CN1736487A

CN1736487A - Bioimplant formulation

Info

Publication number: CN1736487A
Application number: CN 200510097821
Authority: CN
Inventors: 蒂莫西·埃利奥特·特里格; 约翰·德斯蒙德·沃尔什; 德博拉·安·拉特延
Original assignee: Peptech Ltd
Priority date: 1998-07-20
Filing date: 1999-07-20
Publication date: 2006-02-22
Also published as: AUPP473098A0; ZA200100567B

Abstract

The present invention relates to a pharmaceutical and/or veterinary formulation, comprising at least one active agent about 2-30(w/w) percent of the dry weight of the active agent, with a log octanol/water distribution coefficient of within the scope 5.0 to -3.0; a water-soluble pore-forming agent containing lecithin and organic salts about 0.5-20.0 (w/w) percents of the dry weight of the active agent; and the balance stearin.

Description

Bioimplant formulation

The application submitted on July 20th, 1999, and denomination of invention is divided an application for the Chinese patent application 99808961.3 of " Bioimplant formulation ".

Invention field

The present invention relates to the slow release prescription of medicine and/or veterinary's at least a activating agent.Preferred activating agent comprises gonadotropin releasing hormone (GnRH) agonist (as deslorelin), GnRH antagonist (as cetrorelix), somatostatin analogs (as somatostatin-14 and octreotide), lipid lowerers (as simvastatin), cyclosporin (as cyclosporin A), angiotensin-convertion enzyme inhibitor (as captopril), calcitonin, the P substance antagonist, analgesic (as morphine), OPIOIDS antagonist (as naltrexone), antidepressants (as venlafaxine) and NSAID (non-steroidal anti-inflammatory drug) (as naproxen sodium).

Background of invention

Because potentiation effect and attenuating administration frequency, exploitation can cause extensive interest by medicine and the veterinary's prescription to the activating agent sustained release in one period persistent period (as reaching 6 months or the longer time).The exploitation of this kind prescription is particularly conducive to those usually for a long time by the drug types of patient's self-administer (as gonadotropin releasing hormone (GnRH) agonist of insulin, the disease that is used for reproduction control and therapeutic hormonal dependent and the symptom of treatment diabetes) and the drug type that needs the patient highly to comply with.Aspect the veterinary, the slow release prescription can reduce animal and veterinary/owner because of giving the anxiety that activating agent causes repeatedly.

The applicant has found that in 7 days to 2 years time the slow release of activating agent in people and other animal body can realize by using a kind of solid for mulation.This prescription comprises tristerin as excipient, and it combines with a kind of material, although be reluctant to be limited by theory, as if this material forms pore and/or crack in excipient, thereby activating agent is released.

Summary of the invention

Thereby first aspect the invention provides a kind of medicine and/or veterinary prescription, comprises at least a activating agent of about 2-30% (w/w) (with the activating agent dry weight basis), the pore former of about 0.5-20.0% (w/w), and the tristerin of surplus.

In an embodiment preferred, this prescription comprises at least a activating agent of about 5-10% (w/w) (with the activating agent dry weight basis), the pore former of about 1.0-10.0% (w/w), and the tristerin of surplus.

One more in the embodiment preferred, this prescription comprises at least a activating agent of about 5-10% (w/w) (with the activating agent dry weight basis), the pore former of about 2.0-5.0% (w/w), and the tristerin of surplus.

Second aspect the invention provides the disease of a kind of people of treatment or other animal and the method for symptom, and this method comprises the prescription of administration of human or other animal first aspect present invention.

Invention is open in detail

At least a activating agent that uses in the prescription of the present invention can be selected from the material with pharmacy or veterinary's meaning, and can be any or multiple combination among peptide class (as hormone and antigen), polypeptide and protein, nucleic acid compound and derivant thereof such as DNA and the RNA.

Preferred activating agent comprises:

(1) The GnRH agonist

Particularly preferred GnRH peptide agonists is deslorelin (as described in US4218439), flutamide is (as FR7923545, WO86/01105 and PT100899 are described), goserelin is (as US4100274, US4128638, GB9112859 and GB9112825 are described), leuprorelin is (as US4490291, US3972859, US4008209, US4005063, DE2509783 and US4992421 are described), dioxalan derivant for example EP413209 is described, triptorelin is (as US4010125, US4018726, US4024121, EP364819 and US5258492 are described), meterelin (as described in EP23904), buserelin is (as US4003884, US4118483 and US4275001 are described), histrelin (as described in EP217659), nafarelin is (as US4234571, WO93/15722 and EP52510 are described), lutrelin (as described in US4089946), leuprorelin (as Plosker et al.Drugs48930-967,1994 is described) and LHRH analog be EP181236 for example, US4608251, US4656247, US4642332, US4010149, described in US3992365 and the US4010149.Above patent specification and article are incorporated herein for referencial use.

