Patent Abstract:
the invention relates to a controlled - release injectable microparticle comprising a polyvinyl alcohol polymer and one or more hormones , in particular progesterone . said microparticle induces estrus in female mammals after a single application . the invention also relates to a method for obtaining the microparticle .

Detailed Description:
the method for obtaining microparticles for the release of drugs consists in 6 basic or fundamental stages : 1 ) preparing an aqueous solution containing polyvinyl alcohol , reticulation or gelling additives , and the drug or drugs to be released . this solution is named solution a . 2 ) preparing an aqueous saline solution with the eventual adding of other additives . this solution is named solution b . the microparticles obtained may be injected into animals for veterinary purposes , or eventually in humans for medical purposes . 1 ) preparing an aqueous solution containing polyvinyl alcohol , reticulation or gelling additives , and the drug or drugs to be released . this solution is named solution a . solution a may be prepared in different ways . the pva of this solution must have a viscosity evaluated according to norm din 53015 , between 5 and 110 mpa · s , preferably between 20 and 70 mpa · s , more preferably between 30 and 50 mpa · s . three forms of preparing solution a are mentioned as examples . 1a ) appropriate quantities of water , pva , additives and drugs are added for obtaining solution a . the mix is stirred until a major part of the pva and the additives is dissolved . a coadjuvant or surfactant may be necessary . the drug should remain practically insolubilised in the medium . help from heat , or heat and pressure , may eventually be used to speed up the dissolution process . the maximum temperature used should always be , as a minimum , less than the temperature at which the least stable compound in the mix starts to decompose or denaturalise . 1b ) a first component of the mix is dissolved in the total volume of water . once it has dissolved , a second component is added to be dissolved , and likewise with the rest of the components , which are all added gradually and dissolved one by one until solution a is obtained . 1c ) pva and the additives are both dissolved separately in water . the drug is dispersed in water . a coadjuvant or surfactant may be necessary . then these three solutions are mixed to obtain the final solution a . the help of heat , or of heat and pressure , may eventually be used to speed up the various dissolution and / or dispersion processes , provided that the properties of the mix components are not altered . 2 ) preparing an aqueous saline solution with the eventual adding of other additives . this solution is named solution b . solution b may be prepared in different ways . three forms of preparing solution b are mentioned as examples . 2a ) appropriate quantities of water , salts , and additives are added to obtain solution b . the mix is stirred until a major part of the salts and additives are dissolved . a coadjuvant or surfactant may be necessary . the help of heat , or heat and pressure , may eventually be used to speed up the dissolution process . the maximum temperature used should always be less than the temperature at which the least stable compound in the mix starts to decompose or denaturalise . 2b ) a first component of the mix is dissolved in the total volume of water . once it has dissolved , the second component is added to be dissolved , and likewise with the rest of the components , which are all added gradually and dissolved one by one until solution b is obtained . 2c ) each one of the components of the mix are dissolved separately in water . a coadjuvant or surfactant may be necessary . then these solutions are mixed to obtain solution b . the help of heat , or of heat and pressure , may eventually be used to speed up the various dissolution and / or dispersion processes , provided that the properties of the mix components are not altered . 3 ) dispersion of solution a in solution b . each solution a droplet dispersed in solution b forms a semisolid polyvinyl alcohol - based sphere , with the drug remaining entrapped in its interior . the dispersion of solution a in solution b is performed by dripping . solution a is dripped into solution b . the dripping process may be performed in multiple ways . these ways basically differ in how the droplets are released from the tip of the drip head or heads . the drip head consists in one or multiple needles , a cluster of tubes , or even holes . three forms of dripping are mentioned as examples . 3a ) traditional dripping . this dripping is performed by gravity feed . droplets are released from the head by gravity feed . 