CN100444848C - Pharmaceutical composition for improved administration of HIV gp41-derived peptides,And its use in therapy - Google Patents

Abstract

Provided is a pharmaceutical composition comprising a solution comprised of synthetic peptide in a final concentration of not less than 70 mg/ml in admixture with a polyol; wherein the synthetic peptide is an HIV fusion inhibitor, and wherein the polyol is in a final concentration of no less than 5 weight % and no more than 75 weight % of the pharmaceutical composition. Also provided is a synthetic peptide-containing pharmaceutical composition as a unit dose comprising an aqueous formulation comprised of synthetic peptide in a final concentration of not less than 70 mg/ml in admixture with a polyol; wherein the synthetic peptide is an HIV fusion inhibitor, and wherein the polyol is in a final concentration of no less than 5 weight % and no more than 75 weight % of the pharmaceutical composition. Further provided is a method of treating HIV infection by administering to an HIV-infected individual a pharmaceutical composition according to the present invention.

Description

The pharmaceutical composition that improves medication of HIV gp41-derived peptide

Technical field

The present invention relates to a kind ofly mix the pharmaceutical composition of forming by polymer with from the synthetic peptide of HIV (human immunodeficiency virus) (HIV) gp41.More particularly, the present invention comprises a kind of pharmaceutical composition, and it contains a kind of polyhydric alcohol and the mixture that has from the synthetic peptide of the aminoacid sequence in the HR1 district of HIVgp41 or HR2 district.

Background technology

Well-known at present, cell can be infected by HIV by a kind of fusion process that occurs between cell membrane and the viromembrane.The pattern that this process is usually generally acknowledged is, virus coat glycoprotein complex (gp120/gp41) combines with cell surface receptor on the target cell membrane.After gp120 is attached on the cell receptor (for example, CD4 and chemokine coreceptor such as CCR-5 or CXCR-4 combine), induce the variation of conformation in the gp120/gp41 complex, make gp41 be inserted in the target cell membrane and regulate film and merge.

In different HIV bacterial strains, the aminoacid sequence of gp41 and its mutant are well known.Fig. 1 is the diagram (note according to the HIV bacterial strain, aminoacid sequence number can change a little) of the gp41 functional areas of usually generally acknowledging.Fusogenic peptide (fusion gene (fusogenic) zone) is considered to participate in inserting and destroying target cell membrane.Contain the diaphragm area of striding of striding film anchor sequence and be positioned at this proteic C-end.At fusogenic peptide with to stride between the film anchor be the zone of two uniquenesses, be commonly referred to as 7 one group repetition (HR) zone, each zone has many seven one group.Usually be described to comprise from about 545 to about 595 amino acid residue of the aminoacid sequence of gp160 (SEQ ID NO:1) from the terminal nearer regional HR1 of this albumen N-.Yet the aminoacid numbering of gp160 depends on the bacterial strain that this aminoacid sequence is inferred.The aminoacid sequence that comprises the HR1 district is zone (Shu et al., 1999, Biochemistry, the 38:5378-5385 of high conservative in the coat protein of HIV-1 with the aminoacid sequence that comprises the HR2 district; Hanna et al., 2002, A/DS 16:1603-8).Compare with the HR1 district, the HR2 district advanced of this proteic C-end of distance is described to comprise from about 628 to about 678 locational aminoacid of the aminoacid sequence of gp160 (SEQ ID NO:2) usually.These HR district apokoinou construction and functional characters.For example, each HR district has many 7 amino acid residue continuous parts or " 7 one group " (7 aminoacid in each 7 group are named as " a " to " g "), and is wherein normally hydrophobic at the aminoacid of " a " position and " d " position.And being present in each HR district is one or more leucine zipper shape motifs (referring to " repetition of leucine zipper shape " again), and containing with isoleucine or leucine is the eight amino acid sequence that initial sum stops.The most continually, the HR2 district only has a leucine zipper shape motif, and the HR1 district has 5 leucine zipper shape motifs.Each of these 7 one group and leucine zipper shape motif all helps to form the coiled coil structure of gp41 and from the coiled coil structure of the peptide in HR district.Usually, known coiled coil is made of around the spiral that forms oligomer each other two or more, coiled coil has such characteristics, has amino acid whose 7 one group repetition in the hydrophobic residue advantage of first (" a ") and the individual position of the 4th (" d "), charged residue is usually in the 5th (" e ") and the individual position of the 7th (" g "), and the aminoacid in " a " position and " d " position is that the factor of determination that influences oligomeric state and chain direction (is seen, as, Akey et al., 2001, Biochemistry, 40:6352-60).

The synthetic peptide inhibition HIV that finds to derive from the HR1 district (HR1 peptide) of HIVgp41 or HR2 district (HR2 peptide) in vitro tests and body in the clinical research (sees to the propagation of host cell, for example, Wild et al., 1994, Proc.Natl.Acad.Sci.USA, 91:9770-9774; License to assignee of the present invention's United States Patent (USP) 5,464,933 and 5,656,480; With Kilby et al., 1998, Nature Med.4:1302-1306).More particularly, the HR1 peptide is as (also being commonly referred to as T21 by DP107; SEQ ID NO:3) illustrate, with the 50% valid density value (EC50) of 1 μ g/ml stoped the T cell infection (see, for example, Lawless et al., 1996, Biochemistry, 35:13697-13708).The HR2 peptide is as (also being commonly referred to as T20 by DP178; SEQ ID NO:4) illustrates, stoped the infection of T cell with 50% valid density value (EC50) of ng/ml scope.The effectively synthetic peptide of finding at first was described in front, it contains one or more enhancement sequences that are connected on the core HIV gp41 aminoacid sequence, inhibition HIV film merges also thereby stops virus to the propagation of host cell (to be seen, as, the United States Patent (USP) 6,258,782 and 6 that this assignee assigns, 348,568).At present,, carry the effective dose of antiviral activity most effectively as other peptide known in the art, so often medication of synthetic peptide quilt (as, injection every day) in blood flow, to reach and to keep a kind of level of abundant therapeutical effect.In addition, in the individuality of the Injectable solution prescription of accepting present obtainable HIV fusion inhibitor, injection site reaction is the most common side effect.For example, in studying in the III phase of the subcutaneous medication of T20, use mannitol fill a prescription substantially (not resembling the polyhydric alcohol of instructing among the present invention), 98% patient who receives treatment produce injection site reaction (injection reaction by one or more redden, swelling and discomfort show), 3.3% patient is with the reason of this reaction as the proposition abandoning cure.Another limitation of the Injectable solution prescription of HIV fusion inhibitor is at present, be difficult to obtain ideal contain inviscid (similar gels of filling a prescription here rather than solution) and/or the stability that synthetic peptide concentration is not less than 100mg/ml (as, surpass the scheduled time, synthetic peptide breaks away from the precipitation of solution) Injectable solution of problem.

Found to work as polyhydric alcohol, when particularly Polyethylene Glycol (PEG) was used for the Injectable solution of drug formulation as pharmaceutically acceptable carrier, it showed as good toleration and is considered to have low relatively toxicity.Therefore, in the medicine Injectable solution prescription of being approved by many regulations that contains the Chemical composition that composition except peptide and albumen, PEG has been used as pharmaceutically acceptable carrier.The amount of PEG typically exists with about 0.1 percentage by weight to about 5 percentage by weights of this prescription in such prescription.PEG also is not used as the pharmaceutically acceptable carrier that keeps albumen and peptide in the solution, but is used to peptide and proteic precipitation.For example, the PEG (w/v of use 1% to 10%; See, as United States Patent (USP) 5462863) but circulation precipitation purification hepatitis B surface antigen protein; Excretory IgA can precipitate with the PEG of 15-25% (w/v) concentration; The fibrin proper energy precipitates with the PEG that amounts to weight 2.5% that the N enzyme can precipitate with the PEG solution of 40-60 weight % and antihemophilic factor can precipitate with the final concentration of 3% to 6%PEG (w/v).Therefore, the PEG that use is equal to or greater than 5 weight % concentration is to be precipitated out from solution with the fill a prescription albumen or the peptide of administration of Injectable solution as a problem of pharmaceutically acceptable carrier in pharmaceutical composition, and this is a result who does not wish very much to obtain.(see) in an example as United States Patent (USP) 6,004,549, disclosure be a kind of pharmaceutical composition of forming by the suspension of albumen in polyhydric alcohol; Be (numeral of PEG back is about Dalton molecular weight size of the PEG that quoted, will more go through among the application) in a kind of solution or gel of a kind of interferon crystal form solution of being suspended in the aqueous solution of a kind of 40%PEG8000 of comprising (w/v) or 50%PEG3350.

