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
- Authority
- CA
- Canada
- Prior art keywords
- alkylene
- preparation according
- pharmaceutical preparation
- cyclosporin
- component
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229930182912 cyclosporin Natural products 0.000 title claims abstract description 12
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 title claims abstract description 11
- 229930105110 Cyclosporin A Natural products 0.000 title claims abstract description 11
- 108010036949 Cyclosporine Proteins 0.000 title claims abstract description 11
- 229960001265 ciclosporin Drugs 0.000 title claims abstract description 11
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 239000004721 Polyphenylene oxide Substances 0.000 claims abstract description 4
- 229920000728 polyester Polymers 0.000 claims abstract description 4
- 229920000570 polyether Polymers 0.000 claims abstract description 4
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 4
- 239000008158 vegetable oil Substances 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 10
- 239000003981 vehicle Substances 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 125000005456 glyceride group Chemical group 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000007903 gelatin capsule Substances 0.000 claims 1
- 229960005150 glycerol Drugs 0.000 claims 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 abstract 1
- 239000000306 component Substances 0.000 description 10
- 150000002500 ions Chemical class 0.000 description 10
- 108010013381 Porins Proteins 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 102000007739 porin activity proteins Human genes 0.000 description 6
- 108010036941 Cyclosporins Proteins 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 2
- 239000003096 antiparasitic agent Substances 0.000 description 2
- 230000035622 drinking Effects 0.000 description 2
- 229920001281 polyalkylene Polymers 0.000 description 2
- -1 prese~vati~es Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 101000837192 Drosophila melanogaster Teneurin-m Proteins 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 101710072850 Poxin Proteins 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- IOVGROKTTNBUGK-SJCJKPOMSA-N ritodrine Chemical compound N([C@@H](C)[C@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJCJKPOMSA-N 0.000 description 1
- 230000014860 sensory perception of taste Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000012748 slip agent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Transplantation (AREA)
- Biophysics (AREA)
- Molecular Biology (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 |
|---|---|---|---|
| DEP4312728.2 | 1993-04-20 | ||
| DE4312728 | 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 (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5766629A (en) * | 1995-08-25 | 1998-06-16 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| US5962019A (en) * | 1995-08-25 | 1999-10-05 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| US5834017A (en) * | 1995-08-25 | 1998-11-10 | Sangstat Medical Corporation | Oral cyclopsporin 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 |
| EP0988046B1 (en) * | 1997-01-30 | 2004-09-15 | Novartis AG | Oil-free pharmaceutical compositions containing cyclosporin a |
| US6008192A (en) * | 1997-03-12 | 1999-12-28 | Abbott Laboratories | Hydrophilic binary systems for the administration of lipophilic compounds |
| US6008191A (en) * | 1997-09-08 | 1999-12-28 | Panacea Biotec Limited | Pharmaceutical compositions containing cyclosporin |
| 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 |
| US20030220234A1 (en) | 1998-11-02 | 2003-11-27 | Selvaraj Naicker | Deuterated cyclosporine analogs and their use as immunodulating agents |
| WO1999029316A1 (en) | 1997-12-10 | 1999-06-17 | Severson, Mary, L. | Pharmaceutical compositions containing an omega-3 fatty acid oil |
| US6979456B1 (en) | 1998-04-01 | 2005-12-27 | Jagotec Ag | Anticancer compositions |
| US6207179B1 (en) | 2000-05-18 | 2001-03-27 | Phoenix Scientific, Inc. | Parasiticidal formulation for animals and a method of making this formulation |
| CN100334106C (en) | 2001-10-19 | 2007-08-29 | 伊索泰克尼卡股份有限公司 | Synthesis of cyclosporin analogs |
| 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 |
| EP0365044A3 (en) * | 1984-08-02 | 1990-08-22 | Sandoz Ag | Novel pharmaceutical use of (nva)2-cyclosporine |
| DE68900991D1 (en) † | 1988-01-29 | 1992-04-23 | Sankyo Co | CYCLOSPORIN COMPOSITIONS. |
| GB2222770B (en) † | 1988-09-16 | 1992-07-29 | Sandoz Ltd | Pharmaceutical compositions containing cyclosporins |
| GB2230440B (en) † | 1989-02-09 | 1993-05-19 | Sandoz Ltd | Novel cyclosporin galenic forms |
-
1994
- 1994-04-20 CA CA002161143A patent/CA2161143A1/en not_active Abandoned
- 1994-04-20 SK SK1298-95A patent/SK283442B6/en not_active IP Right Cessation
- 1994-04-20 CZ CZ19952729A patent/CZ291237B6/en not_active IP Right Cessation
- 1994-04-20 DK DK94915073T patent/DK0697881T3/en active
- 1994-04-20 JP JP52278294A patent/JP3862273B2/en not_active Expired - Fee Related
- 1994-04-20 ES ES94915073T patent/ES2178653T3/en not_active Expired - Lifetime
- 1994-04-20 AT AT94915073T patent/ATE218878T1/en not_active IP Right Cessation
- 1994-04-20 HU HU9503019A patent/HUT72738A/en unknown
- 1994-04-20 EP EP94915073A patent/EP0697881B2/en not_active Expired - Lifetime
- 1994-04-20 WO PCT/EP1994/001228 patent/WO1994023733A1/en not_active Ceased
- 1994-04-20 PT PT94915073T patent/PT697881E/en unknown
-
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 |
|---|---|
| EP0697881B1 (en) | 2002-06-12 |
| SK129895A3 (en) | 1997-02-05 |
| EP0697881A1 (en) | 1996-02-28 |
| HU9503019D0 (en) | 1995-12-28 |
| EP0697881B2 (en) | 2009-05-06 |
| JP3862273B2 (en) | 2006-12-27 |
| NO954152D0 (en) | 1995-10-18 |
| PT697881E (en) | 2002-10-31 |
| SK283442B6 (en) | 2003-07-01 |
| FI954986A0 (en) | 1995-10-19 |
| WO1994023733A1 (en) | 1994-10-27 |
| ATE218878T1 (en) | 2002-06-15 |
| FI116120B (en) | 2005-09-30 |
| DK0697881T3 (en) | 2002-10-07 |
| NO321076B1 (en) | 2006-03-13 |
| HUT72738A (en) | 1996-05-28 |
| JP2006206615A (en) | 2006-08-10 |
| ES2178653T3 (en) | 2003-01-01 |
| JPH08508984A (en) | 1996-09-24 |
| NO954152L (en) | 1995-10-18 |
| FI954986L (en) | 1995-10-19 |
| CZ291237B6 (en) | 2003-01-15 |
| CZ272995A3 (en) | 1996-02-14 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |