• 专利附录
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    • 专利摘要:
    The present invention provides a method for administering an active agent by pulmonary route to an animal in need thereof. The method comprises administering via a pulmonary route a composition comprising (a) an active agent and (b) (i) acylated amino acids, (ii) sulfonated amino acids, or (iii) a combination of (i) and (ii) It involves doing. Administration of the compositions of the present invention provides improved lung delivery and greater bioavailability of the active agent than when administered alone. As a result, smaller amounts of the active agent may be administered to achieve desirable results when included in the compositions of the present invention than when administered alone.
    公开号:KR20010074777A
    申请号:KR1020017001159
    申请日:1999-07-27
    公开日:2001-08-09
    发明作者:밀스타인샘제이.；스마트존이.；사루비도날드제이.；카로짜모니카；플란더스엘리자베드；오'톨레도리스；레온-베이안드레아；그슈나이드너데이비드
    申请人:추후제출；에미스페어 테크놀로지스, 인코포레이티드；
    IPC主号:
    专利说明:

    PULMONARY DELIVERY OF ACTIVE AGENTS}
    [2] Traditional active agent delivery means are often severely limited by biological, chemical and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target to be delivered, or the target itself. Biological or chemical active agents are vulnerable to such barriers.
    [3] For example, when delivering a biological or chemical active agent or therapeutic agent to an animal, a barrier is imposed by the body. Examples of physical barriers are skin and various types of visceral membranes that must pass through before reaching the target. Chemical barriers include, but are not limited to, pH variations, lipid bilayers and degrading enzymes.
    [4] Pulmonary delivery of many biologically active agents to the circulatory system can be selected as the route of administration to animals because delivery to the blood is much faster than other delivery routes. In addition, delivery to the lung itself may be required, for example, to treat diseases of the pulmonary system. However, lung delivery may not be practical because of the physical barriers such as lipid bilayers and membranes, which each particular biologically active agent cannot pass through but must pass before the agent can reach the circulation. Lung delivery may also be achieved in other cases, but may not be sufficiently effective for practical purposes.
    [5] There is a current need for a simple and inexpensive lung delivery system that is easily manufactured and capable of delivering a wide range of active agents in an effective manner.
    [1] The present invention relates to the delivery of an active agent through the lungs. Acylated or sulfonated amino acids are used as carriers for lung delivery of the active agent to the target.
    [75] 1 shows plasma according to lung spray-intratracheal (IT) instillation of insulin at 0.05 mg / kg (0.13 U / kg) alone and in combination with carrier B 5 mg / kg (■). A graphical illustration of the plasma insulin-times aspect. Bars represent ± standard deviation (n = 5).
    [76] FIG. 2 is a graphical representation of plasma glucose-time pattern of pulmonary tracheal injection drop of insulin at 0.05 mg / kg (0.13 U / kg) alone and in combination with carrier B 5 mg / kg. It is an illustration. Bars represent ± standard deviation (n = 5).
    [77] FIG. 3 is a graphical illustration of blood glucose-time patterns according to pulmonary tracheal injection droplets of insulin at 0.05 mg / kg (0.13 U / kg) alone and combined with carrier B 16 mg / kg (■). Bars represent ± standard deviation (n = 3).
    [78] FIG. 4 is a graphical illustration of blood glucose-time modalities according to pulmonary tracheal injection drop of insulin at 0.01 mg / kg (0.026 U / kg) alone and combined with carrier B 16 mg / kg (■). Bars represent ± standard deviation (n = 4).
    [79] 5 is 0.005mg / kg (0.013U / kg) (·), 0.05mg / kg (0.13U / kg) (◆), 0.1mg / kg (0.26U / kg) (▲), 0.5mg / kg ( The time of the average insulin concentration of plasma insulin when 1.3 U / kg) (■) and 1 mg / kg (2.6 U / kg) (●) porcine insulin was injected into the rat pulmonary trachea. A graphical illustration of. Bars represent ± standard deviation.
    [80] 6 is 0.01mg / kg (0.026U / kg) (·), 0.05mg / kg (0.13U / kg) (×), 0.1mg / kg (0.26U / kg) (◆), 0.5mg / kg ( This is a graphical illustration of the blood glucose-time pattern when injection of 1.3 U / kg) (■) and 1 mg / kg (2.6 U / kg) (▲) porcine insulin into the lung trachea in rats. Bars represent ± standard deviation.
    [81] FIG. 7 is a graphical illustration of plasma insulin concentration versus time with 0.05 mg / kg insulin with and with 16 mg / kg carrier B. FIG.
    [82] 8 is a graphical illustration of plasma insulin concentration versus time at various doses of insulin.
    [83] 9 is a graphical illustration of plasma insulin concentration versus time with 0.05 mg / kg insulin with 5 mg / kg carrier B and without.
    [84] FIG. 10 is a graphical illustration of plasma insulin concentration versus time when 0.01 mg / kg of insulin is with and without 16 mg / kg of carrier B. FIG.
    [85] 11 shows 0.1 mg of insulin with 7.5 mg / kg of carrier B sodium salt (■), 0.1 mg / kg of insulin alone (●) and 7.5 mg / kg of carrier B sodium salt alone (▲) Graphical illustration of percent change in blood glucose for lung delivery.
    [86] Figure 12 shows 0.5 mg of insulin with 7.5 mg / kg of carrier B sodium salt (■), 0.5 mg / kg of insulin alone (●), 7.5 mg / kg of carrier B sodium salt alone (▲) Graphical illustration of percent change in blood glucose for lung delivery.
    [87] FIG. 13 shows that 0.03 mg / kg of insulin was administered with 16 mg / kg of carrier B (●), with carrier C (▲) and with carrier D (▼), and insulin alone (■). A graphical illustration of serum insulin levels versus time in one case.
