KR0148748B1 (en) † | 1988-09-16 | 1998-08-17 | 장 크라메르, 한스 루돌프 하우스 | A multiphase cyclosporin composition |
| BE1003009A5 (en) † | 1989-02-09 | 1991-10-22 | Sandoz Sa | NOVEL PHARMACEUTICAL COMPOSITIONS BASED ON CYCLOSPORINS. |
-
1994
- 1994-04-20 CA CA002161143A patent/CA2161143A1/en not_active Abandoned
- 1994-04-20 JP JP52278294A patent/JP3862273B2/en not_active Expired - Fee Related
- 1994-04-20 SK SK1298-95A patent/SK283442B6/en not_active IP Right Cessation
- 1994-04-20 HU HU9503019A patent/HUT72738A/en unknown
- 1994-04-20 ES ES94915073T patent/ES2178653T3/en not_active Expired - Lifetime
- 1994-04-20 DK DK94915073T patent/DK0697881T3/en active
- 1994-04-20 PT PT94915073T patent/PT697881E/en unknown
- 1994-04-20 AT AT94915073T patent/ATE218878T1/en not_active IP Right Cessation
- 1994-04-20 WO PCT/EP1994/001228 patent/WO1994023733A1/en active IP Right Grant
- 1994-04-20 EP EP94915073A patent/EP0697881B2/en not_active Expired - Lifetime
- 1994-04-20 CZ CZ19952729A patent/CZ291237B6/en not_active IP Right Cessation
-
1995
- 1995-10-18 NO NO19954152A patent/NO321076B1/en not_active IP Right Cessation
- 1995-10-19 FI FI954986A patent/FI116120B/en active IP Right Grant
-
2006
- 2006-05-10 JP JP2006131593A patent/JP2006206615A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| NO954152D0 (en) | 1995-10-18 |
| EP0697881A1 (en) | 1996-02-28 |
| CZ291237B6 (en) | 2003-01-15 |
| SK129895A3 (en) | 1997-02-05 |
| NO954152L (en) | 1995-10-18 |
| JP3862273B2 (en) | 2006-12-27 |
| JPH08508984A (en) | 1996-09-24 |
| EP0697881B2 (en) | 2009-05-06 |
| PT697881E (en) | 2002-10-31 |
| SK283442B6 (en) | 2003-07-01 |
| DK0697881T3 (en) | 2002-10-07 |
| FI954986A (en) | 1995-10-19 |
| HUT72738A (en) | 1996-05-28 |
| WO1994023733A1 (en) | 1994-10-27 |
| ES2178653T3 (en) | 2003-01-01 |
| ATE218878T1 (en) | 2002-06-15 |
| CZ272995A3 (en) | 1996-02-14 |
| JP2006206615A (en) | 2006-08-10 |
| FI116120B (en) | 2005-09-30 |
| FI954986A0 (en) | 1995-10-19 |
| EP0697881B1 (en) | 2002-06-12 |
| NO321076B1 (en) | 2006-03-13 |
| HU9503019D0 (en) | 1995-12-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |