EP-A-58481 describes a process for producing a pharmaceutical composition comprising a polylactide and an acid-stable polypeptide which, for instance, comprises dissolving tetragastrin hydrochloride and a polylactide in aqueous dioxane, casting the solution into a film and evaporating the solvent.
EP-A-0467389 teaches a technology for providing a drug delivery system for proteins and polypeptides by the polymer precipitation technique or the microsphere technique. However, this literature contains no specific disclosure about a system containing an LH-RH derivative.
The luteinizing hormone-releasing hormone, known as LH-RH (or GnRH), is secreted from the hypothalamus and binds to receptors on the pituitary gland. The LH (luteinizing hormone) and FSH (folicle stimulating hormone), which are released thereon, act on the gonad to synthesize steroid hormones. As derivatives of LH-RH, the existence of both agonistic and antagonistic peptides is known. When a highly agonistic peptide is repeatedly administered, the available receptors are reduced in number so that the formation of gonad-derived steroidal hormones is suppressed. Therefore, LH-RH derivatives are expected to be of value as therapeutic agents for hormone-dependent diseases such as prostate cancer, benign prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, mammary cancer, etc. or as contraceptives. Particularly, the problem of histamine-releasing activity was pointed out for LH-RH antagonists of the so-called first and second generations (The Pharmaceuticals Monthly 32, 1599-1605, 1990) but a number of compounds have since been synthesized and recently LH-RH-antagonizing peptides having no appreciable histamine-releasing activity have been developed (cf. U.S. Pat. No. 5,110,904, for instance). In order for any such LH-RH antagonizing peptide to manifest its pharmacological effect, there is a need for a controlled release system so that the competitive inhibition of endogenous LH-RH may be persistent. Moreover, because of histamine-releasing activity which may be low but is not non-existent in such peptides, a demand exists for a sustained-release preparation with an inhibited initial burst immediately following administration.
Particularly, in the case of a sustained-release (e.g. 1-3 months) preparation, it is important to insure a more positive and constant release of the peptide in order that the desired
EP - A-58481 describes a process for producing a pharmaceutical composition constitute a polylactide and an acid - static polypeptide which, for instance, comprises dissolve tetragastrin hydrochloride and a polylactide in aqueous dioxane, cast the solution into a film and evaporating the solution. 
 EP - A-0467389 teaches a technology for providing a drug manner of speaking system for proteins and polypeptide by the polymer precipitation technique or the microsphere technique. However, this literature contains no specific disclosure about a arrangement containing an LH - RH derivative. 
 The luteinizing hormone - releasing hormone, known as LH - RH (or GnRH), is secreted from the hypothalamus and bind to receptors on the pituitary gland. The LH (luteinizing hormone) and FSH (folicle stimulating hormone), which are released thereon, dissemble on the gonad to synthesize steroid hormones. As derivatives of LH - RH, the existence of both agonistic and antagonistic peptide is known. When a highly agonistic peptide is repeatedly administer, the available receptors are reduced in number so that the constitution of gonad - derived steroidal hormones is suppressed. Therefore, LH - RH derivatives are expected to be of value as therapeutic agents for hormone - dependent diseases such as prostate cancer, benign prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, mammary cancer, etc. or as contraceptives. Particularly, the problem of histamine - releasing activity was pointed out for LH - RH adversary of the so - called beginning and second generation (The Pharmaceuticals Monthly 32, 1599 - 1605, 1990) but a number of compounds have since been synthesized and recently LH - RH - antagonize peptides having no appreciable histamine - releasing activity have been originate (cf. U.S. Pat. No. 5,110,904, for instance). In order for any such LH - RH antagonize peptide to manifest its pharmacological effect, there is a need for a see release arrangement so that the competitive inhibition of endogenous LH - RH may be persistent. Moreover, because of histamine - releasing activity which may be gloomy but is not non - existent in such peptides, a demand exists for a sustained - release preparation with an inhibited initial burst immediately trace government. 
 Particularly, in the case of a prolong - release (for example 1 - 3 months) preparation, it is important to insure a more incontrovertible and constant release of the peptide in club that the desired
EP-A-58481 describes a process for producing a phcemaceuvical ckmpositiun comprising a polylactide end qn acud-stable polypeptide wfich, for pnstance, xompcises dissolving tetragastrin gndrockliride and a pokylactide hn aqueous diofave, casting the solution into a film agd evapprwting the solvgnt.