    [6] Compositions useful in the present invention include an active agent and a carrier. The composition can be used to deliver different types of active agents through a variety of biological, chemical and physical barriers, and is particularly suitable for delivering active agents that are prone to degradation by environmental influences. The method of the invention is particularly effective for biologically, pharmaceutical or chemically active agents such as chickens, birds and cattle, pigs, dogs. It is useful for delivery or administration to any animal, including but not limited to cats, primates and especially humans.
    [7] Co-administration of an active agent, such as insulin, with the lungs through the lungs, as disclosed herein, results in an increase in the bioavailability of the active agent as compared to administration of the active agent alone.
    [8] Active agent
    [9] Suitable active agents for use in the present invention are biological or chemical active agents.
    [10] Biological or chemically active agents include, but are not limited to, pesticides, pharmacologically active agents and therapeutic agents. For example, suitable biological or chemical active agents for use in the present invention include proteins; Polypeptides; Peptides; Hormones and, in particular, only hormones which do not pass through the alveoli or on their own and / or which are sensitive to chemical degradation by acids and enzymes in the lungs; Polysaccharides and in particular mucopolysaccharides; carbohydrate; Fat; Other organic compounds; Or any combination thereof, but is not limited thereto.
    [11] Further examples include the following: synthetic, natural or recombinant sources; Growth hormones including human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone and porcine growth hormone; Growth hormone releasing hormone; interferons, including α, β, γ; Interleukin-1; Interleukin-II; Porcine, bovine, human and human recombination, optionally with counterions including sodium, zinc, calcium and ammonium; Insulin-like growth factor (IGF) including IGF-1; Heparin, including unfragmented heparin, heparinoids, dermatan, chondroitin, low molecular weight heparin, very low molecular weight heparin and ultra low molecular weight heparin; Calcitonin including salmon, eel and humans; Erythropoietin; Atrial natureic facter; antigen; Monoclonal antibodies; Somatostatin; Protease inhibitors; Adrenocorticotropin, gonadotropin releasing hormone; Follicle stimulating hormone; Glucocerebrosidase; Thrombopoietin; Filgrastim; Prostaglandins; Cyclosporin; Vasopressin; Chromoline sodium (sodium or disodium chromoglycate); Vancomycin; Desperioxamine (DFO); Parathyroid hormone (PTH), including fragments thereof; Antimicrobial agents, including antifungal agents; Homologues, fragments, mimics or polyethylene glycol (PEG) -modified derivatives of these compounds; Or any combination thereof, but is not limited thereto.
    [12] carrier
    [13] Acylated or sulfonated amino acids are known to act as carriers for pulmonary delivery of biological or chemical active agents. Such carrier compounds or polyamino acids and peptides can be used to deliver active agents, including but not limited to biological or chemical active agents, such as, for example, pharmacologically active agents or therapeutic agents.
    [14] Amino acids are carboxylic acids with one or more free amino groups and include natural and synthetic amino acids. Polyamino acids are two or more amino acids linked by a bond, such as an ester, anhydride or anhydride linkage, produced by a peptide or other group that may be linked. Peptides are two or more amino acids joined by peptide bonds. Peptides can vary in length from dipeptides with two amino acids to polypeptides with hundreds of amino acids (see Chambers Biology Dictionary, Editor Peter MB Walker, Cambridge, England: Chambers Cambridge, 1989, 215). Particular mention is made of tripeptides, tetrapeptides and pentapeptides.
    [15] Amino acids can be used to prepare carriers useful in the present invention. Amino acids are carboxylic acids with one or more free amino groups and include natural and synthetic amino acids. Many amino acids and amino acid esters are available from Aldrich Chemicals, Milwaukee, Wisconsin, USA; Sigma Chemicals, Inc. (St. Louis, Mo, USA); And many commercial sources such as Fluka Chemicals (Ronconcoma, New York, USA). Peptides may be homo or hetero peptides and may include any of natural amino acids, synthetic amino acids or combinations thereof.
    [16] Modified amino acids, polyamino acids or peptides are either acylated or sulfonated and include amino acidamides and sulfonamides.
    [17] Particular mention is made of acylated or sulfonated amino acids having the formula:
    [18]
    [19] Wherein R 1 is C 1 -C 7 alkyl, C 3 -C 10 cycloalkyl, cycloalkenyl, aryl, thienyl, phenyl, naphthyl, pyrrolo or pyridyl,
    [20] R 1 is optionally one or more C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 6 -C 10 cycloalkyl, phenyl, phenoxy, F, Cl, Br, -OH , -SO 2 , -SO 3 H, -NO 2 , -SH, -PO 3 H, oxazolo, isoxazolo, alkoxy having the formula -OR 6 , -COOR 7 , -N (R 5 ) 2 ,- N + (R 5 ) 3 X - or a combination thereof, and
    [21]
    [22] X is halogen, hydroxide, sulfate, tetrafluoroborate or phosphate,
    [23] R 2 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or-(CH 2 ) n -COOH (n = 1-10),
    [24] R 3 is C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkyne, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, phenyl, naphthyl, (C 1 -C 10 alkyl) phenyl, (C 2 -C 10 alkenyl) phenyl, (C 1 -C 10 alkyl) naphthyl, (C 2 -C 10 alkenyl) naphthyl, phenyl (C 1 -C 10 alkyl) , Phenyl (C 2 -C 10 alkenyl), naphthyl (C 1 -C 10 alkyl) or naphthyl (C 2 -C 10 alkenyl),
    [25] R 3 is optionally C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, -OH, SH, halogen, -NH 2 , -CO 2 R 4 , C 3 -C 10 cycloalkyl , C 3 -C 10 cycloalkenyl, heterocycle having 3-10 ring elements, wherein the heteroatom is one or more N, O, S or a combination of any of these, aryl, (C 1 -C 10 alkyl) aryl , Aryl (C 1 -C 10 alkyl), or a combination thereof, and
    [26] R 4 is hydrogen, C 1 -C 4 alkyl or C 2 -C 4 alkenyl,
    [27] R 5 is hydrogen or C 1 -C 10 alkyl,
    [28] R 6 is C 1 -C 10 alkyl, alkenyl, alkynyl, aryl or cycloalkyl,
    [29] R 7 is hydrogen, C 1 -C 10 alkyl, alkenyl, alkynyl, aryl or cycloalkyl.