Yet, contain by synthetic peptide (HIV fusion inhibitor) and polyhydric alcohol, be not less than the PEG of 5 weight % (as, weight/volume percent) and no more than 75 weight % as final concentration, the up to the present also not disclosed mistake of pharmaceutical composition of the solution formed of mixture.Before the present invention finds, this area still has the demand of long-term serious hope to the drug regimen composition formula that meets the following requirements: (a) can be used as Injectable solution, (b) be used for specific purpose having enough stability, in addition, can minimizing need give the frequency injection of the synthetic peptide of effective dose to reach therapeutic effect, contain the synthetic peptide (HIV fusion inhibitor) that concentration is not less than 100mg/ml in the solution and (c) injection site reaction is dropped to minimum.The present invention satisfies these requirements.

Summary of the invention

The present invention is for satisfying this demand, a kind of pharmaceutical composition is provided, it comprises a kind of pharmaceutical composition that is mixed the solution of forming by synthetic peptide (HIV fusion inhibitor) and polyhydric alcohol, wherein the final concentration of polyhydric alcohol is not less than 5 weight % of pharmaceutical composition and is not higher than 75 weight %, preferably is not less than 10 weight % and is not higher than 50 weight %.This pharmaceutical composition comprises a kind of injection solution prescription with unexpected effect, and compares with the prescription of present use, and great raising is arranged.Especially, pharmaceutical composition of the present invention comprises a kind of Injectable solution prescription, and when filling a prescription substantially with mannitol or other prescription well known in the art when comparing, its (a) greatly reduced the dissolution time in the pharmaceutical compositions process; (b) greatly reduced the viscosity of pharmaceutical composition; (c) provide a kind of suitable microenvironment around synthetic peptide (HIV fusion inhibitor), its another benefit be allow high concentration (as, be equal to or greater than 100mg/ml) synthetic peptide (HIV fusion inhibitor) is by in the pass into solution and keep the stabilizing solution of the life of product of expectation; (d) when being used as the injection solution prescription, on scope and intensity, can significantly reduce injection site reaction.

The present invention further provides a kind of method of pharmaceutical compositions, comprise and mix synthetic peptide and polyhydric alcohol, wherein the final concentration of polyhydric alcohol is not less than 5 weight % of pharmaceutical composition and is not higher than 75 weight %, more preferably is not less than 10 weight % and is not higher than 50 weight %.

The present invention also provides a kind of treatment HIV to infect the method for (preferred, HIV-1 infects), comprises to the individuality of infected by HIV and uses pharmaceutical composition of the present invention.Preferably, the consumption of pharmaceutical composition is transmitted to target cell for effectively suppressing HIV, and/or effectively suppresses the fusion of the HIV of gp41-mediation to target cell.

The present invention also provides, in the pharmaceutical composition of comprising of a kind of unit dose of synthetic peptide (HIV fusion inhibitor), wherein pharmaceutical composition comprises a kind of by the following aqueous formulation of forming: (a) unit dose of the polyhydric alcohol that exists as pharmaceutically acceptable carrier, content is not less than 5 weight % of pharmaceutical composition and is not higher than 75 weight %, more preferably, the unit dose content of the polyhydric alcohol that exists as pharmaceutically acceptable carrier is not less than 10 weight % of pharmaceutical composition and is not higher than 50 weight %, (b) content of synthetic peptide is not less than 70mg/ml and is not higher than 500mg/ml, more preferably is not less than 100mg/ml and is not higher than 250mg/ml.The present invention also provides a kind of treatment HIV to infect the method for (preferred HIV-1 infects), comprises the pharmaceutical composition that gives synthetic peptide of containing of unit dose of the present invention (HIV fusion inhibitor) to the individuality of infected by HIV.Preferably, the consumption of this pharmaceutical composition is effectively to suppress the propagation of HIV to target cell, and/or effectively suppresses the fusion of the HIV of gp41-mediation to target cell.

When reading when combining with accompanying drawing, above and other objects of the present invention, feature and advantage are with apparent in the detailed Description Of The Invention below.

Description of drawings

Fig. 1 is the sketch map of HIV gp41, has shown that 7 one group is repeated 1 district (HR1) and 7 one group other functional areas of repeating 2 districts (HR2) together with gp41.Show HR1 (SEQID NO:1) corresponding to HIV-1 bacterial strain LAI and the representative peptide sequence of HR2 (SEQ ID NO:2), be used for illustration purpose.Come numbering according to the position of amino acid residue in the gp160 of bacterial strain HIVIIIB to them.

The specific embodiment

Detailed Description Of The Invention

Definition

Term " individuality " when when this uses, for description and claims, refers to mammal, particularly the people.

Term " target cell " when when this uses, for description and claims, refers to the cell that can be infected by HIV, and is preferred, and this cell is cell of people or a plurality of cells of people; More preferably, be a plurality of cells of the people that can be infected by the process that comprises film and merge by HIV.

Term " pharmaceutically acceptable carrier ", when when this uses, for description and claims, refer to can not change in fact its active component that is added into (as, comprise the synthetic peptide of HIV fusion inhibitor) bioactive carrier agent.According to the present invention, in comprising the pharmaceutical composition of aqueous injectable formulations of the present invention, polyhydric alcohol is pharmaceutically acceptable carrier.Except the polyhydric alcohol that is wherein comprised, pharmaceutical composition can comprise one or more extra pharmaceutically acceptable carriers (one or more pharmaceutically acceptable carriers except that polyhydric alcohol just).Known as those skilled in the art, for being used for Injectable solution or aqueous formulation, suitable pharmaceutically acceptable carrier can comprise one or more materials, include but not limited to, water, buffered water, normal saline, 0.3% glycine, aqueous alcohol, etc. ooze aqueous buffer; And can further comprise one or more materials for example glycerol, oils and fats, salt such as sodium, potassium, magnesium and ammonium, phosphate, carbonic ester, fatty acid, saccharide (as, mannitol), polysaccharide, excipient and antiseptic and/or stabilizing agent (in order to strengthen self in life-span or as the manufacturing of compositions and provide and deliver necessary and suitable).Preferably, carrier is suitable for vein, muscle, subcutaneous or parenteral medication (for example, by injection).

Term " aminoacid ", employed synthetic peptide for description and claim and in according to the present invention refers to the molecule with at least one free amino group and at least one free hydroxyl.This aminoacid can have more than one amino, or an above hydroxyl, or can further comprise the chemical reactive group of one or more freedom except that amino or hydroxyl (as, hydroxyl, sulfydryl, etc.).This aminoacid can be spontaneous aminoacid (as, L-aminoacid), non-spontaneous aminoacid (as, D-aminoacid), synthesizing amino acid, modified aminoacid, amino acid derivativges, amino acid precursor and conservative substitution.One of ordinary skill in the art in will know, integrate with amino acid whose distinctive physics, chemistry or the biological characteristics that depends on that in a way antiviral peptide is required that be chosen in of peptide.These characteristics to a certain extent by 26S Proteasome Structure and Function determine decide (as, be described in detail in the antiviral activity among the application).For example, the description of those skilled in the art from the application will know that the aminoacid of synthetic peptide can be made up of one or more spontaneous (L)-aminoacid and non-spontaneous (D)-aminoacid.Can use preferred amino acids, the aminoacid except preferred is foreclosed.