Highly preferred GnRH agonist is goserelin, deslorelin, leuprorelin, triptorelin, meterelin, buserelin, histrelin, nafarelin and its combination.The molecular formula of these chemical compounds is as follows:

Goserelin C ₅₉H ₈₄N ₁₈O ₁₄C ₂H ₄O ₂

D-Ser (bu ^t) ⁶Azgly ¹⁰-LHRH acetate

3-[5-oxygen-L-prolyl-L-tryptophanyl-L-seryl-L-cheese ammonia

The smart ammonia of acyl-(the 3-O-tert-butyl group)-D-seryl-L-leucyl-L-

Acyl-L-prolyl] cabazamide acetate

Deslorelin 6-D-tryptophan-9-(N-ethyl-L-prolineamide)-10-

Deglycinamide

P glutamine-histidine-tryptophan-serine-tyrosine-D-

Tryptophan-leucine-Arg-Pro-buserelin

Leuprorelin C ₅₉H ₈₄N ₁₆O ₁₂, C ₂H ₄O ₂

Leuprorelin acetate

5-oxygen-L-prolyl-L-histidyl--L-tryptophanyl-L-seryl

-L-tyrosyl-D-leucyl-L-arginyl-N-ethyl-L-dried meat ammonia

Amide acetate

Triptorelin C ₅₉H ₈₄N ₁₆O ₁₂, C ₂H ₄O ₂

D-Trp ⁶-LHRH

5-oxygen-L-prolyl-L-histidyl--L-tryptophanyl-L-seryl

-L-tyrosyl-D-tryptophanyl-L-leucyl-L-arginyl-L-dried meat

The aminoacyl Aminoacetamide

Meterelin Des Gly ¹⁰-2-methyl D-Trp ⁶-Pro-ethyl-amide ⁹LHRH

Buserelin C ₆₀H ₈₆N ₁₆O ₁₃, C ₂H ₄O ₂

D-Ser (Bu ^t) ⁶-Pro9-NEt LHRH acetate

Oxygen-L-prolyl-L-histidyl--L-tryptophanyl-L-seryl-L-

The smart ammonia of the tyrosyl-O-tert-butyl group-D-seryl-L-leucyl-L-

Acyl-N-ethyl-L-prolineamide acetate

Histrelin Pro-His-Trp-Ser-Tyr-Leu-D (N-benzyl) His-Arg-

The Pro-N-buserelin

Nafarelin C ₆₆H ₈₃N ₁₇O ₁₃, xC ₂H ₄O ₂YH ₂O oxygen-L-prolyl-L-group

Aminoacyl-L-tryptophanyl-L-seryl-L-tyrosyl-3-(2-naphthyl)

-D-alanyl-L-leucyl-L-arginyl-N-ethyl-L-dried meat ammonia

Acyl Aminoacetamide acetate hydrate

The GnRH of containing agonist according to the present invention can be used to control reproductive function as the prescription of at least a activating agent, or is used for the treatment of those long-term sex hormone levels that reduce to its useful disease or symptom.The disease of prostrate cancer, ovarian cancer and breast carcinoma, the benign hormonal dependent benign prostate hypertonicity of the active inhibition of bacterial cell in the inducing of metratrophia, the chemotherapy, hirsutism, circulation auditory function obstacle, child's porphyria and puberty precocity, Canis familiaris L. before endometriosis, muscular tumor and premenstrual tension, fibroma uteri, the operation for example for example, and be used for the symptom that other castrating has useful clinical effectiveness, comprise the recovery of T-cell mediated immunity.

(2) The GnRH antagonist

Particularly preferred GnRH antagonist is ramorelix (L-prolone, 1-(N2-(N-(N-(N-(N-(N-(N-(N-acetyl group-3-(2-naphthyl)-D-alanyl)-4-chloro-D-phenylalanyl-D-tryptophanyl)-L-seryl)-L-tyrosyl-O-(6-deoxidation-α-L-mannopyranose base)-D-seryl)-L-leucyl)-L-arginyl)-2-(amino carbonyl) hyrazide, Teverelix (D-aminopropanamide, N-acetyl group-3-(2-naphthyl)-D-alayl-4-chloro-D-phenylalanyl-3-(3-pyridine radicals)-D-alanyl-L-seryl-L-tyrosyl-N6-(amino carbonyl)-D-lysyl-L-leucyl-N6-(1-Methylethyl)-L-lysyl-L-prolyl, cetrorelix (D-aminopropanamide, N-acetyl group-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridine radicals)-D-alanyl-L-seryl-L-tyrosyl-N5-(amino carbonyl)-D-ol-L-leucyl-L-arginyl-L-prolyl, ganirelix (N-Ac-D-Nal, D-pCl-Phe, D-Pal, DhArg (Et) 2, hArg (Et) 2, D-Ala) GnRH, alanex, Ah times's Rake (D-aminopropanamide, N-acetyl group-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridine radicals)-D-alanyl-L-seryl-N-methyl-L-tyrosyl-D-aspartoyl-L-leucyl-N6-(1-Methylethyl)-L-lysyl-L-prolyl; N-(S)-tetrahydrofuran base-Gly-D2Nal-D4Ciphe-D3Pal-Ser-NmeTyr-D-lys (Nic) Leu-Lys (Isp)-Pro-D-Ala-NH2; Isopropyl-13-(N-benzyl-N-aminomethyl)-7-(2, the 6-difluorobenzyl)-4,7-dihydro-2-(4-isobutylamino phenyl)-4-oxygen thieno (2,3-b) pyridine-5-carboxylate hydrochloride).Other preferred GnRH antagonist is as described in US5110904, US5300492, US5807983, US5169932, US5296468 and the US5502035.