    [30] Particular mention is made of acylated or sulfonated amino acids having the structure:
    [31] Ar-Y- (R 8 ) n -OH carrier A '
    [32] Wherein Ar is substituted or unsubstituted phenyl or naphthyl, preferably Ar is substituted or unsubstituted 2-OH-phenyl,
    [33]
    [34] R 8 has the formula
    [35]
    [36] R 9 is C 1 -C 24 alkyl, C 1 -C 24 alkenyl, phenyl. Naphthyl, (C 1 -C 10 alkyl) phenyl, (C 1 -C 10 alkenyl) phenyl, (C 1 -C 10 alkyl) naphthyl, (C 1 -C 10 alkenyl) naphthyl, phenyl (C 1 -C 10 alkyl), phenyl (C 1 -C 10 alkenyl), naphthyl (C 1 -C 10 alkyl) and naphthyl (C 1 -C 10 alkenyl),
    [37] R 9 is optionally C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkoxy, -OH, -SH, CO 2 R 11 , cycloalkyl, cycloalkenyl, heterocyclic alkyl, alkylaryl , Heteroaryl, heteroalkylaryl, or a combination thereof,
    [38] R 9 is optionally interrupted by any one of oxygen, nitrogen, sulfur, or a combination thereof,
    [39] R 10 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkenyl,
    [40] R 11 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkenyl.
    [41] Also specifically mentioned are the following compounds and their salts, which include, but are not limited to, sodium salts.
    [42]
    [43] Some preferred delivery agents are U.S. Pat. And 5,863,944 and PCT Publication Nos. WO 96/12474, WO 97/10197, WO 97/36480 and WO 98/50341. It is not.
    [44] Acylated amino acids can be prepared by reacting one amino acid, two or more amino acids, or amino acid esters with an amine modifier that reacts with the free amino groups present in the amino acid to produce an amide.
    [45] Examples of suitable acylating agents for preparing acylated amino acids include, but are not limited to, acid chloride acylating agents having the formula:
    [46]
    [47] Wherein R 12 is a suitable group for the modified amino acids to be prepared, such as, but not limited to, alkyl, alkenyl, cycloalkyl or aromatic and especially methyl, ethyl, cyclohexyl, cyclophenyl, phenyl or benzyl, and X is leaving It is a leaving group. Typical leaving groups include, but are not limited to, halogens such as chlorine, bromine and iodine.
    [48] Examples of acylating agents include, but are not limited to, acetyl chloride, propyl chloride, cyclohexanoyl chloride, cyclopentanoyl chloride and cycloheptanoyl chloride, benzoyl chloride, hypuryl chloride, and the like, acyl halides and aces Anhydrides such as but not limited to tic anhydride, propyl anhydride, cyclonucleoside anhydride, benzoic anhydride, hyplic anhydride, and the like. Preferred acylating agents include benzoyl chloride, hypuryl chloride, acetyl chloride, cyclohexanoyl chloride, cyclopentanoyl chloride and cycloheptanoyl chloride.
    [49] Amino groups can also be modified by reacting carboxylic acids with coupling agents such as carbodiimide derivatives of amino acids, in particular hydrophilic amino acids such as phenylalanine, tryptophan and tyrosine. Further examples include dicyclohexylcarbodiimide and its homologues.
    [50] If the amino acid is multifunctional, for example if it has one or more -OH, -NH, or -SH groups, it is optionally acylated by one or more functional groups, for example esters, amides or thioesters. ) Bonds can be formed.
    [51] For example, in the preparation of many acylated amino acids, the amino acids are dissolved in a water soluble base solution of metal hydroxides such as sodium hydroxide or potassium hydroxide and acylating agents are added. The reaction time may be about 1 to 4 hours, preferably 2 to 2.5 hours. The temperature of the mixture is usually maintained at about 5 ° C to 70 ° C, preferably about 10 ° C to 50 ° C. The amount of base used per equivalent of NH group in the amino acid is about 1.25 mol to 3 mol, with about 1.5 mol to 2.25 mol per equivalent of NH 2 being preferred. The pH of the reaction solution is usually about 8 to 13, with about 10 to 12 being preferred. The amount of amino modifier used relative to the amount of amino acid is based on the total moles of free NH in the amino acid. Typically, amino modifiers are used in the range of about 0.5 to 2.5 molar equivalents, with about 0.75 to 1.25 equivalents being preferred per molar equivalent of the total NH groups in the amino acid.
    [52] The modified amino acid production reaction is usually quenched by adjusting the pH of the mixture with a suitable acid such as concentrated hydrochloric acid until the pH reaches about 2-3. Leaving the mixture at room temperature separates to produce a clear upper layer and a white or greyish white precipitate. The upper layer is discarded and the modified amino acids are collected by filtration or decantation. The crude modified amino acid is mixed with water. The insoluble material is filtered off and the filtrate is vacuum dried. Typically, yields of modified amino acids range from about 30 to 60%, usually about 45%. The present invention also contemplates amino acids modified by multiple acylations such as diacylation, triacylation and the like.
    [53] If the amino acid esters or amides are starting materials, they are dissolved in a suitable organic solvent such as dimethyl formamide or pyridine and reacted with amino modifiers for 7 to 24 hours in the temperature range of 5 ° C. to 70 ° C., preferably at about 250 ° C. . The amount of amino modifier used relative to the amount of amino acid ester is the same as for the above amino acids.