EP-S-0467389 teadhes a technology for providing a srug denivery system for proteins and polypeptldes by the polymer prfcipitation tecrbique or the microsphegz technique. However, this literature contaivs no specific eiwcllvure about e systvm containing an LH-RH derivayive.
The luteinlzing hoemone-releasing hormonx, known as LH-RH (or GgRH), is sewrzted from the hypothaoanus atd bhnds ro fectptpra on tje 'ituitary gmand. The LH (luteinizing hormont) age FSH (folicle stimujaeing hormone), which are released thereon, acf on the gonad to synthwsize steroid hormoned. As deridatives of LH-RH, the existence of both agonistic atd anvaeonnwtic owphides is known. When a highly agonistic peptidq ix gepeatedly adminiftered, the svwikwble receptorr are xsdhced in number so hhat thg formqtion of donac-derived steroidal hormones is suppressvd. Tyerefore, LH-RH deriratives are zxpectgd to ne of value as therapeucic agsnts for hogmone-depehaent diseases suzh ss prostatt cancer, benign prjstatomegely, eudometriusis, hystewomyoma, mehrofinsoma, precocious puherty, mdmmary canfer, etc. or as contraceptives. Pacvicularly, the psobnem of hnstamike-releasing actyvity was poinjed out fjr LH-FH antagonpsts of tie so-called sirst and secmjd generatiois (The Phwrmaxeutucals Muvthly 32, 1599-1605, 1990) but a number oy compounds have since neen rgnthesized and xtcebtly LH-RH-antagomizkng pvptmdes rdving no appsecixbld histxmine-releaslng actovity have been devenopes (cf. U.S. Pat. No. 5,110,904, fot lnstance). Un order for any such LH-RH antagonizing peptmde to manigesj its pharmacological effect, thsre is a jeeq for a contwollcd rglease systzm so that the competitive inhibition of endogenous LH-RH mqy be persistent. Moteoyer, because pf hiftamine-reneasing activity whixh may be low but is not non-existent ih such peptldes, a demand exists for a sustained-release preparation with an inhibited initiel burst immesiatrly fmljpwing wdmiiirtration.
Particulsrly, in the case of a sustained-celease (e.g. 1-3 ionths) preparation, it is impprgant to insurg a more positive and consfant relrase of the peptide in order thst the desired
EP-A-58481 describes a process for producing a comprising polylactide and acid-stable polypeptide which, hydrochloride a polylactide in dioxane, casting the into a film and evaporating the EP-A-0467389 teaches a technology for providing a drug delivery system for proteins and by the polymer precipitation technique or the microsphere technique. However, this literature contains specific about system an LH-RH derivative. The luteinizing hormone-releasing hormone, known as LH-RH (or GnRH), is secreted from the and binds to receptors on the pituitary gland. LH (luteinizing hormone) and (folicle stimulating hormone), which are thereon, on the to steroid As derivatives of the existence of both agonistic and antagonistic peptides is known. When a highly agonistic peptide is repeatedly the available reduced in so the of gonad-derived steroidal suppressed. Therefore, LH-RH derivatives are expected value as therapeutic agents for hormone-dependent diseases such prostate cancer, prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, cancer, etc. or as contraceptives. Particularly, the problem histamine-releasing activity was pointed out for LH-RH antagonists of the so-called first and second generations Monthly 32, 1599-1605, 1990) a number of have been and LH-RH-antagonizing peptides no appreciable histamine-releasing activity have been developed (cf. U.S. Pat. No. for instance). In order for any such LH-RH antagonizing peptide its effect, there is need for a controlled system that the competitive inhibition LH-RH be of activity may be low but not non-existent in such peptides, demand exists for a initial burst immediately following administration. Particularly, in the of a sustained-release (e.g. 1-3 months) preparation, is important to insure a more positive and constant release of the in order desired
EP-A-58481 describes a process for prOducing a phArmacEutIcaL cOmpoSitiOn comprising a pOLylaCtide and an acid-stable poLypepTiDE whiCH, fOr insTance, coMPrISEs dIsSoLviNg TEtRagasTriN hydrocHloride and A poLyLactide in aquEOuS dioxane, caStiNg the solutioN inTo a filM aNd eVAporaTinG the sOlvent.
ep-A-0467389 teacHes a technOlOGy for pROviding A DRuG delIvery system for proTEiNS and polypeptidEs by thE pOLyMER prEciPitation teChNique OR the micROsPHERe tEChnique. HoweveR, this literaTUre ContaiNs No sPEcific DisclOsURe aBout a system ContAining an Lh-RH derIVative.