" conservative substitution ", relevant with the aminoacid sequence of the synthetic peptide that uses among the present invention, it is the term that hereinafter uses, for description and claim, refer to one or more amino acid replacements in the synthetic peptide sequence, so that antiviral activity do not have substantial change (as, its suppressed the fusion of HIV gp41 mediation with concentration of nM scope before displacement, the displacement back is still observed in the nM scope to the inhibition of the fusion of HIV gp41 mediation so).As well known in the art, " conservative substitution " defines by aforesaid function, and comprises having the amino acid whose as an alternative displacement of aminoacid of identical polar, size, hydrophilic and/or armaticity in fact.These displacements are known for those of ordinary skill in the art, and it includes, but not limited to glycine-alanine-valine; Isoleucine-leucine; Tryptophan-tyrosine; Aspartic acid-glutamic acid; Arginine-lysine; Agedoite-glutamine; And serine-threonine.These displacements also can comprise the polymorphism according to the different aminoacids position, relevant HR district of the gp41 that is found in laboratory and/or clinical HIV separated strain, and HIV separated strain wherein is easy to acquisition and is well known in the art from disclosed data base.

Term " native sequences ", when when this uses, for description and claim and according to the aminoacid sequence in HR1 district or the HR2 district of HIV-1gp41, refer to the spontaneous sequence that is found in breadboard HIV bacterial strain and/or HIV clinical separation strain.These sequences are easy to obtain from disclosed gene database such as GenBank, as the displacement of the different aminoacids position of the aminoacid sequence in HR1 district that is found in HIV gp41 and HR2 district (as, polymorphism).

Term " polyol ", when when this uses, for description and claim, refer to the polymer that is used as pharmaceutically acceptable carrier, preferably water miscible polyhydric alcohol, it can comprise, but be not limited to, Polyethylene Glycol (" PEG "), polypropylene glycol (" PPG "), diethylene glycol, triethylene glycol, ethylene glycol, dipropylene glycol, comprise PPG (as the copolymer of, ethylene glycol/PPG), comprise PEG copolymer (as, PEG/PPG) and analog.Polyhydric alcohol comprises homopolymer and copolymer, and can further have by the structure that well known to a person skilled in the art that branched structure and linear structure are formed.Preferably, when in the individual body planted agent time spent, this polymer comes down to nontoxic.In a preferred instantiation, the molecular weight ranges of this polymer is that about 200 dalton are to about 20,000 dalton; In a preferred instantiation, the molecular weight ranges of this polymer is that about 300 dalton are to about 10,000 dalton.Be applied to preferred polymer of the present invention and comprise Polyethylene Glycol, be applied to preferred polymer of the present invention and comprise that molecular weight ranges is not less than 1000 dalton and is not higher than 10,000 daltonian Polyethylene Glycol.For example, Polyethylene Glycol is made up of many multiple oxyethylene groups, and the par of multiple oxyethylene group is relevant with the mean molecule quantity of this Polyethylene Glycol usually.In successive embodiment, polyethylene glycol 6000 (PEG6000) be described to have molecular weight ranges be 5000 dalton to 7000 dalton (as, molecular weight ranges is not less than about 1000 dalton and is not higher than 10,000 dalton).To be described to have molecular weight ranges be about 1430 dalton to about 1570 dalton to PEG1500 similarly.Preferred polymer can be applied among the present invention, and the polymer except preferred is foreclosed.

Term " synthetic peptide " and " HIV fusion inhibitor " are used by synonym at this, relevant with the peptide in being applied to the present invention, for description and claim, refer to that a kind of peptide (a) prepares by the fragmentation of chemosynthesis, recombinant expressed, macromolecular biochemistry or enzyme, macromolecular chemolysis, aforesaid combination or, usually, produce by this area any other method, and separated; (b) comprise that length is not less than about 15 aminoacid and is not higher than the aminoacid sequence of about 60 amino acid residues, and form by the HR1 district that is contained in HIV (more preferably HIV-1) gp41 of at least 10 adjacency or the aminoacid in HR2 district; (c) can suppress HIV to the propagation of target cell (preferred, the HR district by being attached to HIV-1gp41 also suppresses fusion between HIV-1 and the target cell), can by in the evaluation body and/or external antiviral activity measure, will describe in detail more among the application.Term " isolating " when using according to peptide, refers to synthetic peptide and does not contain the composition that does not become peptide self an internal structure part in fact; For instance, for example when producing, do not contain cell material or culture medium in fact,, do not contain precursor or other chemical drugs in fact perhaps when chemosynthesis or utilize biochemistry or chemical method when producing by recombinant technique.In its aminoacid sequence, synthetic peptide can comprise one or more preservative replacement and/or the one or more polymorphism in the sequence that is found in HIV gp41 relevant range, perhaps can comprise one or more amino acid replacements that can increase helical structure stability and/or influence oligomerization, it cause peptide self to be assembled into trimer (trimer), if can keep the anti-HIV-1 virus activity.In addition, this aminoacid sequence is except having the core peptide that derives from HIV gp41, also can comprise one or more enhancing peptides that are connected on the core peptide, as at N-end, terminal or at N-end and C-end at C-, perhaps can have the core peptide that derives from one or more HIV-1, HIV-2 and SIV (sees, as United States Patent (USP) 6,258,782).According to the synthetic peptide that is applied in the pharmaceutical composition, this synthetic Toplink exists with monomer, or exists with oligomerization form (oligomeric form), and it includes, but not limited to dimer, trimer, the tetramer or pentamer.For example, the synthetic peptide that comprises modified HR1 peptide preferably self is assembled into trimer (as, the trimer of being made up of three molecule synthesis peptides).Preferably, be applied to synthetic peptide of the present invention and can comprise that length is not less than the sequence of 15 aminoacid and no more than 60 amino acid residues, preferred, length is not less than 36 aminoacid and no more than 51 aminoacid, more preferably, length is not less than about 41 aminoacid and no more than about 51 aminoacid.Preferably, synthetic peptide for the sequence that comprises the HR1 district that derives from HIV-1gp41, should synthesize the contiguous sequence that peptide comprises at least 15 amino acid residues on the SEQ ID NO:1 aminoacid sequence, as the HR1 district (for instance, as, mark by single-letter aminoacid title, NNLLRAIEAQQHLLQLTVWGIKQLQARI LAVERYLKD, it is 54 amino acid residues of the 18th amino acid residue to the of SEQ ID NO:1) in important factor of determination be found structure, biochemistry and the antiviral parameter that influences described in the application.Preferably, synthetic peptide sequence for the HR2 district that derives from HIVgp41, should synthesize the contiguous sequence that peptide comprises at least 15 amino acid residues on the SEQ ID NO:2 aminoacid sequence, more preferably, QQEKNEQEL (its for 51 amino acid residues of the 43rd amino acid residue to the of SEQ ID NO:2) has been found structure, biochemistry and the antiviral parameter that influences described in the application as the important factor of determination in the HR2 district.Numerous synthetic peptides of this kind of the present invention that can be applicable to before were disclosed in, as, United States Patent (USP) 5656480,6133418,6258782.For chart, can be applicable to the synthetic peptide that typical synthetic peptide of the present invention includes, but not limited to comprise the aminoacid sequence of listing among the SEQ ID NOs:3-95." polyhydric alcohol " or " PEG " in " synthetic peptide " and the application is when using jointly, composition with respect to pharmaceutical composition of the present invention, and concerning description and claim, refer to synthetic peptide and polymer do not combine (as, do not have covalent bond).

Term " percentage by weight " as this area standard, can use with the percent weight in volume synonym, be used for herein concerning description and claim, refer to every milliliter of (ml) solution Chinese medicine compositions a certain composition (as, polyhydric alcohol) milligram number (mg), multiply by 0.1, this will be more apparent in the following description.

Term " solution ", standard as this area, refer to and be dissolved with one or more solid aqueous solutions in it, be used for the application concerning description and claim, refer under the service condition of actual concentrations and temperature, that describe in detail as the application and as the standard of this area injectable drug prescription, contain the aqueous solution of the synthetic peptide of dissolving and polyhydric alcohol in it.Contrast with the form of suspension, have multiple known method to differentiate the form of solution in this area, as detecting vision definition (compare with the suspension of muddiness, solution is transparent), light is propagated, and similar method.

The present invention will be described in detail in the following embodiments, and these embodiment are not the restriction purposes.