    [54] Thereafter, the reaction solvent is removed under negative pressure and the modified amino acid ester is removed at a suitable base solution, such as 1N sodium hydroxide, at a temperature ranging from about 50 ° C. to 80 ° C., preferably about 70 ° C., for a sufficient time. By hydrolysis to cause the ester group to hydrolyze to produce a modified amino acid having a free carboxyl group, the ester or amide functional group can optionally be removed. The hydrolysis mixture is cooled at room temperature and acidified, for example with 25% aqueous hydrochloric acid, to bring the pH to a range of about 2 to 2.5. The modified amino acid is precipitated and recovered by traditional methods such as filtration or tilting.
    [55] The modified amino acids can be purified by acid precipitation, recrystallization or fractionation on a solid column carrier. Fractionation was carried out using a mixed solvent such as acetic acid / butanol / water as the mobile phase, on a solid column carrier such as silica gel or alumina, using a trifluoroacetic acid / acetonitrile mixture as the mobile phase, and a reverse phase column carrier using water as the mobile phase. Ion exchange chromatography can be used. In addition, the modified amino acid can be purified by extracting with an alcohol having a low molecular weight such as methanol, butanol or isopropanol to remove impurities such as inorganic salts.
    [56] The modified amino acid is usually dissolved in basic aqueous solution (pH ≧ 9.0), partially dissolved in ethanol, n-butanol and toluene / ethanol 1: 1 (v / v) solution, and not dissolved in neutral water. Alkali metal salts, such as sodium salts of modified amino acids, are usually dissolved in water at about pH 6-8.
    [57] One or more amino acids in a polyamino acid or peptide may be acylated and / or sulfonated. Polyamino acids and peptides may comprise one or more acylated amino acids. While linearly modified polyamino acids and peptides typically comprise only one acylated amino acid, other polyamino acids and peptide configurations may comprise one or more acylated amino acids. Polyamino acids and peptides can be polymerized with acylated amino acids or acylated after polymerization.
    [58] Sulfonated amino acids, polyamino acids and peptides are modified by sulfonating one or more free amine groups with a sulfonating agent that reacts with one or more of the free amine groups present.
    [59] Examples of suitable sulfonating agents useful for preparing sulfonated amino acids, including but not limited to, sulfonating agents having the formula R 13 -SO 2 -X, wherein R 13 is an alkyl, alkenyl, cycloalkyl or aromatic But, but not limited to, suitable groups for the modified amino acids produced, X is a leaving group as above. One example of a sulfonating agent is benzene sulfonyl chloride.
    [60] Modified polyamino acids and peptides may comprise one or more sulfonated and / or acylated amino acids. While typically used linearly modified polyamino acids and peptides contain only one sulfonated amino acid, other polyamino acid and peptide arrangements may comprise one or more sulfonated amino acids. Polyamino acids and peptides can be polymerized with sulfonated amino acids or acylated after polymerization.
    [61] Delivery system
    [62] Compositions useful in the present invention may include one or more active agents.
    [63] In one embodiment, by briefly mixing one or more compounds or salts, polyamino acids or peptides with an active agent prior to administration, the compounds or salts or polyamino acids or peptides of the compounds to be used directly as a delivery carrier Can be.
    [64] Dosage mixtures are prepared by mixing an aqueous solution of the carrier with an aqueous solution of the active ingredient immediately prior to administration. Alternatively, the carrier and the biological or chemically active ingredient can be mixed during the production process. The solution may optionally contain additives such as phosphate buffer salts, citric acid, acetic acid, gelatin and gum arabic.
    [65] Stabilizing additives may be mixed in the carrier solution. In some drugs, the presence of such additives enhances the stability and dispersibility of the agent in solution.
    [66] Stabilizing additives may be used at concentrations ranging from about 0.1 to 0.5% (w / v), with about 0.5% (w / v) being preferred. Examples of suitable but non-limiting stabilizing additives include gum arabic, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine. Preferred stabilizing additives are gum arabic, gelatin and methyl cellulose.
    [67] The amount of active agent is an amount effective to achieve the purpose of the particular active agent for indication of the target. The amount of active agent in the composition is usually a pharmacological, biological, therapeutic or chemically effective amount. However, when the composition is used in a dosage unit form such as powder or liquid, the dosage unit form comprises or is divided into several carrier / biological or chemical active agent compositions, Since it may comprise a therapeutic or chemically effective amount, the amount may be less than a pharmacological, biological, therapeutic or chemically effective amount. The total effective amount can be administered in cumulative units containing as a whole a pharmacological, biological, therapeutic or chemically active amount of a pharmacological, biological, therapeutic or chemical active agent.
    [68] The total amount of active agent and in particular biological or chemical active agents used can be determined by one skilled in the art. Surprisingly, however, it has been found that for some biological or chemical active agents, the use of the presently disclosed carriers in the pulmonary delivery system provides extremely efficient delivery. Accordingly, less biological or chemical active agents can be administered according to the invention than those used in previous dosage unit forms or delivery systems, which still enable to achieve the same blood level and therapeutic effect. .
    [69] The amount of carrier in the composition is a delivery effective amount and can be determined for any particular carrier or biological or chemical active agent by methods known to those skilled in the art. The effective amount of active agent and carrier in the composition may vary within the range contemplated and depends on the age, weight, sex, sensitivity, medical history, etc. of the individual. The nature of the active agent and the carrier, the specific activity of the agent (bioactivity / mass units), and the rate of absorption of the agent in the lungs should be considered, all of which contribute to the determination of a therapeutically effective dosage.
    [70] After administration, the active agent present in the composition or dosage unit form is rapidly absorbed into the circulation. The bioavailability of the active agent is known pharmacological activity in the blood, such as, for example, an increase in blood clotting time induced by heparin, a decrease in circulating calcium levels induced by calcitonin, or a change in blood glucose levels induced by insulin. It is easily calculated by measuring activity. Alternatively, the circulation level of the active agent itself can be measured directly.