3b ) dripping assisted by vibration . in this dripping , the head is vibrated to facilitate the release of droplets . this vibration can be induced mechanically , by sound , or by means of electric or piezoelectric pumps activated with alternating currents . 3c ) electrostatic dripping . in this dripping , an electrostatic force is added to gravity feed . to do so , a vertically oriented electrostatic field is generated . the droplets are released from the head by the joint action of gravity feed and the electrostatic force . 3d ) dripping assisted by blowing . in this case , the droplets are released from the head by using a gaseous current , generally air . 4 ) microparticle stabilisation . a microparticle stabilisation process originating in solution a and immersed in solution b after the dispersion process is commonly necessary . in some cases , microparticle stabilisation is fast enough to consider that it occurs during the dispersion process itself and will not require an additional process . the stabilisation process may be performed in various ways . three forms of stabilisation are mentioned as examples . 4a ) microparticles formed from solution a and immersed in solution b are stabilised for a certain time in solution b itself . 4b ) microparticles formed from solution a and immersed in solution b are stabilised for a certain time in a modified solution b by adding stabilisers or stabilisation accelerating agents . 4c ) microparticles formed from solution a and immersed in solution b are recovered by sedimentation , flotation , centrifugation , or filtration . once recovered , they are immersed or washed in another solution with stabilising capacity . multiple washes , immersions , or combinations of both can be employed . 5 ) microparticle recovery . once stabilised mechanically and chemically , the microparticles can be easily manipulated . depending on the case , the microparticles can be recovered to go on to the following process , or otherwise , for their immediate use or storage . the recovery process can be performed in various ways . three forms of recovery are mentioned as examples . 5a ) recovery by filtration , sedimentation , centrifugation , or flotation . in this type of recovery , the physical separation of the particles from the stabilising solution is sought by applying any of the methods mentioned above . the resulting microparticles can either go on to the following process , be injected or used immediately , or else be packaged or stored for their subsequent use . 5b ) recovery by volume reduction . in this case , a part of the stabilising solution can be extracted to concentrate the microparticles . then the remaining solution can be modified to condition the mix of microparticles concentrated in this solution , and go on to the following process , be injected or used immediately , or else be packaged or stored for their subsequent use . 5c ) recovery by modifying the stabilising solution . in this case , some physical change is induced in the microparticles by means of a chemical change in the stabilising solution . these changes include dehydration , densification , or solvent exchange in the microparticles . the microparticles in these conditions can go on to the following process , be injected or used immediately , or else be packaged or stored for its subsequent use . 6 ) microparticle conditioning . microparticle conditioning is a general term that indicates the preparation of microparticles for their immediate application or storage . in this stage , the final characteristics of the microparticles are adjusted . the conditioning can consist in various processes or their combinations . three types of conditionings are indicated below as examples . 6a ) bulk conditioning . this conditioning refers to the interior of the microparticles . the interior of the microparticles can be conditioned by adjusting the residual water , inducing a chemical reaction , extracting a certain component present in the microparticles but undesirable for its application or storage , or adding a certain component desirable for its application or storage . 6b ) superficial conditioning . this conditioning refers to the surface of the microparticles . the surface of the microparticles can be conditioned by inducing some chemical reaction , forming or eliminating membranes , extracting a certain component present in the surface of the microparticles but undesirable for its application or storage , or adding a certain component to the surface of the microparticles that may be desirable for its application or storage . 