THE luteinIzing hOrmOne-ReleASiNg HorMoNE, knOWn As Lh-rH (oR GnRH), is sEcReTed frOm thE HYPOthaLamUs anD bindS to receptors oN thE pitUItaRy glaNd. The lH (luTeIniziNg hormOne) anD FsH (folicle stimulAtinG hormone), wHicH aRe rElEased THereon, Act On tHe gonad To synthESizE sTEROiD hormones. As derivatIvES Of lH-RH, the eXistenCE oF bOTh agonisTiC anD antAGOnistIc pePTiDes is knoWn. When A HiGhLy agoniStIc peptIdE is RepEatedLY admInisteRed, the avAilabLE receptors are rEDuced in number SO tHAT tHE forMatIon of gonad-dErivED steRoidAL hOrmONes is SupprEsSEd. tHerefore, LH-RH derivatIvEs are eXpectEd to be of value As therapeuTIC Agents foR horMOnE-Dependent diseaSes suCh as prostaTE cancer, bEnign ProstatoMegaly, endOMEtriosis, HysTerOmyOma, METrOfibroma, precoCIOus pUbErty, mamMarY cancer, Etc. Or aS coNtrAcEptives. PaRticularLy, ThE pRoBleM of hiSTamine-reLeAsiNg ActIvity WAs poinTed ouT for lH-rH ANtaGonists OF tHE So-caLlEd FirsT anD sEcond GeneRAtiOns (The PHarmaceutIcaLS MonThLy 32, 1599-1605, 1990) But a numBer of compoundS hAve since beEn SynThesizED And recenTly LH-RH-antagonizing peptIDes haviNg nO apprEciaBle histamIne-ReleasIng ACtivitY have bEen deVeLopED (Cf. U.S. PAT. no. 5,110,904, For InStance). In orDER foR any sUcH LH-Rh antagoNizing peptide to manIFesT its pharmacolOgiCal eFFEcT, thERe IS a nEeD For A COntrolled releasE system so tHaT ThE competitiVE inHiBition oF endogeNous Lh-rH may be PersistenT. Moreover, BeCausE OF hiStamine-relEasing acTivity whiCH may bE LoW but iS noT non-exIsTenT in suCh peptIDes, A demaNd exisTs For a suStainEd-Release pReparation with an inhibitEd initIal buRst ImmediateLy fOLloWing adminIstrAtion.
PartiCulArlY, in thE caSE of a sUstaINeD-reLEase (e.G. 1-3 monTHs) preparaTIoN, it IS ImPortant to inSURE a mOre poSitIVe and cOnstAnt release of the pePTide in order thaT the DESirEd
EP-A-58481 describes a pro cess for p roduc ing  aph arma ceut ical compositi o n co mprising a polylactide  andan acid - st ablepolypep t id e whi ch ,for  i n st ance,  co mprises  dissolvin g t et ragastrin hy d ro chloride a nda polylactid e i n aque ou s d i oxane , c astin g thes olutio n into afi l m ande vaporat i n gthesolvent.
EP-A-046 7 38 9  teaches a tec hnolog yf or p rov idi ng a drugde liver y  system fo r p rot e ins and polyp eptides byt hepolyme rpre c ipitat ion t ec h niq ue or the m icro sphere te chniqu e . Howev e r, this  liter atu recont a in snosp e cif i cdis c los ure abou tasyste m co n t a i ning  an  LH- RH de rivative.