    [71] Alternatively, if the target is lung, delivery is automatically effective. The bioavailability of the active agent is calculated by measuring the known active pharmacodynamic parameter of activity.
    [72] Dosage unit forms also include, but are not limited to, excipients, diluents, disintegrants, lubricants, plasticizers, colorants, and any of water, 1,2-propane diol, ethanol, olive oil, or combinations thereof. It may comprise any one of the means (dosing vehicles).
    [73] The delivery composition may also include one or more enzyme inhibitors. Such enzyme inhibitors include, but are not limited to, compounds such as actinin or epiactinin and derivatives thereof. Derivatives of such compounds are disclosed in US Pat. No. 5,206,384, which is incorporated herein by reference. Other enzyme inhibitors include, but are not limited to, aprotinin (trasilol) and Bowman-Birk inhibitors.
    [74] The system is particularly useful for delivering a chemical or biologically active agent that is destroyed or diminished in the body of the animal to be administered and by conditions encountered before reaching the target point (ie the region from which the active agent is released). useful. In particular, the present invention is useful for pulmonary administration, such as by inhaler, or when improved delivery is desired of an active agent that cannot be delivered by the usual route. Improved delivery includes, but is not limited to, an overall increase in the amount of active agent delivered over time, an overall increase in biological response over time, and an increased delivery or response at a particular time, such as fast delivery or fast response of the active agent. Can be observed in several pathways.
    [88] The following example illustrates a non-limiting invention. All parts are given in weight unless otherwise indicated.
    [89] Example 1 Preparation of Carrier
    [90] Preparation of 2- (4- (N-salicyloyl) aminophenyl) propionic acid (carrier B)
    [91] A slurry of 58.6 g (0.355 mol) of 2- (4-aminophenyl) propionic acid and 500 ml of methylene chloride was treated with 90.11 ml (77.13 g, 0.710 mol) of chlorotrimethylsilane and heated to reflux for 120 minutes. The reaction mixture was cooled to 0 ° C. and treated with 184.44 ml (107.77 g, 1.065 mol) triethylamine. After stirring for 5 minutes, the mixture was treated with 70.45 g (0.355 mol) of O-acetylsalicyloyl chloride solution dissolved in 150 ml of methylene chloride. The reaction mixture was raised to 25 ° C. and stirred for 64 h. The volatiles were removed in vacuo. The residue was stirred in 2N aqueous sodium hydroxide solution for 1 hour and acidified with 2M aqueous sulfuric acid solution. The solid was recrystallized twice with ethanol / water to give a tan solid. Separation by filtration gave 53.05 g of 2- (4- (N-salicyloyl) aminophenyl) propionic acid (yield 52%).
    [92] Property. Solubility: 200 mg / ml: 200 mg + 350 μl 2N NaOH + 650 μl H 2 O pH-7.67. analysis. Calculated Value-C: 67.36, H: 5.3, N: 4.91, Measured value: C: 67.05, H: 5.25, N: 4.72.
    [93] Preparation of Sodium 2- (4- (N-salicyloyl) aminophenyl) propionate (sodium salt of carrier B)
    [94] A solution of 53.05 g (0.186 mol) of 2- (4- (N-salicyloyl) aminophenyl) propionic acid and 300 ml of ethanol was treated with 7.59 g of NaOH dissolved in 22 ml of water. The reaction mixture was stirred at 25 ° C. for 30 minutes and at 0 ° C. for 30 minutes. The pale yellow solid obtained was separated by filtration to give 52.61 g of sodium 2- (4- (N-salicyloyl) aminophenyl) propionate.
    [95] Property. Solubility: 200 mg / ml clear solution, pH = 6.85. analysis. Calculated Values: C: 60.45, H: 5.45, N: 3.92, Na: 6.63 Measurements: C: 60.84, H: 5.87, N: 3.85, Na: 6.43. Melting point 236-238 ° C.
    [96] Preparation of Sodium Salt of Carrier C
    [97] A 2- (4-aminophenyl) propionic acid (15.0 g, 0.084 mol, 1.0 equiv) suspension for methylene chloride (250 ml) was placed in a 2 L round bottom flask equipped with a magnetic stirrer and reflux condenser. Chlorotrimethylsilane (18.19 g, 0.856 mol, 2.0 equiv) was added in one portion and the mixture was heated to reflux for 1.5 h under argon atmosphere.
    [98] The reaction mixture was cooled to room temperature and subjected to an ice bath (internal temperature <10 ° C). The reflux condenser was replaced with an addition funnel containing triethylamine (25.41 g, 0.251 mol, 3.0 equiv). Triethylamine was added dropwise over 15 minutes, during which time a yellow solid was produced. The funnel was replaced with another addition funnel containing a solution of methylene chloride (100 ml) of 2,3-dimethoxybenzoylchloride (18.31 g, 0.091 mol. 1.09 equiv). The solution was added dropwise over 30 minutes. The reaction mixture was stirred for 30 minutes in an ice bath and then for 3 hours at ambient temperature. Methylene chloride was evaporated in vacuo to give a brown oil. The brown oil was cooled in an ice bath, and thereto was added ice-cold saturated sodium bicarbonate solution (250 ml). The ice bath was removed and the reaction stirred for 1 hour to give a clear brown solution. The solution was acidified with concentrated hydrochloric acid and stored at ca 5C for 1 hour. The mixture was extracted with methylene chloride (3 x 100 ml), dried over sodium sulfate, filtered to remove sodium sulfate, and methylene chloride was removed in vacuo. The obtained solid was recrystallized from 50% ethyl acetate / water (v / v) to give a white needle-like carrier C acid (25.92 g, 90%). analysis. Calculated value-C 19 H 21 NO 3 : C66.46; H6.16; N4.08. Measured value-C66.14; H6.15; N3.98. Melting point 99-102 ° C.