6c ) excipient conditioning . an excipient is understood as a substance , commonly inactive , that is mixed with the microparticles to give it consistency , stability , fluidity , or another characteristic to the mix , or else , to facilitate some aspect or aspects of its use . the conditioning of the excipient can consist in adding excipient to a group of microparticles , or in modifying a mix of microparticles immersed in a stabilising or recovery solution . polyvinyl alcohol - based microparticles charged with progesterone with applications in the control of oestrus and ovulation of production animals 1 ) preparing solution a . the strategy described in section 1a ) above is used . an aqueous solution is prepared : pva with an hydrolysis degree of 95 %, 10 % in weight , that could be between 5 and 50 % in weight , plus its viscosity , evaluated according to norm din 53015 , presenting a value of 45 mpa · s , that could be between 5 and 110 mpa · s ; glycerol ( gl ) at 0 . 5 %, that could be between 0 . 05 and 1 % in weight ; boric acid ( bh ) at 1 %, that could be between 0 . 05 and 5 % in weight ; and progesterone at 5 % that could be aggregated at between 5 and 70 % in weight . all the components are weighed and mixed in the same container . the mix is stirred softly in a thermostated bath at a temperature of 30 ° c ., although this phase could also be performed at a temperature between 10 and 90 ° c . during 25 minutes , being extendable up to 5 to 240 minutes until total dissolution of the pva , bh and gl . the progesterone is dispersed in the mix given that it is practically insoluble in aqueous solvents . 2 ) preparing solution b . the strategy described in section 2a above is used an aqueous solution of sodium hydroxide is prepared at 0 . 8 %, ranging between 0 . 05 and 1 % in weight being also possible . this dissolution is fast , and it does not need heat or other additives . 3 ) dispersing solution a in solution b . the strategy described in section 3a above is used . solution a is made to drip by gravity feed into solution b at a volumetric ratio of 10 parts of solution b for each art of solution a , that could be extended up to ranges from 5 to 50 parts of solution b for each part of solution a . each solution a droplet that is submerged in solution b is transformed almost instantaneously into a semisolid microparticle . dripping continues until solution a runs out . 4 ) microparticle stabilisation . the strategy described in section 4a above is used . once dripping of solution a into solution b is concluded , the suspension of a microparticles in solution b is left under moderate stirring for a period of time of 20 minutes , being possible to extend it up to 2 to 90 minutes at a temperature of 25 ° c ., that could be of between 20 to 90 ° c . microparticles of 1 . 5 mm of diameter are thus obtained , that could be of between 0 . 2 to 5 mm of diameter and a dispersion in diameters of 0 . 04 mm , that could be of between 00 . 01 to 0 . 1 mm . besides , this microparticles present a spherecity of 1 . 1 , that could be the same of between 1 and 1 . 5 . 5 ) microparticle recovery . the strategy described in section 5a above is used . the microparticles are recovered by filtration . the remaining solution b can be discarded or reconditioned to be reused in step 2 . 6 ) microparticle conditioning . a combination of strategies 6a , 6b and 6c described above is used . bulk conditioning consists in removing the remaining solvation water from the microparticles . the water is removed by hot air drying at a temperature at 50 ° c ., that could also be of between 25 and 120 ° c . under conditions of a fluidised bed . superficial conditioning consists in the formation of a membrane by superficial reticulation of the pva chains . an aqueous glycerol solution is prepared at 20 % in weight , that could also be of between 10 and 60 % in weight . the solution is distributed on the surface of the microparticles by spraying . then the system is subjected to a temperature of 100 ° c ., that could also be ranging between 100 and 120 ° c . and a pressure of 50 bar , that could also be of between 20 and 100 bar . the system is cooled off and can be fractioned , packaged and stored . conditioning the excipient consists in dispersing the microparticles in 2 - pyrrolydone to provide fluidity to the system and to enable its passage through veterinary needles . the microparticles of the present invention can release drugs with various applications . the microparticles are fractioned and stored in vials . from the vials , the microparticles are taken by means of a veterinary syringe to be then injected in animals . the type , quantity , and injection site will depend on each specific application . eventually , they can be introduced into the digestive tract of the