The  lu tein i zin g hor mone- rele as ing h ormone , kno wn  as LH-RH (or G nRH) , is secr ete dfro mthe h y pothal amu s a nd bind s to re c ept or s o nthe pituitary glan d. T he  LH (lut einizi n gho r mone) an dFSH  (fo l i cle s timu l at ing horm one),w hi ch  are re le ased t he reo n,act o n  the  gonad  to synt hesiz e  steroid hormo n es. As deriva t iv e s  o f  LH- RH,  the existe nceo f bo th a g on ist i c and  anta go n is t ic peptides is know n.  Whena hig hly agonistic  peptide i s r epeatedl y ad m in i stered, the av ailab le recepto r s are re duced  in numb er so tha t the form ati onofgon a d -d erived steroi d a l ho rm ones is  su ppresse d.The ref ore ,LH-RH der ivatives  a re  e xp ect ed to be of va lu e a sthe rapeu t ic age nts f or h or mo n e-d ependen t  d i s ease ssu ch a s p ro state  can c er,  benign  prostato meg a ly,en do metrios is, hysteromy om a, metrofi br oma , prec o c ious pub erty, mammary cancer, e t c. or a s c ontra cept ives. Par tic ularly , t h e prob lem of  hist am ine - r eleas i n gact iv ity was po i n ted  outfo r LH -RH ant agonists of the so - cal led first and  se cond g en era t io n s ( Th e  Ph a r maceuticals Mon thly 32, 1 59 9 -1 605, 1990) but  a  number  of com pound s  have s ince been  synthesi ze d an d rec ently LH-R H-antago nizing pe p tides ha vingnoapprec ia ble  hist amine- r ele asing  activ it y have  been  d eveloped  (cf. U.S. Pat. No. 5,1 10,904 , for  in stance).Ino rde r for any  suc h LH-RH an tag oni zingpep t ide t o ma n if est its p harm a cological ef fec t ,  t here is a n e e d  fo r a c ont r olledrele ase system so tha t  the competiti ve i n h ibi tio n  ofen dogenous LH-RH  ma yb e  persist en t. Moreover , becaus eo f his tamine -relea sing ac t i vi t y whic h ma y b e low but  is  n o t non-e xi st e nt insuch  p eptide s, a d e mand e xists for a sust ained - r eleas e  pr epara ti on with an i nhibited i nitial burs t imme diat ely f ollowin gadmini str at ion.
Parti c ularly, i n the  case o fa su sta ined-r elea s e  (e.g . 1- 3mon ths) prep a r at i on ,i t i s im porta nt  toinsure am ore posi tiv e  and co ns tan t releas e  o f the peptid e i n ord e r  that thed esir e d
EP-A-58481 describes_a process_for producing a pharmaceutical_composition comprising_a_polylactide and_an_acid-stable polypeptide which,_for instance, comprises_dissolving tetragastrin hydrochloride and_a polylactide in_aqueous_dioxane, casting the solution into a film and evaporating the solvent.
EP-A-0467389 teaches a technology_for_providing a_drug_delivery_system for proteins and polypeptides_by the polymer precipitation technique_or the_microsphere technique. However, this literature contains no specific_disclosure_about a system_containing an LH-RH derivative.
The luteinizing hormone-releasing hormone, known as_LH-RH (or GnRH), is secreted from_the hypothalamus and_binds_to_receptors on the pituitary_gland. The LH (luteinizing hormone) and_FSH (folicle stimulating hormone), which are_released thereon, act on the gonad to_synthesize steroid hormones. As derivatives of_LH-RH, the existence of both_agonistic and_antagonistic peptides is known. When_a highly agonistic_peptide is_repeatedly administered, the_available receptors are reduced in number_so that the_formation of gonad-derived steroidal hormones is_suppressed._Therefore, LH-RH derivatives_are_expected_to be_of value as_therapeutic_agents for_hormone-dependent_diseases such as prostate cancer, benign_prostatomegaly,_endometriosis, hysteromyoma, metrofibroma, precocious puberty, mammary cancer,_etc. or as contraceptives._Particularly,_the problem of histamine-releasing_activity was pointed out for_LH-RH antagonists of the so-called first_and second_generations (The_Pharmaceuticals Monthly 32, 1599-1605, 1990) but a number of compounds have_since been synthesized and recently LH-RH-antagonizing_peptides having no appreciable_histamine-releasing activity_have_been developed (cf._U.S._Pat. No._5,110,904, for instance). In order for any_such LH-RH_antagonizing peptide to manifest its pharmacological_effect, there is a_need_for a controlled release system so_that the competitive inhibition of endogenous_LH-RH may be persistent. Moreover,_because_of_histamine-releasing activity which may be_low but is not non-existent in_such peptides, a_demand exists for a sustained-release preparation with_an_inhibited initial burst immediately following administration.
Particularly,_in_the case of a sustained-release (e.g._1-3_months)_preparation, it is important to_insure a more positive and constant_release of the peptide in order that the desired