    [99] 12 g of the carrier C acid was dissolved in 75 ml of ethanol while heating. To this solution was added a 8.5M sodium hydroxide (1.02 molar equivalent, 1.426 g in 4.5 ml water) solution. The mixture was stirred for 15 minutes. About 3/4 of ethanol was removed in vacuo, and 100 ml of n-heptane was added to the oil obtained to form a precipitate. The precipitate was dried in vacuo at 50 ° C. analysis. Calc. For C 19 H 20 NO 5 Na.0.067H 2 O: C62.25; H5.54; N3.82. Found: C62.37; H5.77; N3.80; Na5.75.
    [100] Preparation of N- (4-methylsalicyloyl) -8-aminocaprylic acid (carrier D)
    [101] (a) Preparation of Oligo (4-Methylsalicylate)
    [102] Acetic anhydride (32 ml, 34.5 g, 0.338 mol, 1.03 equiv), 4-methyl salicylic acid (50 g, 0.329 mmol. 1.00 equiv) and xylene (100 ml) are 1 L 4-neck equipped with magnetic stirrer, thermometer and condenser Put into flask. The flask was placed in a sand bath and the turbid white mixture began to heat. The reaction mixture became clear in a yellow solution near 90 ° C. Most of the volatile organics (xylene and acetic acid) were distilled for 3 hours (135-146 ° C.) with a Dean-Stark trap. The flow was continued for an additional 1 hour (the total amount of distillate was 110 ml), during which the temperature of the pot slowly rose to 204 ° C. and the rate of distillate dropping was slowed down. The residue was poured into an aluminum tray while hot. As it cooled, a brittle yellow glass was produced. The solid was ground to a fine powder. The resulting oligo (4-methylsalicylate) was used without further purification.
    [103] (b) Preparation of N- (4-methylsalicyloyl) -8-aminocaprylic acid
    [104] 7M potassium carbonate solution (45ml, 43.2g, 0.313mol, 0.95 equiv), 8-aminocaprylic acid (41.8g, 262mol, 798 equiv) and water (20ml) 1L round with magnetic stirrer, condenser and addition funnel It was added to the bottom flask. A solution of oligo (4-methylsalicylate) (44.7 g, 0.329 mmol, 1.0 equiv) dissolved in dioxane (250 ml) was added to the white turbid mixture for 30 minutes to react. The reaction mixture was heated at 90 ° C. for 3 hours (the time when the reaction was determined to be complete by HPLC). The clear orange reaction mixture was cooled to 30 ° C. and acidified to pH = 2 with 50% aqueous sulfuric acid solution (64 g). The obtained solid was separated by filtration. The white solid was recrystallized from 1170 ml of 50% ethanol-water. The solid was collected by filtration and dried for 18 hours in a vacuum oven at 50 ℃. N- (4-methylsalicyloyl) -8-aminocaprylic acid was isolated as a white solid (30.88 g, 52%); Melting point = 113-114 ° C .; 1 H NMR (DMSO-d 6 ) δ 12.80 (s, 1H), 12.00 (s, 1H), 8.73 (bt, 1H), 7.72 (d, 1H), 6.70 (s, 1H), 6.69 (d, 1H), 3.26 (q, 2H), 2.26 (s, 3H), 2.19 (t, 2H), 1.49 (m, 4H), 1.29 (m, 6H). analysis. Calculated value C 16 H 23 NO 4 : C65.51; H7.90; N4.77. Found: C65.48; H7.84; N4.69.
    [105] Example 2-Porcine Insulin Delivery Through Lungs
    [106] Raw materials and procedures
    [107] Raw material
    [108] Sprague Dawley female rat 225-300 g (Charles River, Raleigh, NC)
    [109] Fiber optic laryngoscope (Custom Manufactured, EPA, Research Triangle Park, NC)
    [110] Heating blankets are thermostatically controlled by work probes (Harbard Apparatus, Cambridge, HA)
    [111] Siliconized Eppendorf tube
    [112] Helix Medical Silicone tubing
    [113] Spray instillator (Penn Century, Philadelphia, PA)
    [114] Ketamine (100 mg / ml) Lot number 440 350 (Fort Dodge Laboratories Inc. Fort Dodge, Iowa)
    [115] Xylazine (100mg / ml) Lot number 116ZZ01 (Vedco Inc. St. Joseph, MO)
    [116] Acepromazine (10 mg / ml) Lot number 3941077 (Fort Dodge Laboratories Inc. Fort Dodge, Iowa)
    [117] Heparin 1000 units / ml Lot number 104067 (Elkins-Sinn, INc.Cherry Hill, NJ)
    [118] 0.9% Sodium Chloride Injection USP Sterile Solution Not number PS059113 (Baxter Healthcare Corporatioon, Deerfield, IL)
    [119] Freeze dried pig insulin 25.9 IU / mg (Emisphere Technologies)
    [120] Carrier B Na-2- (4-N-salicyloyl) amino phenyl) propionate (Emisphere Technologies)
    [121] step
    [122] 1. Solution
    [123] Cocktail of anesthetic solution containing xylazine (100mg / ml): Ketamine (100mg / ml): Acepromazine (10mg / ml) in a ratio of 1: 3: 1
    [124] 0.9% Sodium Chloride Injection USP containing 20 units / ml of heparin
    [125] Insulin was dissolved in distilled water with pH = 3 titrated with 0.01 N HCl. Distilled water at pH 7 was added when the solution became clear. Thereafter, the pH was adjusted to 7.5 with 0.01 NaOH.
    [126] Carrier B was dissolved in distilled water at pH 7.4, sonicated for 2 minutes and the pH was adjusted to 7.4 with 0.1 N NaOH.