animals by means of hoses or applicators specifically designed for that purpose . detailed description of the advantages for the case of polyvinyl alcohol - based microparticles charged with progesterone with applications in the control of oestrus and ovulation in production animals in comparison to other technological alternatives advantages of a hormone release system by preformed microparticles of the present invention in comparison to intravaginal devices : its small and uniform size facilitates its storage and transportation . there are no risks implicit in fortuitous contacts between the microparticles and the operator &# 39 ; s skin . microparticles are stored in vials , the doses are picked up by syringes , and are injected in the animals . at no time is there any risk of contact . as it is injectable , there is no need for immobilising the animal , or rigorous sanitising of the animal as required for the introduction of intravaginal devices . as rigorous hygiene is unnecessary , it is also unnecessary to have ample availability of clean water . by controlling the volume of microparticles injected , an optimum dose of the hormone load can be attained for each animal in particular . with the use of intravaginal devices , on the contrary , only one hormone load is available and there are always risks of an under - or overdose . moreover , once the microparticles are injected , they remain in the animal without any risk of their falling out as in the case of intravaginal devices . the application of injectables can be performed by non - specialised personnel in comparison to the high cost of training required for the introduction of intravaginal devices . by using microparticles , 100 % of the hormone load is used in comparison to intravaginal devices , where as little as 30 % is used . it is not necessary to extract the exhausted microparticles , in comparison with the multiple tasks involved in immobilising , sanitising , extracting , and burning or burying the intravaginal devices . advantages of the hormone release system by preformed microparticles of the present invention in comparison to implantable systems under the skin or dewlap : the advantages of injectable preformed microparticles in comparison to implants are the ease of dosing the hormone load of the microparticles in comparison to the fixed hormone load of implants , the high content of residual hormone remaining in the implants , and no need for implant surgery and the eventual implant removal surgery with its implications as to the need of immobilising the animal , the decrease in infection risks , hygiene requirements and the training of the personnel involved . advantages of the hormone release system by preformed microparticles of the present invention in comparison to subcutaneous release systems implantable in the ear : the advantages of injectable preformed microparticles in comparison to implants in the ear are their ease of dosing in relation to the fixed dosing of implants and no need for implant removal surgery . advantages of the hormone release system by preformed microparticles of the present invention in comparison to transdepot - type injectable release systems : the advantages of the injectable preformed microparticles compared to transdepot devices are non - functionality with the temperature of the microparticles compared to thermoplastic pastes , a perfectly defined and reproducible release surface of the microparticles compared to irregular and unrepeatable forms and surfaces commonly observed in transdepot devices , the non - presence of toxic elements in the microparticles compared to the presence of surfactants , solvents , and other additives used in the transdepots , and the unpredictability in the hardening reactions of thermoplastic pastes , in - situ reticulation , gelling , and polymer precipitation with its implications as to the rate of hormone release . advantages of the hormone release system by preformed polyvinyl alcohol - based microparticles of the present invention compared to preformed microparticles based on polymers derived from lactic acid , glycolic acid , caprolactone and others : the main advantage is cost , because the technology already described in this document implies a diminish in costs of polymeric prime materials in the process of manufacture , of at least 50 % in comparison with the use of other polymers . there is no prior information about obtaining microparticles by sequencing the processes described above and independently from its material base , type and quantity of drugs in its interior and field of application . there is no prior information for obtaining polyvinyl alcohol - based microparticles for veterinary applications . 