Embodiment 1

In this embodiment, elaboration be a kind of according to pharmaceutical composition of the present invention, wherein used T1249 (SEQ ID NO:5 sees United States Patent (USP) 6,258,752) in several instantiations of Chan Shuing.Yet, be appreciated that (showing by embodiments herein) synthetic Toplink except T1249 (SEQ ID NO:5) is used to according to pharmaceutical composition of the present invention, particularly because this class synthetic peptide (HIV fusion inhibitor peptide) apokoinou construction, biochemistry and functional character.More particularly, the synthetic peptide of this class all contains 7 one group repetition of coiled coil, and this helps the interaction between shla molecule in the aqueous solution of the polyhydric alcohol described in detail in containing the application.Other total structure, biochemistry and functional character includes, but not limited to contain aminoacid sequence, coiled coil tendency, the oligomerization tendency of one or more leucine zipper shape motifs and suppresses the ability that HIV propagates to target cell.

The peptide that is used for the embodiment of the present application synthesizes by use standard solid-phase synthetic technology and standard FMOC chemistry of peptides on peptide synthesizer, and is perhaps synthetic by the fragments of peptides assembling of describing in the United States Patent (USP) 6281331.In these embodiments, synthetic peptide further comprises reactive functionality; As, block the N-end and block the C-end by acetyl group by amino.After cutting off from resin, the synthetic peptide of precipitation, and with the precipitate lyophilizing.Use these peptides of reversed phase high-performance liquid chromatography purification then; Re-use the concordance that electron spray (electrospray) mass spectral analysis confirms peptide.

Described in present embodiment, a kind of pharmaceutical composition by solution composition is provided, this solution is included in the synthetic peptide that final concentration in the pharmaceutical composition is not less than 100mg/ml, be not less than 5 weight % of pharmaceutical composition and be not higher than 75 weight % with final concentration, more preferably be not less than 10 weight % and be not higher than the polyhydric alcohol of 50 weight %.The pharmaceutical composition of synthetic peptide of containing of a kind of unit dose (HIV fusion inhibitor) also is provided, wherein pharmaceutical composition comprises a kind of aqueous formulation, this aqueous formulation comprises: content is not less than 5 weight % of unit dose drug compositions, more preferably, be not less than the polyhydric alcohol that exists with pharmaceutically acceptable carrier of 10 weight %.In a preferred instantiation, polyhydric alcohol is not higher than 75 weight % of pharmaceutical composition, more preferably no higher than 50 weight % of pharmaceutical composition.The final concentration of synthetic peptide is not less than 70mg/ml and is not higher than 500mg/ml in the preferred pharmaceutical compositions, more preferably, is not less than 100mg/ml and is not higher than 250mg/ml.The pharmaceutical composition of synthetic peptide of containing of a kind of unit dose (HIV fusion inhibitor peptide) further is provided, wherein this pharmaceutical composition comprises a kind of aqueous formulation, this aqueous formulation comprises: content is not less than 10 weight % of unit dose drug compositions, but is not higher than the polyhydric alcohol that exists with pharmaceutically acceptable carrier of 50 weight %.Preferably, the final concentration of synthetic peptide is not less than 70mg/ml and is not higher than 500mg/ml in the pharmaceutical composition, more preferably, is not less than 100mg/ml and is not higher than 250mg/ml.

The previous clinically Injectable solution prescription that uses comprises T1249 (SEQ ID NO:5), and its unit dose is 12.5mg/ml, 25mg/ml or 48mg/ml, and the basis of prescription is " a mannitol prescription ".For example, the 48mg/ml unit dose comprises the freeze-dried composition that contains 55mgT1249 and 40mg mannitol, and wherein mannitol is regulated pH value in advance, dissolves with the 1.1ml sterilized water before as the unit dose injection then.The injection solution prescription that contains high dose (wishing to obtain ground most, is that unit dose is not less than 100mg/ml) T1249 (SEQ ID NO:5) there is the demand of long-term serious hope.As describing in detail in the application, dispose various pharmaceutical composition to satisfy this demand.Table 1 shown contain standard content PEG (as, about 0.5 weight %) and the solution formula of synthetic peptide (" prescription A ") and pharmaceutical composition of the present invention (as, be not less than 10 weight %) contrast between (" prescription B "), all use the 1.1ml sterilized water to dissolve for every kind.Surprisingly, A compares with prescription, the pharmaceutical composition (prescription B) that contains 10 weight %PEG has greatly reduced dissolution time, yet a kind of solution by the injection use (injectivity (syringibility) refers to the passage that meets as 27 gage needle of the Injectable solution of pharmaceutical formulation by a kind of) still can be provided.Use the method for this area standard to measure content by high pressure lipuid chromatography (HPLC).

Table 1

	Prescription A	Prescription B
			T-1249(SEQ ID NO：5)	118mg/ml	118mg/ml
PEG 1500 content	5.5mg/ml	110mg/ml
			Mannitol content	27.5mg/ml	27.5mg/ml
Dissolution time	19 minutes	12 minutes
			Injectivity	Be	Be
pH	6.8	6.8

Generation is to the additional description of pharmaceutical composition (see, as table 2, prescription " 1 ", " 2 ", " 3 ", " 4 " and " 5 "), and wherein the content of PEG1500 is selected from the amount ranges between 110mg/ bottle (10 weight %) and the 330mg/ bottle (30 weight %).As shown in table 2, in the process with the preparation of pharmaceutical compositions Injectable solution prescription of 1ml water (medicine rank) dissolving lyophilized form, the scope of dissolution time is from less than 1 minute to about 5 minutes.Table 2 has shown that also injectivity (syringibility) is all qualified for the drug regimen composition formula of all tests; And physical stability (as, at room temperature, the vision definition/transparency by solution records) all satisfactory for the drug regimen composition formula of all tests.Also to studying according to the stability of drug products of the pharmaceutical composition with powder type of the present invention, exhibit stabilization is fit to medicinal application well known in the art as a result.

Table 2

	1	2	3	4	5
						T-1249 (SEQ ID NO:5) content (mg/ml)	118	118	118	118	118
PEG1500 content (mg/ml)	110	165	220	275	330
						Mannitol content (mg/ml)	27.5	27.5	27.5	27.5	27.5
Dissolution time in the 1ml aqueous solution (minute)	3-4	5	3-4	3-4	＜1
						Use the injectivity (Syringibility) of 27 gage needle	Be	Be	Be	Be	Be
Physical stability under the room temperature	＞4 days	＞4 days	＞4 days	＞4 days	＞4 days

The other embodiment that comprises the synthetic pharmaceutical composition of peptide in polyhydric alcohol solutions according to the present invention is illustrated in order to estimate clinical practice by system.Some illustrative embodiment are provided in table 3, comprise that containing final concentration is not less than the synthetic peptide of 100mg/ml (" prescription X ", " prescription Y ", " prescription Z ") pharmaceutical composition, and the pharmaceutical composition (" prescription H " that contains the synthetic peptide of final concentration 200mg/ml, " formula I ", " prescription K ").Wherein the pH scope is shown in table 3, uses sodium hydroxide or acetic acid or other suitable alkali or acid to regulate PH to the PH scope of wanting to obtain.And prescription H-J contains ethanol, and more preferably the concentration of ethanol (200 strength criterion) is 120mg/ml.

Table 3

	X	Y	Z	H	I	J
							T-1249(SEQ ID NO：5)(mg/ml)	100	100	100	200	200	200
PEG 1500(mg/ml)	92	91.7	91.7	167	167	167
							Mannitol (mg/ml)	23.	22.9	22.9	---	---	---
pH	6.5- 9.0	6.8	8.0	6.8- 9.0	6.8	8.0

In addition, also to solution form according to the present invention (as, the prescription Y of table 3) pharmaceutical composition carries out stability of drug products research, after 48 hours and under the different temperatures (as 5 ℃, 25 ℃ and 40 ℃), estimate these parameters as synthetic peptide content, permeability, PH and solution appearance, the result does not observe significant change.