(3) Somatostatin analogs

Particularly preferred somatostatin analogs comprises somatostatin-14, octreotide, Lanreotide and angiopeptin cyclic peptide (US5569647).

The somatostatin analogs that contains according to the present invention can be used for the treatment of for example hyperinsulinemia and peptic ulcer as the prescription of at least a activating agent.

(4) Lipid lowerers

Particularly preferred lipid lowerers comprises the chemical compound that suppresses HMG CoA reductase, for example cerevastatin, mevastatin, simvastatin, pravastatin and lovastatin.

The prescription that contains these reagent according to the present invention can be used for the treatment of for example hyperlipoproteinemia.

(5) Cyclosporin

Preferred cyclosporin comprises naturally occurring cyclosporin (for example Dreyfuss et al., described in (1976) Europ.J.Appl.Microbiol.Vol.3:125-133) and analog, and (for example Wanger R.M. (1982) is at " cyclosporin A " White D.G.G.ed.Amsterdam; Described in the chemistry of the cyclosporin among the Elsevier).

Cyclosporin or the cyclosporin analog of containing according to the present invention can be as the immunosuppressant that for example prevents and treat the organ rejection in the heteroplastic transplantation as the prescription of at least a activating agent.

(6) Angiotensin-convertion enzyme inhibitor

Preferred ACE inhibitor comprises captopril, enalapril, trandolapril spy, Perindoprilat, Quinaprilat, fasidotril, Pa Pulila difficult to understand and lisinopril.

The prescription that contains these reagent according to the present invention can be as for example antihypertensive.

(7) Calcitonin

Preferred calcitonin comprises people, salmon and pig calcitonin.The analog of these polypeptide is suitable for too.

The prescription that contains calcitonin or calcitonin-like according to the present invention for example can be used for the treatment of hypercalcemia, is used to reduce hyperparathyroidism, poisoning by vitamin D and molten bone bone shift the intravital phosphate concn of patient.

(8) The P substance antagonist

Preferred P substance antagonist comprises that fragment 4-11 (is Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH ₂And variant form), fragment 5-11 (is Gln-Gln-Phe-Phe-Gly-Leu-Met-NH ₂And variant form), fragment 6-11 (is Gln-Phe-Phe-Gly-Leu-Met-NH ₂And variant form), fragment 7-11 (is Phe-Phe-Gly-Leu-Met-NH ₂And variant form), fragment 8-11 (is Phe-Gly-Leu-Met-NH ₂And variant form) and fragment 9-11 (be Gly-Leu-Met-NH ₂And variant form).Other suitable substance P substance antagonist comprises those described in the Australian temporary patent application No.PP9008 that applies at the same time as the applicant.

Prescription according to the P of containing substance antagonist of the present invention can be used for the treatment of cancer, comprises nausea and vomiting, pain, allergy, asthma, inflammation (comprising inflammatory bowel) and depression that chemotherapy causes.

(9) Analgesic

Preferred analgesic comprises OPIOIDS for example morphine, levorphan and pethidine (Pethidine), and the amide local anesthetic is bupivacaine, lignocaine, clothing ferrum caine and mepivacaine for example.

The prescription that contains these analgesic according to the present invention can be used for the treatment of acute pain (for example the hip replacement patient is experienced) and chronic local pain.

(10) The OPIOIDS antagonist

Preferred OPIOIDS antagonist comprises naltrexone, naloxone and methadone.

The prescription that contains the OPIOIDS antagonist according to the present invention can be used for the treatment of the dependency to OPIOIDS.

(11) Antidepressants

Preferred antidepressants comprise venlafaxine, triflupromazine, methotrimeprazine, promethazine, buspirone, gepirone and fluoxetine (fluoxetine).

(12) NSAID (non-steroidal anti-inflammatory drug)

Preferred NSAID (non-steroidal anti-inflammatory drug) comprises naproxen sodium indomethacin, sulindac, tolmetin, rantudil, McN 2783-21-98, mefenamic acid, fenoprofen, flufenamic acid, Phenylbutazone, flurbiprofen, ketorolac and capsaicin.