3 becaluba f . 2006 . metodos de sincronizacion de celos en bovinos . www . produccion - animal . com . ar 4 j . f . roche . control of oestrus in cattle . world rev . anim . prod . 15 ( 1979 ) 49 - 76 . 5 r . d . smith , r . j . pomerantz , w . e . beale , j . p . mccann , t . e . pilbeam , w . hansel . insemination of holstein heifers at a preset time after etrus cycle synchronization using progesterone and prostaglandin . j . anim . sci . 58 ( 1984 ) 792 - 800 . 6 j . f . roche . control of time of ovulation in heifers treated with progesterone and gonadotrophin releasing hormone . j . reprod . fertil . 43 ( 1975 ) 471 - 477 . 7 v . w . winkler , s . borodkin , s . k . webel , j . t . mannebach . in vitro and in vivo considerations of a novel matrix controlled bovine progesterone - releasing intravaginal device . j . pharm . sci . 66 ( 1977 ) 816 - 818 . 8 j . f . roche . retention rate in cows and heifers of intravaginal silastic coils impregnated with progesterone . j . reprod . fertil . 46 ( 1976 ) 253 - 255 . 9 j . f . roche . fertility in cows after treatment with a prostaglandin analogue with or without progesterone . j . reprod . fertil . 46 ( 1976 ) 341 - 345 . 10 j . f . roche , j . j . ireland . effect of exogenous progesterone on time of occurrence of the lh surge in heifers . j . anim . sci . 52 ( 1981 ) 580 - 586 . 11 j . f . roche . synchronisation of oestrus in cows using intravaginal silastic coils containing progesterone . ann . biol . anim . biochem . biophys . 15 ( 1975 ) 301 - 302 . 12 j . f . roche . control of oestrus in cattle using progesterone coils . anim . reprod . sci . 1 ( 1978 ) 145 - 154 . 13 r . e . mauer , s . k . webel , m . d . brown . ovulation control in cattle with progesterone releasing intravaginal device ( prid ) and gonadotropin releasing hormone ( gnrh ). ann . biol . anim . biochem . biophys . 15 ( 1975 ) 291 - 296 . 14 j . f . roche , d . j . prendiville . synchronisation of oestrus and pregnancy diagnosis in heifers bred in autumn and winter . vet . rec . 102 ( 1978 ) 12 - 14 . 15 j . f . roche . comparison of pregnancy rate in heifers and suckler cows after progesterone or prostaglandin treatments . vet . rec . 99 ( 1976 ) 184 - 186 . 16 j . f . roche , d . j . prenderville , w . d . davis . calving rate following fixed time insemination after a 12 - day progesterone treatment in dairy cows , beef cows and heifers . vet . rec . 101 ( 1977 ) 417 - 419 . 17 a . shaham , y . folman , m . rosenberg . progesterone concentration in the reproductive tissues of dairy cows treated with a progesterone releasing intravaginal device ( prid ). proc . 12th int . cong . anim . reprod ., 1992 , pp . 1184 - 1186 . 18 r . k . munro . concentrations of plasma progesterone in cows after treatment with 3 types of progesterone pessaries . aust . vet . j . 64 ( 1987 ) 385 - 386 . 19 r . k . munro . the effects of duration and concentration of plasma progesterone on the fertility of post - partum cows treated with pregnant mare serum gonadotrophin and intravagainal progesterone . aust . vet . j . 66 ( 1989 ) 43 - 45 . 20 j . f . roche . calving rate of cows following insemination after a 12 - day treatment with silastic coils impregnated with progesterone . j . anim . sci . 43 ( 1976 ) 164 - 169 . 21 j . f . roche , j . p . gosling . control of estrus and progesterone levels in heifers given intravaginal progesterone coils and injections of progesterone and estrogen . j . anim . sci . 44 ( 1977 ) 1026 - 1029 . 22 n . a . robinson , k . e . leslie , j . s . walton . effect of treatment with progesterone on pregnancy rate and plasma concentrations of progesterone in holstein cows . j . dairy sci . 72 ( 1989 ) 202 - 207 . 23 y . folman , m . kaim , z . herz , m . rosenberg . reproductive management of dairy cattle based on synchronization of estrus cycles . j . dairy sci . 67 ( 1984 ) 153 - 160 . 24 y . folman , s . r . mcphee , i . a . cumming , i . f . davis , w . a . chamley , conception rates in cows after various synchronisation techniques using progesterone releasing intravaginal devices . aust . vet . j . 60 ( 1983 ) 44 - 47 . 25 m . e . wehrman , m . s . roberson , a . s . cupp , f . n . kojima , t . t . stumpf , l . a . werth , m . w . wolfe , r . j . kittok , j . e . kinder . increasing exogenous progesterone during synchronization of estrus decreases endogenous 17b - es - tradiol and increases conception in cows . biol . reprod . 49 ( 1993 ) 214 - 220 . 26 m . s . roberson , m . w . wolfe , t . t . stumpf , r . j . kittok , j . e . kinder . luteinizing hormone secretion and corpus luteum function in cows receiving two levels of progesterone . biol . reprod . 41 ( 1989 ) 997 - 1003 . 