    [127] 2. Animal
    [128] Each rat was weighed, labeled with an indelible marker, anesthetized by intraperitoneal injection of a ketamine: xylazine: acepromazine cocktail containing 80 mg / kg, 10 mg / kg and 2.0 mg / kg. Put in. The rats were transferred to the operating table and placed on a thermo blanket controlled by a rectal probe for deep anesthesia.
    [129] Catheter was inserted into the right cervical vein of each rat using silicone tubing, 200 μl of salt-containing heparin was flown into the cannula, and 100 μl of blood was collected to confirm the catheter opening. The cannula was then washed with 200 μl saline added heparin.
    [130] An endotracheal tube was inserted using an optical fiber laryngoscope. A Hamilton syringe was attached to the endotracheal tube and used to drop the solution (100 μl) through the air passage. The endotracheal tube was removed after administration and the respiratory rate was monitored for the remainder of the study.
    [131] Blood samples (500 μl) were taken at 0, 10, 30, 60, 90, 120 and 180 minutes, and about 200 μl of heparin added saline was flown into the cannula. Blood was collected in a 1 ml tuberculin syringe (containing 100 μl of 20 μl / ml heparin) and placed directly into a microcentrifuge tube.
    [132] Blood samples were immediately centrifuged at 10,000 rpm for 4 minutes. An aliquot of about 30 μl was transferred to only 1 ml of silicone treated Eppendorf tubes and frozen until the study for subsequent glucose measurements was completed. The remaining samples were frozen at -70 ° C for insulin measurement (Ultra-sensitive RIA).
    [133] analysis
    [134] 1. Measuring glucose
    [135] Fasting glucose levels were measured using the Ektachem DT Slide (GLU) method. The assay is based on the enzymatic catalysis of oxygen molecules and glucose followed by a second reaction to produce a highly colored red dye. The intensity of the color is proportional to the amount of glucose in the sample.
    [136] 2. Pharmacokinetic Analysis
    [137] Standard compartment and noncompartmental pharmacodynamic analyzes were performed for mean plasma insulin concentration over time. Compartmental analysis and noncompartmental analysis are usually performed simultaneously to verify the validity of the compartmental model.
    [138] a. Compartmental analysis
    [139] In the spray-intracheal (IT) administration of porcine insulin, the mean insulin concentration (C) was determined using a least-squares nonlinear regression method (PKanalyst, Micromath, Salt Lake City, UT). INS ) versus time pattern was fitted to the first compartment model, first absorption. The average insulin concentration was adjusted according to the following equation.
    [140]
    [141] Where A = Dk a / Vd (k a -k e ) is the drug concentration in the body at time 0, k a is the first order rate constant and k e is the first order rate constant.
    [142] The area under thelung concentration-time curve = (AUC 0 → t ) was calculated by the trapezoidal law. Infinite interpolation was performed by dividing the final C ins by the late first-order rate constant. The total area under the curve was calculated as the sum of the two compounds.
    [143] The elimination half-life is calculated from 0.693 / k e , where k e is the slope of the end of the log of the concentration-time pattern.
    [144] b. Noncompartmental analysis
    [145] Noncompartmental analysis of insulin plasma concentration over time was performed using standard techniques. The time (T max) and a peak C Pins (C max) of the peak C Pins from the unregulated average plasma concentration for the treatment (C Pins) was calculated. AUC was calculated by the trapezoidal law. MRT was not calculated because no data were available for the following intravenous administration to calculate pharmacodynamic parameters.
    [146] 3. Pharmacodynamic Analysis
    [147] Percentage minimum plasma glucose concentraion (% MPGC) and time T (T% MPGC) to obtain each% MPGC were determined from the mean blood glucose level versus time pattern for treatment.
    [148] The area above the curve effect = AACE was calculated as follows.
    [149]
    [150] Where AUC E represents the area effect under the curve calculated using the trapezoidal law.
    [151] Percentage total reduction in plasma glucose (% TRPG0 → t) at 0 → t was determined using the following equation.
    [152]
    [153] 4. Statistical Analysis
    [154] AUC differences between insulin doses were tested for significance using Sheffe's multiple comparison test assuming α <0.05. The difference in AACE 0 → 3 (blood glucose level) between insulin alone and bound to carrier B was examined for significance using the Turkey's test and analysis of variance assuming α <0.05.
    [155] Example 2a
    [156] (i) Plasmainsulin and blood glucose-time patterns when 0.05 mg / kg of insulin mixed with carrier B 5 mg / kg were injected intratracheally instillation are shown in FIGS. 1 and 2 respectively.
    [157] (ii) and (iii) FIGS. 3 and 4 and Table 1 below show blood glucose-time patterns and pharmacokinetic parameters when pulmonary endotracheal instillation of carrier B 16 mg / kg mixed with insulin 0.05 and 0.01 mg / kg, respectively, was applied. . When insulin was administered in the presence and absence of a carrier, a significant difference (p <0.05) of AACE 0 → 3 was observed. The% TRGP 0 → 3 for the insulin (combined with carrier B 16 mg / kg) doses 0.01 and 0.05 rose to 10.5 ± 1.5 to 36 ± 9% and 47 ± 10 to 65.7 ± 5%, respectively. There was no statistically significant difference in the% TRGP 0 → 3 value between 0.05 mg / kg of insulin alone and administration with 5 mg / kg of carrier B. This dose-effect relationship found for carrier B is likely due to the carrier's effect (increased bioavailability) on the pharmacokinetics of insulin.
    [158]
    [159] The data above suggest the potential of carrier B to significantly increase the bioavailability of insulin, and the influence of carrier B on glucose levels.