The prescription that contains NSAID (non-steroidal anti-inflammatory drug) according to the present invention can be used for the treatment of operation back inflammation and the inflammation relevant with for example rheumatic arthritis.

(13) Other

Other suitable activating agent comprises the Paroxetine that is used for the treatment of social anxiety disease/social phobia, the galanin antagonist that is used for the treatment of obesity, eating disorder, depression and pain such as galanin fragment 1-13-Pro-Pro-Ala-Leu-Ala-Leu-Ala amide and galanin (1-13)-spantide 1; The activin and inhibin fragment such as α-subunit fragment 1-32 and the β-fragment 67-94 that are used for population control; The thyroliberin (ACTH) and variant and the fragment that are used for the treatment of west syndrome and infantile spasm; The growth hormone and the analog thereof that are used for growth hormone deficiency child's alternative medicine; The erythropoietin (EPO) and the analog that are used for the treatment of anemia; With prevention congestive heart failure, prophylaxis of acute renal failure and subarachnoid hemorrhage, prevention and treatment arteriosclerosis, treatment hypertension, the Endothelin angiogenic peptide antagonist of prevention of brain hemorrhage and treatment chronic obstructive disease of lung; Be used for the treatment of obesity and eating disorder for example nervous anorexia and the leptin and analog and agonist and the antagonist that are used to lose weight; Be used for the treatment of thyrotrophin-releasing hormone (TRH) and analog (as pGlu-His-Pro-Gly) thereof as epilepsy; With the theophylline and the analog thereof that are used for the treatment of asthma, systemic capillary tube leak syndrome and Parkinson's disease.Vaccine antigen comprises that the dna encoding vaccine antigen is also available according to prescription release of the present invention.

Can comprise the combination of activating agent according to prescription of the present invention.The example of preferred combination (comprising " agent 1 " and " agent 2 ") is as shown in table 1.

Table 1:

Agent 1	Agent 2
Agent 1	Agent 2	HMG Co A reductase inhibitor	Gemfibrozil
NSAID (non-steroidal anti-inflammatory drug)	Mick Fei Nate mofelil	HMG Co A reductase inhibitor	Gemfibrozil
NSAID (non-steroidal anti-inflammatory drug)	Mick Fei Nate mofelil	The GnRH agonist	The Trk tyrosine kinase inhibitors
The GnRH agonist	Testosterone	The GnRH agonist	The Trk tyrosine kinase inhibitors
The GnRH agonist	Testosterone	Calcitonin	Estrogen
Calcitonin	Etridonate	Calcitonin	Estrogen
Calcitonin	Etridonate	Calcitonin	Pamridonate
Octreotide	Alpha-interferon	Calcitonin	Pamridonate
Octreotide	Alpha-interferon	Octreotide	IGF-1
Octreotide	Miclodrine	Octreotide	IGF-1
Octreotide	Miclodrine	The GnRH agonist	Flutan
Oxyethyltheophylline	Theophylline	The GnRH agonist	Flutan

Preferably, this at least a activating agent has and is low to moderate medium lipotropy.More preferably, the scope of the log octanol/water partition coefficient (log P) of this activating agent (Ruelle and Kesselring (1998), J Pharm Sci.Vol.87:1115-24) 5.0 to-3.0.In 1.0 to-3.0 scope those of the activating agent of log P value in 3.0 to-3.0 scope, particularly log P most preferably.

The log P value of the representative of above-mentioned activating agent kind is as shown in table 2.

Table 2:

Agent	Log octanol/water partition coefficient (log P)
Agent	Log octanol/water partition coefficient (log P)	Octreotide	1.40
Cyclosporin A	2.90	Octreotide	1.40
Cyclosporin A	2.90	Captopril	-1.86
The trandolapril spy	1.02	Captopril	-1.86
The trandolapril spy	1.02	Perindoprilat	-0.36
Quinaprilat	0.69	Perindoprilat	-0.36
Quinaprilat	0.69	Morphine	0.76
Lignocaine	2.26	Morphine	0.76
Lignocaine	2.26	Methadone	3.93
Promethazine	4.75	Methadone	3.93
Promethazine	4.75	Indomethacin	4.27
Flufenamic acid	1.14	Indomethacin	4.27
Flufenamic acid	1.14	Phenylbutazone	3.16
Theophylline	-0.02	Phenylbutazone	3.16
Theophylline	-0.02	Oxyethyltheophylline	0.35
TRH	-2.40	Oxyethyltheophylline	0.35

Pore former can be any reagent or these combination of agents that makes this at least a activating agent slow release from the tristerin excipient, and condition is when this at least a activating agent is the GnRH agonist, and pore former can not be a lecithin.