27 a . cupp , m . garcia - winder , a . zamudio , v . mariscal , m . e . wehrman , n . kojima , k . peters , e . bergfeld , p . hernandez , t . sanchez , r . kittock , j . kinder . two concentrations of progesterone ( p4 ) in circulation have a different effect on pattern of ovarian follicular development in the cow . biol . reprod . 45 ( 1992 ) 106 . 28 s . r . mcphee , m . w . doyle , i . f . davis , w . a . chamley . multiple use of progesterone releasing intravaginal devices for synchronisation of oestrus and ovulation in cattle . aust . vet . j . 60 ( 1983 ) 40 - 43 . 29 e . e . custer , w . e . beal , s . j . 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releasing intravaginal device ( prid ) on synchronization of estrus in japanese black cattle . jpn . j . anim . reprod . 30 ( 1984 ) 117 - 126 . 37 s . tjondronegoro , p . williamson , g . j . sawyer , s . atkinson . effects of progesterone intravaginal devices on synchronization of estrus in postpartum dairy cows . j . dairy sci . 70 ( 1987 ) 2162 - 2167 . 38 y . fukui , m . kobayashi , m . tsubaki , n . kikuchi , h . ono . regulating estrus and therapy of repeat - breeder and anestrus holstein heifers using progesterone releasing intravaginal devices ( prid ). jpn . j . vet . sci . 47 ( 1985 ) 943 - 950 . 39 h . uehlinger , h . binder , b . hauser , p . rusch , k . zerobin . hormonanalytischer vergleich der vaginaleinlagen cidr ® and prid bei ovariektomierten kuhen . schweiz . arch . tierheilk . 137 ( 1995 ) 81 - 86 . 40 j . s . stevenson , m . o . mee . pregnancy rates of holstein cows after postinsemination treatment with a progesterone releasing intravaginal device . j . dairy sci 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calving friesian dairy cows . vet . rec . 103 ( 1978 ) 259 - 262 . 50 p . j . h . ball , g . e . lamming . diagnosis of ovarian acyclicity in lactating dairy cows and evaluation of treatment with gonadotrophin - releasing hormone or a progesterone releasing intravaginal device . br . vet . j . 139 ( 1983 ) 522 - 527 . 51 m . w . smith , j . s . stevenson . fate of the dominant follicle , embryonal survival and pregnancy rates in dairy cattle treated with prostaglandin f 2a and progestins in the absence or presence of a functional corpus luteum . j . anim . sci . 73 ( 1995 ) 3743 - 3751 . 52 w . e . beal . a note on synchronization of oestrus in post partum cows with prostaglandin f 2a and a progesterone releasing device . anim . prod . 37 ( 1983 ) 305 - 308 . 53 j . f . smith , h . r . tervit . the successful development of a prid regime for oestrus synchronization in new zealand beef cattle . proc . nz soc . anim . prod . 4 ( 1980 ) 272 - 279 . 54 j . f . smith , c . c . kaltenbach . comparison of techniques for synchronization of oestrus and subsequent fertility in beef cattle . nz j . agric . res . 33 ( 1990 ) 449 - 457 . 55 j . f . smith , l . t . mcgowan . oestrogen and the prid . proc . nz soc . anim . prod . 42 ( 1982 ) 87 - 89 . 56 s . tjondronegoro , p . williamson , g . j . sawyer , c . d . hawkins , s . atkinson . effects of progesterone intravaginal devices on oestrus synchronization in post - partum dairy cows . proc . aust . soc . reprod . biol . 45 ( 1986 ) 45 . 57 m . rosenberg , m . kaim , z . herz , y . folman . comparison of methods for the synchronization of estrus cycles in dairy cows . 1 . effects on plasma progesterone and manifestation of estrus . j . dairy sci . 73 ( 1990 ) 2807 - 2816 . 58 y . folman , m . kaim , z . herz , m . rosenberg . comparison of methods for the synchronization of estrus cycles in dairy cows . 2 . effects of progesterone and parity on contraception . j . dairy sci . 73 ( 1990 ) 2807 - 2816 . 59 a . r . peters . calving intervals of beef cows treated with either gonadotrophin releasing hormone or a progesterone releasing device . vet . rec . 110 ( 1982 ) 515 - 517 . 60 k . j . o &# 39 ; farrell . calving rate of dairy cows and heifers following a 12 - day progesterone and oestradiol benzoate synchronisation treatment . ir . j . agric . res . 16 ( 1977 ) 131 - 140 . 61 g . e . lamming , d . c . bulman . the use of milk progesterone radioimmunoassay in the diagnosis and treatment of subfertility in dairy cows . br . vet . j . 132 ( 1976 ) 507 - 517 . 62 r . l . fogwell , b . m . kanyima , a . villa - godoy , w . j . enright , j . j . ireland . enhanced precision of estrus and luteinizing hormone after progesterone and prostaglandin in heifers . j . dairy sci . 69 ( 1986 ) 2179 - 2185 . 63 a . tegegne , a . c . warnick , e . mukasa - mugerwa , h . ketema . fertility of bos indicus and bos indicus3bos taurus crossbreed cattle after estrus synchronization . theriogenology 31 ( 1989 ) 361 - 370 . 64 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