Embodiment 2

In this embodiment, what set forth is beyond thought effect, promptly when comparing, use the pharmaceutical composition as injection solution according to the present invention to reduce injection site reaction from incidence rate and intensity aspect with the previous known drug regimen composition formula that contains synthetic peptide.Use the master pattern that is used for injection site reaction well known in the art, the pharmaceutical composition that exists with the aqueous injectable formulations form to be measured is granted rabbit by subcutaneous path, can be from experimentally determining injection site reaction.Typically, this aqueous injectable formulations as unit dose, will be injected 4-5 position on each animal.Table 4 has shown the aqueous formulation that contains the synthetic peptide of about 100mg but do not contain polyhydric alcohol (" prescription C ") when using, contain synthetic peptide of about 100mg and 10 weight % polyhydric alcohol (" prescription D " with use, see, as, in the table 2 1) aqueous formulation, and and use the aqueous formulation (" prescription E " contain synthetic peptide of about 100mg and 30 weight % polyhydric alcohol, see, as, in the table 2 5) when comparing, the contrast of injection site reaction, every kind of prescription all on many animals (typically between the 7-15) tested, the quantity of " infection site " is defined as follows:

The quantity of the quantity/injection site in observed injection reaction site.

By stimulation place of visual inspection injection site record, score is defined as follows separately:

Compare " 0 "-do not have recognizable reaction with the peripheral region; " 1 "-slight hyperemia and variable color; " 2 "-medium hyperemia and variable color; " 3 "-obviously variable color; The necrosis of " 4 "-zonule; The necrosis of " 5 "-large tracts of land may comprise subcutaneous muscle.According to the average of stimulation place score, will stimulate divided rank as follows: " nothing "-0.0 is to 0.4; " slightly "-0.5 is to 1.4; " appropriateness "-1.5 are to 2.4; " medium "-2.5 are to 3.4; " significantly "-3.5 are to 4.4.

Table 4

Prescription	The # infection site	Stimulate average	Stimulation levels
				C	11/13	3.8	Significantly
D	08/12	2.2	Medium
				E	04/12	1.2	Slightly

As shown in table 4, comprise that (concentration of HIV fusion inhibitor is not less than 70mg/ml and is not higher than 500mg/ml by synthetic peptide, more preferably be not less than 100mg/ml and be not higher than 250mg/ml) and polyhydric alcohol (as, final concentration is not less than 10 weight % of pharmaceutical composition and is not higher than 50 weight %) pharmaceutical composition of solution that mix to form, when used as the Injectable solution prescription with comprise the synthetic peptide of equivalent but when not having the injection prescription of polyhydric alcohol to compare, on incidence rate and intensity, all reduced injection site reaction.What is interesting is, and when subcutaneous medication, do not have a kind of synthesizing formula to induce significantly (measuring) injection site reaction by stimulation levels when the same prescription of making except not comprising synthetic peptide (C, D and E).

In addition, use the polyhydric alcohol of the present invention's instruction to prepare, thereby allow to obtain the content of synthetic peptide in every ml pharmaceutical composition aqueous injectable formulations greater than 100mg as the condition of dissolubility in the solution and stability.Therefore, when with the present invention before known synthetic peptide prescription (as, contain 25mg/ml or 50mg/ml) when comparing, pharmaceutical composition of the present invention can reduce the synthetic peptide of effective dose of needs uses to reach the frequency injection of therapeutic effect.In this, individuality is divided into two groups: accept the individuality of the mannitol prescription (not having polyhydric alcohol) of 2 subcutaneous dosages, each dosage comprises the synthetic peptide (total amount of the synthetic peptide of conveying is 96mg) of 48mg; With the individuality of the pharmaceutical composition of the present invention of accepting single subcutaneous dosage (see, as, the prescription Y of table 3); Each group of accepting is in identical anatomy position medication.Before analyzing associated biomolecule availability and bioequivalence (as, out of date plasma concentration and change of pharmacokinetics chart (profiles)), plasma concentration is transferred to effective dose.Result of study shows, comprise 2 than the consumption of low dosage mannitol prescription and single dose according to the pharmaceutical composition that comprises synthetic peptide and polyhydric alcohol of the present invention between, bioequivalence is similar with bioavailability.

In another research, (as, the ability of anti-HIV-1 virus) is relatively according to the mannitol prescription (do not have polyhydric alcohol, described as previous this paper) of pharmaceutical composition of the present invention and standard from the biological activity aspect.In this research, use the HIV-1 infection experiment to determine to be compared the potential of antiviral separately of prescription.More particularly, use Infection in Vitro test (" Magi-CCR5 infection experiment ", see, as, United States Patent (USP) 6258782) observed antiviral activity demonstrated with body in observed same HIV fusion inhibitor peptide (see, as, Kilby et al., 1998, Nature Med.4:1302-1307) antiviral activity is rationally relevant.These tests are used and are expressed derive the indicator cell line MAGI of cMAGI or the reduction that CCR5 has write down infective virus titer.Two cell lines all utilize the ability of HIV-1tat to activate the expression of the beta galactosidase reporter gene that is driven by HIV-LTR.β-gal report is positioned in the nuclear by modification, and because intensive nuclear staining in metainfective several days, so can be detected by the X-gal substrate.If before dyeing, have only the infection of wheel, the quantity of infective particle in the inoculum that therefore quantity of the nuclear that is colored so can be interpreted as equaling to excite.Use the CCD-imager to calculate infected cell, the suitable separated strain initial stage and breadboard is shown as linear relationship between the quantity of the infected cell of importing viral and that estimate by imager.In MAGI and cMAGI test, infecting titer reduction by 50% (Vn/Vo=0.5) is highly significant, and tentatively termination value of evaluation antiviral activity (" IC50 " is defined as producing the dilution of infecting titer reduction by 50%) is provided.Each prescription that comprises synthetic peptide that is used to test antiviral activity is diluted in order to correlated same isoconcentration, and being tested in twice or three times of HIV inoculums at about 1500-2000 infected cell/appearance ware (well) of adjusting generation, this appearance ware is the appearance ware of 48 appearance ware microtitration plates.Synthetic peptide (in filling a prescription separately) is added to cMAGI or MAGI cell, next is the virus inoculation body; After 24 hours, add to infect and a kind of inhibitor (as T20, SEQ ID NO:4) of cell-cell fusion stops second virus disseminating of taking turns HIV infection and cell-cell.These cells were cultivated more than 2 days, fixed with the X-gal substrate then and dyeed and detect the cell of infected by HIV.Determine that with the CCD-imager quantity of infected cell in each contrast and peptide dilute, and calculate IC50 then.Relatively be contained in the biological activity of the synthetic peptide in the mannitol prescription and be contained in and (see according to the biological activity of the synthetic peptide in the pharmaceutical composition of the present invention, as, the prescription Y of table 3), as illustrated in the table 5, having shown is not having substantial difference aspect the potential of the virus of HIV-1.

Table 5

Prescription	IC 50(ng/ml)
		The mannitol prescription	3.6±0.2
Pharmaceutical composition (prescription Y)	3.7±0.4

Embodiment 3

Narration from the application, those skilled in the art are very clear, (describe in detail) because this class HIV fusion inhibitor peptide as this paper is previous structure, function and form similar, therefore, according to pharmaceutical composition of the present invention can be by any or multiple HIV fusion inhibitor peptide (as, concentration is not less than 70mg/ml, more preferably be not less than 100mg/ml) with final concentration be not less than pharmaceutical composition weight 10% and be not higher than 50% polyhydric alcohol and mix the solution of forming, as the Injectable solution prescription.In that, T20 (SEQ ID NO:4) is used as the synthetic peptide that is contained in according to pharmaceutical composition of the present invention.Table 6 has shown another illustrative embodiment according to pharmaceutical composition of the present invention.This examples of pharmaceutical compositions, contain final concentration be not less than pharmaceutical composition weight 10% and be not higher than 50% polyhydric alcohol, and shown when comparing that dissolution time reduces with the similar prescription that does not contain polyhydric alcohol.According to the visual detection that surpasses a day, solution keeps stable in room temperature.Generalized method detects the antiviral potential (IC among the ng/ml in use the embodiment of the present application 2 ₅₀), can be equal to mutually with the observed result of pure medicine.

Table 6

	Dissolved
		T20 content (SEQ ID NO:4)	180mg/ml
PEG 1500 content	208mg/ml
		Dissolution time	＜5 minutes
Injectivity	Be
		pH	Be adjusted to 9.0
IC 50	6.6±1.2

The further specifying property embodiment of compositions is provided in table 7.Those skilled in the art are very clear, expect the scope 6.5 to 9.5 of the final pH value of acquisition, can be depending on the amount and/or the form of polyhydric alcohol, and other factors perhaps well known in the art is as using standard method well known in the art to determine.