Preferably, pore former is selected from water miscible material, as inorganic salt (example hydrochloric acid salt, phosphate and sulfate), organic salt is (as acetate, formates, propionate, glutamate, Glu and aspartate), sugar is (as glucose, trehalose, mannose, galactose, sucrose and low-molecular-weight carbohydrate such as hydroxypropyl emthylcellulose (HPMC) and carboxymethyl cellulose (CMC)), amino sugar (as glucosamine and aminogalactose), aminoacid/peptide is (as lysine, arginine, glutamic acid, aspartic acid, carnosine and aspartame), water soluble protein and water soluble vitamins (as vitamin B).

At present, most preferred pore former is lecithin (except this at least a activating agent situation that is the GnRH agonist) and amino acid lysine.Lecithin is the mixture that stearic acid, Palmic acid and oleic diglyceride are connected in the phosphocholine ester.As described in the effect such as international patent application No.PCT/AU96/00370 (WO97/00693) of pore former, the document is incorporated herein for referencial use lecithin in comprising the slow release prescription of deslorelin and tristerin.

Find out obviously that from the embodiment of this paper the characteristic of employed pore former and the variation of quantity make the release conditions of controlling activating agent in order to adapt to the particular treatment purposes become possibility.

Tristerin is amorphousness preferably.Tristerin is partially hydrogenated Petiolus Trachycarpi oil, and as main fatty acid, it contains C16:0 (45%) and C18:0 (53%).The fusing point of tristerin is about 60 ℃.Astoundingly, as if tristerin only cause slight to medium inflammatory reaction in receiver's body, therefore it is believed that using glyceryl stearate is contributive as excipient to the success according to prescription of the present invention, thereby cause this prescription to be encapsulated in fibroblastic thin layer.Thereby those skilled in the art will appreciate that and comprise to other prescription of the included similar excipient of the prescription of first aspect present invention and can cause the slight release that helps activating agent to medium inflammatory reaction similarly.These other prescriptions are regarded as within the scope of the invention.

Can administration of human and other animal that is selected from Canis familiaris L., cat, other domestic animal and captive wild animal according to prescription of the present invention.

(PBS:pH 7.3 to phosphate buffer external usually for these prescriptions, 8.00g sodium chloride, 1.00g disodium hydrogen phosphate,anhydrous, 0.40g two hypophosphite monohydrate sodium dihydrogens (if anhydrous then be 0.31g) and 0.05g Hydrazoic acid,sodium salt be dissolved in 1 liter of deionized water prepare) in, under 37 ℃ at least 7 days extremely in about 2 years time with g/ days speed release bioactive agent of about 2-350 μ.

In addition, the common form that maybe can pass through the shaft that extrudes with the free-flow pearl of this prescription exists as storing prescription.

The shaft that extrudes can be cut into predetermined length is used for people or other animal with standard techniques implantation.Obviously, the dosage and the rate of release of the length of shaft decision activating agent.Long shaft is opposite with implanting, and can be implanted into shaft more than one at everyone or other animal body.The particle matter of injection preparation is the suspension of free-flow pearl for example, also can be by required dosage and speed release bioactive agent.

With the prescription of free-flow pearl and/or implant administration, particularly, can prepare in order to the below method to the prescription of Canis familiaris L. use:

Mix tristerin (diameter is equal to or less than the free-flow pearl of 1mm, is produced by Vandenberg Food) and pore former.Add activating agent then and thoroughly mix with excipient and pore former mixture.This material can be used for injection then.Perhaps, this mixture can be transferred in the bucket of ram extruder, and this ram extruder is connected with a 1mm nozzle, and balance to 55 ℃ (or other enough softens the temperature of tristerin).Load onto hammer, exert pressure (40psi) is until beginning to extrude product.This moment, pressure can descend, and made product reach 55 ℃ (or other enough soften the temperature of tristerin).Product can with for example in 30 seconds the speed of 3g extrude.Extrudate cooling, fragmentation with obtaining extrude with the 1mm nozzle, to guarantee the homogeneity of whole the ingredients of a mixture again.Can use the nozzle of 2.3mm diameter to replace the nozzle of 1mm to extrude product (using and the preceding identical hygral equilibrium process of extrusion) then.Be cut into the length of required weight after the shaft cooling of the length that obtains, cut back gamma ray disinfection.

In addition, with the prescription of bioimplant administration, the prescription that Canis familiaris L. is used particularly, can be in order to the below manufactured:

Mix tristerin and pore former.Add activating agent then, and thoroughly sneak in excipient and the pore former.Mixture can be transferred in the bucket of ram extruder then, and this ram extruder is connected with a 2.3mm nozzle, and balance is to the temperature of enough softening tristerin.Start extruding machine, begin to extrude product, extrudate is cut into Len req.The product that cuts is finally through disinfection.

In addition, in preparation prescription of the present invention, when particularly this at least a activating agent is peptide, polypeptide and protein, preferably this at least a activating agent is comprised that earlier two go on foot the pretreatment of freezing dry process.This lyophilization step can be undertaken by the freeze-drying method commonly used of any protein material.Yet, preferably with activating agent appropriate solvent for example the concentration in 30% (w/w) ethanol water be that 5-50% (5-15% more preferably) solution (w/w) carries out lyophilization.Cryodesiccated activating agent can dissolve again or homogenize in appropriate solvent (as rare weak acid solution of 25-75% (w/w) acetic acid aqueous solution of 1-5% (w/w) for example) and then lyophilization.Therefore, the freezing dry process of activating agent can comprise the steps:

(i) the preparation surfactant concentration is the solution of 5-50% (w/w),

The solution of (ii) lyophilization step (i),

(iii) with described cryodesiccated activating agent prepare solution that concentration is 25-75% or homogeneous thing and

The (iv) described step of lyophilization solution or homogeneous thing (iii).

Term " with the activating agent dry weight basis " is the general meaning in this area.That is, its be used for representing filling a prescription percentage composition (w/w) of peptide agonists or analog is based on the dry weight of peptide agonists or analog.

The term that uses in the description " comprises " and is meant and comprises described step, composition or feature, comprises or do not comprise other step, composition or feature simultaneously.

The present invention will further describe below by non-limiting example and accompanying drawing at this paper.

Brief Description Of Drawings:

Fig. 1 has provided the figure of average day release in vitro situation of three 100mg shafts that show following every kind of prescription:

(I) tristerin of 6% deslorelin, 2% lysine and surplus; With

(II) tristerin of 6% deslorelin, 5% lysine and surplus.

The figure illustrates the initial rapid release of activating agent and thereafter in the lasting release conditions in long period (110 days).

Fig. 2 has provided the figure of average day release in vitro situation of three 100mg shafts that show following every kind of prescription:

(III) tristerin of 6% deslorelin, 2% sodium sulfate and surplus; With

(IV) tristerin of 6% deslorelin, 5% sodium sulfate and surplus.

This figure shows when using 5% sodium sulfate as pore former, the initial rapid release speed of deslorelin bigger (534 μ g are than 438 μ g).After the initial rapid release (about 10 days finish), the rate of release of two kinds of prescriptions is about 10-2 μ g/ days in afterwards 95 days.

Fig. 3 has provided the figure of average day release in vitro situation of three 100mg shafts that show following every kind of prescription:

(V) tristerin of 6% deslorelin, 2% hydroxypropyl emthylcellulose (HPMC) and surplus; With

(VI) tristerin of 6% deslorelin, 5% hydroxypropyl emthylcellulose (HPMC) and surplus.

This figure shows when using 5%HPMC as pore former, the initial rapid release speed of deslorelin bigger (685 μ g are than 403 μ g).After the initial rapid release (about 10 days finish), the rate of release of two kinds of prescriptions is about 10-2 μ g/ days in afterwards 95 days.

Fig. 4 has provided the figure of average day release in vitro situation of three 100mg shafts that show following every kind of prescription:

(VII) tristerin of 6% deslorelin, 2% glucose and surplus; With

(VIII) tristerin of 6% deslorelin, 5% glucose and surplus.

This figure shows that speed bigger (790 μ g are than 403 μ g) is put in initially releasing of deslorelin fast when using 5% glucose as pore former.After the initial rapid release (about 10 days finish), the rate of release of two kinds of prescriptions is about 50-2 μ g/ days in afterwards 95 days.

Fig. 5 has provided the figure of average day release in vitro situation of three 100mg shafts that show following every kind of prescription:

(IX) tristerin of 6% somatostatin, 0% acetate and surplus;

(X) tristerin of 6% somatostatin, 3% acetate and surplus;

(XI) tristerin of 6% somatostatin, 5% lysine and surplus; With

(XII) tristerin of 6% somatostatin, 10% lysine and surplus.

This figure demonstration is compared with using sodium acetate, and when using lysine as pore former, the initial rapid release speed of somatostatin is bigger.After the initial rapid release (about 2 days finish), the rate of release in all situations slows down and settled out at the 7th day.

Fig. 6 has provided the figure of average day release in vitro situation of three 100mg shafts that show following every kind of prescription:

(XIII) tristerin of 6% naltrexone (NX), 0% pore former and surplus;

(XIV) tristerin of 6% naltrexone (NX), 3% acetate and surplus;

(XV) tristerin of 6% naltrexone (NX), 5% lysine and surplus; With

(XVI) tristerin of 6% naltrexone (NX), 10% lysine and surplus.

This figure shows that all prescriptions have all realized slowly progressively discharging of naltrexone in the 23 day time of experiment, although when do not have pore former, average day burst size lower.

Fig. 7 has provided the figure of average day release in vitro situation of three 100mg shafts that show following every kind of prescription:

(XVII) tristerin of 6% lisinopril, 0% sodium acetate and surplus;

(XVIII) tristerin of 6% lisinopril, 3% sodium acetate and surplus;

(XIX) tristerin of 6% lisinopril, 5% lysine and surplus; With

(XX) tristerin of 6% lisinopril, 10% lysine and surplus.