Table 7

				Synthetic peptide	180mg	150mg	75mg
PEG 1500 content	208mg	125mg	125mg
				Required sodium hydroxide	Regulate pH 6.5-9.5	Regulate pH 6.5-9.5	Regulate pH 6.5-9.5
Required hydrochloric acid or acetic acid	Regulate pH 6.5-9.5	Regulate pH 6.5-9.5	Regulate pH 6.5-9.5
				Sterilized water	1.0ml	1.0ml	1.0ml

Embodiment 4

The invention provides pharmaceutical composition, it comprises the synthetic peptide of the HIV fusion inhibitor that contains antiviral activity, and its antiviral activity can be by suppressing the propagation of HIV to target cell, and/or the HIV that suppresses the gp41-mediation is proved to the fusion of target cell.The method that also provides a kind of HIV-1 of treatment to infect comprises the individuality of pharmaceutical composition according to the present invention being granted infected by HIV-1.The amount of preferred this pharmaceutical composition is effectively to suppress the propagation of HIV to target cell, and/or effectively suppresses the fusion of the HIV of gp41 mediation to target cell.This method can be included under the situation of cell existence, and virus is contacted with certain density pharmaceutical composition according to the present invention, effectively suppresses cell and is infected by HIV.This method can comprise that also interpolation is a certain amount of according to pharmaceutical composition of the present invention to virus and cell, effectively suppresses the virus of gp41 mediation and the fusion between the cell.These methods can be used to treat the individuality (curative) that has infected HIV or be used to treat those be exposed in strange mode or with the high-risk mode (as, use or high risk sexual behavior by drugs) be exposed to the individuality (preventative) of HIV.Therefore, for example, infected at individuality under the situation of HIV-1, the pharmaceutical composition of certain effective dose will become enough (combining by himself and/or with the dosage of taking in) and reduce the dosage that HIV virus is assembled in by the treatment individuality.Those skilled in the art are well-known, the assembling that has several standard methods to be used to measure HIV virus, and it includes, but not limited to by the quantitative culture of peripheral blood lymphocytes and the measurement by blood plasma HIV RNA.In the method for the invention, pharmaceutical composition of the present invention can single medication ground, off and on, periodically or continuously be applied, as by medical practitioner determined, as the assembling by monitoring virus.Can demonstrate the potentiation result according to pharmaceutical composition of the present invention, when with other the treatment HIV (as, well known in the art, comprise, but be not limited to, other inhibitor that participates in (as, the CCR5 inhibitor, human homolog (retrocyclin), and analog), hiv integrase inhibitor, reverse transcriptase inhibitors (as, nucleoside or non-nucleoside), protease inhibitor, and analog (see, as, United States Patent (USP) 6475491, the content of its disclosure at this in conjunction with as a reference) antiviral drugs, protease inhibitor, and the analog combination (as, when using simultaneously, or when using with certain medicine cycle alternation) when using, can suppress the propagation of HIV to target cell.

The effective dose of the pharmaceutical composition of the present invention that is applied (" concentration ") can be measured by those skilled in the art's known method; As, by measuring potential, biological half-life, bioavailability and toxicity.In a preferred instantiation, from those skilled in the art's scope of effective dose of having used research method obtains in the known external and body data determination.For example, the Infection in Vitro of antiviral activity test, as known in the art those, make those skilled in the art can be determined as preventions (as, suppress to propagate) the required mean inhibitory concentration (IC) of a certain amount of viral infection (and as, 50% inhibition, IC ₅₀Or 90% suppress IC ₉₀).In addition, can use external hybrid cell to form test and measure the required concentration of fusion target cell that suppresses the gp41 mediation.Those skilled in the art use the pharmacokinetic data that obtains from one or more clinical or experimentatioies can select proper dosage then, cause the minimum plasma concentration that can obtain the conjugation object (C[min]), equal or exceed predetermined IC value.Yet dosage range typically relies on the route of selecting medication and the prescription of dosage, therefore, according to the representative dosage range of pharmaceutical composition of the present invention for being not less than 0.1 μ g/kg body weight and not being higher than the 10mg/kg body weight; The preferred dose scope is about 0.1-100 μ g/kg body weight; More preferably, comprise according to a unit dose of the synthetic peptide of pharmaceutical composition of the present invention for from about 100mg to about 250mg.

Pharmaceutical composition of the present invention can be with any mode administration individuality that can make activating agent arrive target cell (cell that can be infected by HIV).Therefore, pharmaceutical composition of the present invention can with any suitable technique include, but are not limited to injection (as, muscle, endoperitoneal, intravenous or subcutaneous injection or input, subepidermal or implant) administration.The specially good effect route of administration will depend on, as, individual case history, comprise coming any that perceive of administration since then or the expection side effect and by the drug regimen composition formula of administration (as, the polyhydric alcohol that pharmaceutical composition comprises and the character of synthetic peptide).Most preferably, administration is by injection (use, as, vein or subcutaneous mode), but also can be by input continuously (use, as, delayed release device, or minipump such as osmotic pumps, and class device).Can further comprise one or more pharmaceutically acceptable carriers except that polyhydric alcohol according to pharmaceutical composition of the present invention; And can further depend on solution formula, delivery site, medication, administration time arrangement and the known other factors of doctor that expectation obtains.

The foregoing description of the specific embodiment of the invention has been described in detail and has been used for illustration purpose.In view of describing and explanation, others skilled in the art by using existing knowledge, can reasonably be revised and/or the adaptation invention is used for different application, and not deviate from basic scheme; Therefore, these modifications and/or reorganization are defined as within the meaning and scope of appended claim.

Sequence table

＜110〉Trimeris Inc.

＜120〉pharmaceutical composition that improves medication of HIV gp41-derived peptide and the application in treatment thereof