This figure shows all prescriptions (about 1 day finishes) after initial rapid release, in the 25 day time of experiment, all realized slowly progressively discharging of lisinopril, although under the situation of prescription XVII (i.e. 0% pore former), average day burst size in this time is lower.

Fig. 8 has provided the figure of average day release in vitro situation of three 100mg shafts that show following every kind of prescription:

(XXI) tristerin of 6% thyrotrophin-releasing hormone (TRH), 0% acetate and surplus;

(XXII) tristerin of 6% thyrotrophin-releasing hormone (TRH), 3% acetate and surplus;

(XXIII) tristerin of 6% thyrotrophin-releasing hormone (TRH), 5% lysine and surplus; With

(XXIV) tristerin of 6% thyrotrophin-releasing hormone (TRH), 10% lysine and surplus.

This figure shows that prescription XXII, XXIII, XXIV after very fast initial release, have realized slowly progressively discharging of TRH in the 28 day time of experiment.And when not containing pore former, after the 1st day, do not observe the further release of TRH.

Fig. 9 has provided the figure of average day release in vitro situation of three 100mg shafts that show following prescription:

(XXV) tristerin of 6% deslorelin, 3% sodium acetate and surplus.

This figure is presented at the slow release of having realized deslorelin in 110 days of experiment.

Embodiment

The prescription that contains deslorelin and lysine

The preparation method of formula I and II (details is as mentioned above) is as follows:

Tristerin (diameter is equal to or less than the free-flow pearl of 1mm, is provided by Quest International Pty Ltd (Holland)) and lysine spatula manual mixing in small beaker.Deslorelin (Bachem, Switzerland) adds in the excipient and mixing fully with above-mentioned freezing dry process pretreatment then.The material that mixes is transferred in the bucket of ram extruder, this ram extruder is connected with a 1mm nozzle, and balance to 55 ℃.The plunger type extruder pressure is 40psi.Load onto hammer, exert pressure, until beginning to extrude product.This moment, pressure descended, and allowed product reach 55 ℃.Product extrudes with the speed of 3g in 30 seconds.Gained extrudate cooling back is broken also to be extruded with the 1mm nozzle again.This step is in order to guarantee the homogeneity of composition in the whole substrate.The nozzle that replaces 1mm then with the nozzle of 2.3mm diameter.Carry out same product temperature equilibrium process before the extrusion.Extrude product then, after the cooling, the shaft of the length that obtains is cut into the length of required weight.

The external deslorelin that Fig. 1 has provided the 100mg shaft that contains the 6mg deslorelin discharges the result.This analysis comprises each shaft immersed and contains 1ml phosphate buffer (PBS; In the autonomous container as described earlier in this article), this container places 37 ℃ of circulator baths.PBS changes every day, and the PBS that extracts analyzes deslorelin with HPLC.

After this figure is presented at the initial rapid release of deslorelin, realized the slow release in the long term afterwards (110 days).In slow-release period, average day rate of release of deslorelin is 50-2 μ g/ days.

The prescription that contains deslorelin and sodium sulfate

Formula I II and IV use sodium sulfate (Ajax Chemicals, the U.S.) as pore former, adopt the method preparation identical with above-mentioned deslorelin/lysine prescription.

The external deslorelin that Fig. 2 has provided the 100mg shaft that contains the 6mg deslorelin discharges the result.This figure shows and compares with the sodium sulfate of 2% concentration, when the sodium sulfate that uses 5% concentration during as pore former, and the initial rapid release speed of deslorelin bigger (534 μ g are than 438 μ g).After the initial rapid release (about 10 days finish), the rate of release of two kinds of prescriptions is about 10-2 μ g/ days in afterwards 95 days.

The prescription that contains deslorelin and HPMC

Prescription V and VI use hydroxypropyl emthylcellulose (HPMC) as pore former, adopt the method preparation identical with above-mentioned deslorelin/lysine prescription.

The external deslorelin that Fig. 3 has provided the 100mg shaft that contains the 6mg deslorelin discharges the result.This figure shows and compares with the HPMC of 2% concentration, as the HPMC that uses 5% concentration during as pore former, and the initial rapid release speed of deslorelin bigger (685 μ g are than 403 μ g).After the initial rapid release (about 10 days finish), the rate of release of the two is about 10-2 μ g/ days in afterwards 95 days.

The prescription that contains deslorelin and glucose

Prescription VII and VIII use glucose (Aiax Chemicals, the U.S.) as pore former, adopt the method preparation identical with above-mentioned deslorelin/lysine prescription.

The external deslorelin that Fig. 4 has provided the 100mg shaft that contains the 6mg deslorelin discharges the result.This figure shows and compares with the glucose of 2% concentration, when the glucose that uses 5% concentration during as pore former, and the initial rapid release speed of deslorelin bigger (790 μ g are than 403 μ g).After the initial rapid release (about 10 days finish), the rate of release of two kinds of prescriptions is about 50-2 μ g/ days in afterwards 95 days.

The prescription that contains somatostatin and sodium acetate or lysine

Formula I X to XII uses sodium acetate or lysine as pore former, adopts the method preparation identical with above-mentioned deslorelin/lysine prescription.Somatostatin obtains from Bachem (Switzerland).

Fig. 5 discharges the result for the external somatostatin of the 100mg shaft located to contain the 6mg somatostatin.This figure demonstration is compared with sodium acetate, and when using lysine as pore former, the initial rapid release speed of somatostatin is bigger.

The prescription that contains naltrexone and sodium acetate or lysine

Prescription XIII to XVI uses sodium acetate or lysine as pore former, adopts the method preparation identical with above-mentioned deslorelin/lysine prescription.

The external naltrexone that Fig. 6 has provided the 100mg shaft that contains the 6mg naltrexone discharges the result.This figure shows that all prescriptions have all realized slowly progressively discharging of naltrexone in the 23 day time of experiment, although when do not have pore former, average day burst size lower.

The prescription that contains lisinopril and sodium acetate or lysine

Prescription XVII to XX uses sodium acetate or lysine as pore former, adopts the method preparation identical with above-mentioned deslorelin/lysine prescription.Lisinopril is obtained by Sigma Chemical Co. (U.S.).

Fig. 7 discharges the result for the external lisinopril of the 100mg shaft located to contain the 6mg lisinopril.This figure shows all prescriptions (about 1 day finishes) after initial rapid release, in the 25 day time of experiment, all realized slowly progressively discharging of lisinopril, although under the situation of the prescription XVII that does not contain pore former, average day burst size in this time is lower.

The prescription that contains TRH and sodium acetate or lysine

Prescription XXI to XXIV uses sodium acetate or lysine as pore former, adopts the method preparation identical with above-mentioned deslorelin/lysine prescription.TRH obtains from Sigma Chemical Co. (U.S.).

The external TRH that Fig. 8 has provided the 100mg shaft that contains 6mg TRH discharges the result.This figure shows that prescription XXII, XXIII, XXIV after very fast initial release, have all realized slowly progressively discharging of TRH in the 28 day time of experiment.And when not containing pore former, after the 1st day, do not observe the further release of TRH.

The prescription that contains deslorelin and sodium acetate

Prescription XXV uses sodium acetate as pore former, adopts the method preparation identical with above-mentioned deslorelin/lysine prescription.

The external deslorelin that Fig. 9 has provided the 6mg shaft discharges the result.This figure Display Realization the slow release of the deslorelin in 110 days.

Those skilled in the art will appreciate that under the prerequisite that does not depart from broadly described design of the present invention and scope, can carry out a lot of changes and modification the present invention that specific embodiments is showed.Thereby these specific embodiments are in office, and where face all is considered to illustrative, and nonrestrictive.

Claims

1. medicine and/or veterinary prescription, described prescription comprises the activating agent of at least a log octanol/water partition coefficient in 5.0 to-3.0 scopes with the 2-30w/w% of activating agent dry weight basis, the water solublity pore former that comprises lecithin and organic salt of 0.5-20.0w/w%, and the tristerin of surplus.

2. according to the prescription of claim 1, wherein said prescription comprises at least a activating agent with the 5-10w/w% of activating agent dry weight basis, the pore former of 1.0-10.0w/w%, and the tristerin of surplus.

3. according to the prescription of claim 1, wherein said prescription comprises at least a activating agent with the 5-10w/w% of activating agent dry weight basis, the pore former of 2.0-5.0w/w%, and the tristerin of surplus.

4. according to each prescription of claim 1-3, wherein said pore former comprises lecithin and sodium acetate.

5. according to each prescription of claim 1-3, wherein said at least a activating agent is selected from peptide, polypeptide, protein and nucleic acid compound and derivant.

6. according to each prescription of claim 1-3, wherein said at least a activating agent is selected from the GnRH agonist.

7. according to the prescription of claim 6, wherein said GnRH agonist is selected from deslorelin, flutamide, goserelin, the bright third sharp moral, dioxalan derivant, triptorelin, meterelin, buserelin, histrelin, nafarelin, lutrelin, leuprorelin and LHRH analog.

8. according to the prescription of claim 6 or 7, wherein said GnRH agonist is that deslorelin and described pore former comprise lecithin and sodium acetate.

9. according to each prescription of aforementioned claim, the log octanol/water partition coefficient of wherein said at least a activating agent is in 5.0 to-3.0 scope.

10. according to each prescription of aforementioned claim, the log octanol/water partition coefficient of wherein said at least a activating agent is in 1.0 to-3.0 scope.

11. according to each prescription of aforementioned claim, wherein said prescription is the form of free-pouring pearl or shaft.

12. at least a activating agent, the pore former that comprises lecithin and organic salt and tristerin are in the medicine of preparation claim 1 and/or the purposes in veterinary's prescription.