<130>TRM-003

<150>US 60/414,441

<151>2002-09-27

<150>10/

<151>2003-09-16

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＜213〉artificial

<220>

＜223〉synthetic

<400>34

Asn Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Leu Leu Gln Leu

1 5 10 15

Thr Val Trp Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu Ala Val

20 25 30

<210>35

<211>41

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>35

Asn Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Leu Leu Gln Leu

1 5 10 15

Thr Val Trp Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu Ala Val Glu

20 25 30

Arg Tyr Leu Lys Asp Gln Gly Gly Cys

35 40

<210>36

<211>44

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>36

Cys Gly Gly Asn Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Leu

1 5 10 15

Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu

20 25 30

Ala Val Glu Arg Tyr Leu Lys Asp Gln Gly Gly Cys

35 40

<210>37

<211>39

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>37

Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu Leu Arg Ala Ile Glu

1 5 10 15

Ala Gln Gln His Leu Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu

20 25 30

Gln Ala Arg Ile Leu Ala Val

35

<210>38

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>38

Tyr Thr Asn Thr Ile Tyr Thr Leu Leu Glu Glu Ser Gln Asn Gln Gln

1 5 10 15

Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu

20 25 30

Trp Asn Trp Phe

35

<210>39

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>39

Tyr Thr Gly Ile Ile Tyr Asn Leu Leu Glu Glu Ser Gln Asn Gln Gln

1 5 10 15

Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Asn Leu

20 25 30

Trp Asn Trp Phe

35

<210>40

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>40

Tyr Thr Ser Leu Ile Tyr Ser Leu Leu Glu Lys Ser GlnIle Gln Gln

1 5 10 15

Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu

20 25 30

Trp Asn Trp Phe

35

<210>41

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>41

Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln

1 5 10 15

Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu

20 25 30

Phe Asn Phe Phe

35

<210>42

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>42

Trp Gln Glu Trp Glu Gln Lys Val Arg Tyr Leu Glu Ala Asn Ile Thr

1 5 10 15

Ala Leu Leu Glu Gln Ala GlnIle Gln Gln Glu Lys Asn Glu Tyr Glu

20 25 30

Leu Gln Lys Leu

35

<210>43

<211>42

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>43

Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu

1 5 10 15

Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu

20 25 30

Asp Lys Trp Ala Ser Leu Trp Asn Trp Phe

35 40

<210>44

<211>48

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>44

Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu

1 5 10 15

Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu

20 25 30

Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp Phe

35 40 45

<210>45

<211>42

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>45

Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr

1 5 10 15

Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys

20 25 30

Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys

35 40

<210>46

<211>46

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>46

Trp Gln Glu Trp Glu Gln Lys Val Arg Tyr Leu Glu Ala Asn Ile Thr

1 5 10 15

Ala Leu Leu Glu Gln Ala Gln Ile Gln Gln Glu Lys Asn Glu Tyr Glu

20 25 30

Leu Gln Lys Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp Phe

35 40 45

<210>47

<211>50

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>47

Asn Asn Met Thr Trp Gln Glu Trp Glu Gln Lys Val Arg Tyr Leu Glu

1 5 10 15

Ala Asn Ile Thr Ala Leu Leu Glu Gln Ala Gln Ile Gln Gln Glu Lys

20 25 30

Asn Glu Tyr Glu Leu Gln Lys Leu Asp Lys Trp Ala Ser Leu Trp Asn

35 40 45

Trp Phe

50

<210>48

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>48

Trp Asn Trp Phe Ile Thr Ala Leu Leu Glu Gln Ala Gln Ile Gln Gln

1 5 10 15

Glu Lys Asn Glu Tyr Glu Leu Gln Lys Leu Asp Lys Trp Ala Ser Leu

20 25 30

Trp Asn Trp Phe

35

<210>49

<211>46

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>49

Trp Gln Glu Trp Asp Arg Glu Ile Ser Asn Tyr Thr Ser Leu Ile Thr

1 5 10 15

Ala Leu Leu Glu Gln Ala Gln Ile Gln Gln Glu Lys Asn Glu Tyr Glu

20 25 30

Leu Gln Lys Leu Asp Glu Trp Ala Ser Leu Trp Glu Trp Phe

35 40 45

<210>50

<211>40

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>50

Trp Gln Glu Trp Glu Arg Glu Ile Ser Ala Tyr Thr Ser Leu Ile Thr

1 5 10 15

Ala Leu Leu Glu Gln Ala Gln Ile Gln Gln Glu Lys Ile Glu Tyr Glu

20 25 30

Leu Gln Lys Leu Glu Trp Glu Trp

35 40

<210>51

<211>39

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>51

Trp Gln Glu Trp Asp Arg Glu Ile Thr Ala Leu Leu Glu Gln Ala Gln

1 5 10 15

Ile Gln Gln Glu Lys Asn Glu Tyr Glu Leu Gln Lys Leu Asp Lys Trp

20 25 30

Ala Ser Leu Trp Asn Trp Phe

35

<210>52

<211>39

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>52

Trp Gln Glu Trp Asp Arg Glu Ile Thr Ala Leu Leu Glu Gln Ala Gln

1 5 10 15

Ile Gln Gln Glu Lys Asn Glu Tyr Glu Leu Gln Lys Leu Asp Glu Trp

20 25 30

Ala Ser Leu Trp Glu Trp Phe

35

<210>53

<211>35

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>53

Trp Gln Glu Trp Asp Arg GluIle Thr Ala Leu Leu Glu Gln Ala Gln

1 5 10 15

Ile Gln Gln Glu Lys Asn Glu Tyr Glu Leu Gln Lys Leu Asp Glu Trp

20 25 30

Glu Trp Phe

35

<210>54

<211>35

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>54

Trp Gln Glu Trp Glu Arg Glu Ile Thr Ala Leu Leu Glu Gln Ala Gln

1 5 10 15

Ile Gln Gln Glu Lys Ile Glu Tyr Glu Leu Gln Lys Leu Ile Glu Trp

20 25 30

Glu Trp Phe

35

<210>55

<211>35

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>55

Trp Gln Glu Trp Glu Arg Glu Ile Thr Ala Leu Leu Glu Gln Ala Gln

1 5 10 15

Ile Gln Gln Glu Lys Asn Glu Tyr Glu Leu Gln Lys LeuIle Glu Trp

20 25 30

Glu Trp Phe

35

<210>56

<211>35

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>56

Trp Gln Glu Trp Glu Arg GluIle Thr Ala Leu Leu Glu Gln Ala Gln

1 5 10 15

Ile Gln Gln Glu Lys Ile Glu Tyr Glu Leu Gln Lys Leu Asp Glu Trp

20 25 30

Glu Trp Phe

35

<210>57

<211>39

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>57

Trp Gln Glu Trp Glu Gln Lys Ile Thr Ala Leu Leu Glu Gln Ala Gln

1 5 10 15

Ile Gln Gln Glu Lys Asn Glu Tyr Glu Leu Gln Lys Leu Asp Lys Trp

20 25 30

Ala Ser Leu Trp Asn Trp Phe

35

<210>58

<211>39

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>58

Trp Gln Glu Trp Glu Gln Lys Ile Thr Ala Leu Leu Glu Gln Ala Gln

1 5 10 15

Ile Gln Gln Glu Lys Asn Glu Tyr Glu Leu Gln Lys Leu Asp Lys Trp

20 25 30

Ala Gly Leu Trp Glu Trp Phe

35

<2l0>59

<211>39

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>59

Trp Gln Glu Trp Glu Gln Lys Ile Thr Ala Leu Leu Glu Gln Ala Gln

1 5 10 15

Ile Gln Gln Glu Lys Asn Glu Tyr Glu Leu Gln Lys Leu Ala Glu Trp

20 25 30

Ala Gly Leu Trp Ala Trp Phe

35

<210>60

<211>35

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>60

Trp Gln Glu Trp Glu Gln Lys Ile Thr Ala Leu Leu Glu Gln Ala Gln

1 5 10 15

Ile Gln Gln Glu Lys Ile Glu Tyr Glu Leu Gln Lys Leu Ile Glu Trp

20 25 30

Glu Trp Phe

35

<210>61

<211>41

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>61

Gln Gln Gln Asn Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Leu

1 5 10 15

Leu Gln Leu Thr Ala Trp Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu

20 25 30

Ala Val Glu Arg Tyr Leu Lys Asp Gln

35 40

<210>62

<211>41

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>62

Gln Gln Gln Asn Asn Lau Leu Arg Ala Ile Glu Ala Gln Gln His Leu

1 5 10 15

Leu Gln Leu Thr Val Ala Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu

20 25 30

Ala Val Glu Arg Tyr Leu Lys Asp Gln

35 40

<210>63

<211>49

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>63

Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu

1 5 10 15

Leu Arg Ala Ile Glu Ala Gln Gln His Ala Leu Gln Ala Thr Val Trp

20 25 30

Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr Leu

35 40 45

Lys

<210>64

<211>51

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>64

Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu

1 5 10 15

Leu Arg Ala Ile Glu Ala Gln Gln His Ala Leu Gln Ala Thr Val Trp

20 25 30

Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr Leu

35 40 45

Lys Asp Gln

50

<210>65

<211>49

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>65

Gln Ala Arg Gln Leu Val Ser Gly Leu Val Gln Gln Gln Asn Asn Ile

1 5 10 15

Leu Arg Ala Leu Glu Ala Thr Gln His Ala Val Gln Ala Leu Val Trp

20 25 30

Gly Val Lys Gln Leu Gln Ala Arg Val Leu Ala Leu Glu Arg Tyr Ile

35 40 45

Lys

<210>66

<211>49

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>66

Gln Ile Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu

1 5 10 15

Leu Arg Ala Ile Glu Ala Ile Gln His Ala Leu Gln Ala Ile Val Trp

20 25 30

Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu Ala Val G1u Arg Tyr Leu

35 40 45

Lys

<210>67

<211>49

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>67

Gln Ala Arg Gln Leu Val Ser Gly Leu Val Gln Gln Gln Asn Asn Ile

1 5 10 15

Leu Arg Ala Leu Glu Ala Thr Gln His Ala Val Gln Ala Leu Val Trp

20 25 30

Gly Val Arg Gln Leu Gln Ala Arg Val Leu Ala Leu Glu Arg Tyr Ile

35 40 45

Lys

<210>68

<211>51

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>68

Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu

1 5 10 15

Leu Arg Ala Ile Glu Ala Thr Gln His Ala Val Gln Ala Leu Val Trp

20 25 30

Gly Val Lys Gln Leu Gln Ala Arg Val Leu Ala Leu Glu Arg Tyr Ile

35 40 45

Lys Asp Gln

50

<210>69

<211>51

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>69

Gln Ala Arg Gln Leu Val Ser Gly Leu Val Gln Gln Gln Asn Asn Ile

1 5 10 15

Leu Arg Ala Leu Glu Ala Gln Gln His Ala Leu Gln Ala Thr Val Trp

20 25 30

Gly Ile Lys Gln Leu Gln Ala Arg Val Leu Ala Leu Glu Arg Tyr Ile

35 40 45

Lys Asp Gln

50

<210>70

<211>51

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>70

Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu

1 5 10 15

Leu Arg Ala Ile Glu Ala Gln Gln His Ala Leu Gln Ala Thr Val Trp

20 25 30

Gly Val Lys Gln Leu Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr Leu

35 40 45

Lys Asp Gln

50

<210>71

<211>41

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>71

Gln Gln Gln Asn Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Leu

1 5 10 15

Leu Gln Leu Thr Val Phe Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu

20 25 30

Ala Val Glu Arg Tyr Leu Lys Asp Gln

35 40

<210>72

<211>49

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>72

Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu

1 5 10 15

Leu Arg Ala Ile Glu Ala Gln Gln His Leu Leu Gln Leu Thr Val Phe

20 25 30

Gly Ile Arg Gln Leu Gln Ala ArgIle Leu Ala Val Glu Arg Tyr Leu

35 40 45

Lys

<210>73

<211>51

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>73

Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu

1 5 10 15

Leu Arg Ala Ile Glu Ala Gln Gln His Leu Leu Gln Ala Thr Val Trp

20 25 30

Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr Leu

35 40 45

Lys Asp Gln

50

<210>74

<211>41

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>74

Gln Gln Gln Asn Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Leu

1 5 10 15

Leu Gln Ala Thr Val Trp GlyIle Lys Gln Leu Gln Ala ArgIle Leu

20 25 30

Ala Val Glu Arg Tyr Leu Lys Asp Gln

35 40

<210>75

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>75

Asn Ala Ser Trp Ser Asn Lys Ser Leu Glu Gln Ile Trp Asn Asn Met

1 5 10 15

Thr Trp Met Glu Trp Asp Arg GluIle Asn Asn Tyr Thr Ser LeuIle

20 25 30

His Ser Leu Ile

35

<210>76

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>76

Asn Lys Ser Leu Glu Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp

1 5 10 15

Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu

20 25 30

Glu Ser Gln Asn

35

<210>77

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>77

Lys Ser Leu Glu Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp

1 5 10 15

Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu

20 25 30

Ser Gln Asn Gln

35

<210>78

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>78

Ser Leu Glu Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg

1 5 10 15

Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser

20 25 30

Gln Asn Gln Gln

35

<210>79

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>79

Leu Glu Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu

1 5 10 15

Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln

20 25 30

Asn Gln Gln Glu

35

<210>80

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>80

Glu Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile

1 5 10 15

Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn

20 25 30

Gln Gln Glu Lys

35

<210>81

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>81

Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn

1 5 10 15

Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln

20 25 30

Gln Glu Lys Asn

35

<210>82

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>82

Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn

1 5 10 15

Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln

20 25 30

Glu Lys Asn Glu

35

<210>83

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>83

Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr

1 5 10 15

Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu

20 25 30

Lys Asn Glu Gln

35

<210>84

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>84

Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr

1 5 10 15

Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys

20 25 30

Asn Glu Gln Glu

35

<210>85

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>85

Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser

1 5 10 15

Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn

20 25 30

Glu Gln Glu Leu

35

<210>86

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>86

Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu

1 5 10 15

Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu

20 25 30

Gln Glu Leu Leu

35

<210>87

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>87

Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile

1 5 10 15

His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln

20 25 30

Glu Leu Leu Glu

35

<210>88

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>88

Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His

1 5 10 15

Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu

20 25 30

Leu Leu Glu Leu

35

<210>89

<211>35

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>89

Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser

1 5 10 15

Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu

20 25 30

Leu Glu Asp

35

<210>90

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>90

Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu

1 5 10 15

Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu

20 25 30

Glu Leu Asp Lys

35

<210>91

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>91

Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile

1 5 10 15

Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu

20 25 30

Leu Asp Lys Trp

35

<210>92

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>92

Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln

1 5 10 15

Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser

20 25 30

Leu Trp Asn Trp

35

<210>93

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>93

Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu

1 5 10 15

Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp

20 25 30

Asn Trp Phe Asn

35

<210>94

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>94

Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys

1 5 10 15

Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn

20 25 30

Trp Phe Asn Ile

35

<210>95

<211>36

<212>PRT

＜213〉artificial

<220>

＜223〉synthetic

<400>95

Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn

1 5 10 15

Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp

20 25 30

Phe Asn Ile Thr

35

Claims (10)

1, a kind of pharmaceutical composition is by the solution composition of the mixture that comprises synthetic peptide and polyhydric alcohol; Wherein this polyhydric alcohol is from by Polyethylene Glycol, polypropylene glycol, diethylene glycol, triethylene glycol, ethylene glycol, dipropylene glycol, the copolymer that comprises polypropylene glycol, comprise in the group that the copolymer of Polyethylene Glycol constitutes and select, should synthetic peptide be a kind of isolating HIV fusion inhibitor, comprise that length is not less than 15 aminoacid and is not higher than the aminoacid sequence of 60 amino acid residues, and form by the HR1 district that is contained in HIV gp41 of at least 10 adjacency or the aminoacid in HR2 district, and can suppress the propagation of HIV to target cell, can be by estimating in the body and/or external antiviral activity is measured, the final concentration of this synthetic peptide in pharmaceutical composition is not less than 70mg/ml and is not higher than 500mg/ml; Wherein the final concentration of polyhydric alcohol is not less than 5 weight % of pharmaceutical composition and is not higher than 75 weight %.

2, pharmaceutical composition according to claim 1, the wherein synthetic final concentration of peptide in pharmaceutical composition is not less than 100mg/ml and is not higher than 250mg/ml.

3, the described pharmaceutical composition of claim 1, wherein the final concentration of polyhydric alcohol is not less than 10 weight % of pharmaceutical composition and is not higher than 50 weight %.

4, pharmaceutical composition according to claim 1, wherein polyhydric alcohol is a Polyethylene Glycol.

5, pharmaceutical composition according to claim 1 further comprises a kind of pharmaceutically acceptable carrier except that polyhydric alcohol.

6, a kind of pharmaceutical composition that contains synthetic peptide of unit dose, wherein this pharmaceutical composition comprises the aqueous formulation of being made up of following:

(a) content that exists as pharmaceutically acceptable carrier is not less than 5 weight % of unit dose drug compositions and is not higher than the polyhydric alcohol of 75 weight %, this polyhydric alcohol from by Polyethylene Glycol, polypropylene glycol, diethylene glycol, triethylene glycol, ethylene glycol, dipropylene glycol, comprise polypropylene glycol copolymer, comprise the group that the copolymer of Polyethylene Glycol constitutes and select; With

(b) final concentration in pharmaceutical composition is not less than 70mg/ml and is not higher than the synthetic peptide of 500mg/ml, should synthetic peptide be a kind of isolating HIV fusion inhibitor, comprise that length is not less than 15 aminoacid and is not higher than the aminoacid sequence of 60 amino acid residues, and form by the HR1 district that is contained in HIV gp41 of at least 10 adjacency or the aminoacid in HR2 district, and can suppress the propagation of HIV to target cell, can be by estimating in the body and/or external antiviral activity is measured.

7, the pharmaceutical composition that comprises synthetic peptide according to claim 6, the wherein synthetic final concentration of peptide in pharmaceutical composition is for being not less than 100mg/ml and not being higher than 250mg/ml.

8, the pharmaceutical composition that comprises synthetic peptide according to claim 6, wherein the final concentration of polyhydric alcohol is to be not less than 10 weight % of pharmaceutical composition and not to be higher than 50 weight %.

9, the pharmaceutical composition that comprises synthetic peptide according to claim 6, wherein polyhydric alcohol is a Polyethylene Glycol.

10, the pharmaceutical composition that comprises synthetic peptide according to claim 6 further comprises a kind of pharmaceutically acceptable carrier except that polyhydric alcohol.

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