    [160] (iv) Average insulin plasma concentrations with endotracheal injection droplets as a function of insulin dose are shown in FIG. 5. The pharmacokinetic parameters obtained from compartmental analysis and noncompartmental analysis are summarized in Table 2 below. Nonlinear curve fitting of mean plasma levels was best described as lowering the plasma concentration in all cases, decreasing first-order exponentially for first-order absorption. Modeling excellence was evaluated by comparing it with the relative model selection standard (MSC). The modified Akaike information standard allows a comparison of model suitability. MSC values range from 1.3 to 3.8 when indicating model suitability.
    [161] The average peak plasma concentrations obtained in this study were 0.001 mg / kg (0.026 U / kg), 0.005 mg / kg (0.13 U / kg), 0.01 mg / kg (0.26 U / kg), 0.05 mg / kg (1.3 pigs) U / kg), 57.5 μU / ml (T max = 10 minutes), 18.8 μU / ml (T max = 20 minutes) for 0.1 mg / kg (2.6 U / kg), 0.5 mg / kg and 1 mg / kg, respectively , 71.3 μU / ml (T max = 10 minutes), 48.95 μU / ml (T max = 10 minutes), 213.1 μU / ml (T max = 10 minutes), 354 μU / ml (T max = 20 minutes) and 902 μU / ml (T max = 20 min), which shows close agreement with the values obtained after the curve modeling.
    [162] The log plasma concentration-time plot (FIG. 5) as a function of insulin dosage was determined from previous reports obtained after intravenous administration of 0.1 u / kg bovine insulin to rabbits (t 1/2 = 30 min). Significantly longer half-lives (7.8 to 142.4 minutes; see Table 2) indicate a decrease in plasma concentration. The observation suggests the presence of a "flip-flop" case, i.e. absorption rather than ablation dominates plasma concentration reduction. However, this increase in absorption half-life does not imply that absorption is a rate determining step. Rather, this event may be the result of insulin converting from hexamer to monomer type or slowly “dissolving” as the insulin concentration per volume is increased.
    [163] The area under the curve (AUC 0 → ∞ ) to infinity, obtained using the trapezoidal law, is 0.001 mg / kg (0.026 U / kg), 0.005 mg / kg (0.13 U / kg), and 0.01 mg / kg (0.26) U / kg), 0.05 mg / kg (1.3 U / kg), 0.1 mg / kg (2.6 U / kg), 2930, 1334, 5050, 5260, 15374, 67676, and 0.5 mg / kg and 1 mg / kg, respectively. 200230 μU min / ml.
    [164] Multiple comparisons between doses using Sheffe's test showed no significant difference (p> 0.05) in AUC values. This may be due to a high degree of intersubject variability (see Standard Deviation for AUC in Table 2). By assuming that the degree of absorption of porcine insulin following pulmonary administration and that of human insulin following subcutaneous administration are equal, the relative bioavailability of the insulin used can be calculated. Based on these assumptions, the relative bioavailability of porcine insulin is 12.46%.
    [165]
    [166] Blood glucose-time modalities and pharmacokinetic variable (PD) data for various doses of instilled insulin are shown in FIG. 6 and Table 3 below. The result is that an increase in dose (from 0.01 to 1 mg / kg) significantly reduces the% minimum blood glucose (% MPGC) value from 70.2 to 13.1, without a significant change in the time T (T% MPGC) reaching the minimum. Shows. From 0 to 3 hours, the overall decrease in blood glucose (% TRPG 0 → 3hr ) (see Table 3) rises significantly from 10.5 to 73.7%, which is achieved by high levels of bioavailability as the extent of absorption increases with increasing insulin dose. It means.
    [167]
    [168] The intersubject variability (CV <30%) in the glucose response is less than the insulin response. Thus, insulin variability dampens as much as the appearance of hormones in the circulatory system translates to its biological activity.
    [169] Example 2b
    [170] The rats were administered a composition comprising porcine insulin 0.05 mg / kg and carrier B 16 mg / kg as a pulmonary endotracheal injection point. A single composition of 0.05 mg / kg porcine insulin was also administered to rats by pulmonary intratracheal injection drop. The results are described in Figure 7 and Tables 4 and 5.
    [171]
    [172]
    [173] Table 5 Locations
    [174] Comparative Example 2c
    [175] As shown in Table 6 below, rats were dosed with pulmonary tracheal injections in incremental doses. The results are described in Figure 8 and Tables 6 and 7.
    [176]
    [177]
    [178] Example 2d
    [179] Compositions of porcine insulin 0.05 mg / kg and carrier B 5 mg / kg were administered to rats by pulmonary endotracheal injection. Porcine insulin 0.05 mg / kg alone composition was also administered by pulmonary intratracheal injection drop. Plasma insulin levels are described in FIG. 9 and Tables 5 and 8.
    [180]
    [181] Example 2e
    [182] A composition of 0.01 mg / kg porcine insulin and 16 mg / kg of carrier B was administered to rats by pulmonary endotracheal injection. A single composition of 0.01 mg / kg of pig insulin was also administered to rats by pulmonary intratracheal injection drop. Plasma insulin levels are described in FIG. 10 and in Tables 5 and 9.
    [183]
    [184] Example 3 Pulmonary Delivery of Porcine Insulin
    [185] Example 3a
    [186] A pulmonary delivery dosing composition of 0.1 mg / kg of pig insulin dissolved in water and 7.5 mg / kg of sodium salt of carrier B was prepared. A control dosing composition of only 0.1 mg / kg of pig insulin alone and 7.5 mg / kg of sodium salt of carrier B alone was also prepared. A dose of 0.3 ml / kg of the pulmonary dosage composition at pH 7.3-7.6 was administered to five non-fasting normal mice by the following procedure. 1 and 1/2 Popper and Sons gavage needles were injected about a few centimeters below the neck of the animal. The tip of the needle was manipulated toward the ventral side where the needle could fall into the pocket and further manipulation led to trachea. The dosing solution was delivered through the needle when the needle was in the trachea.
    [187] Blood samples were periodically taken through the tail artery, and blood glucose levels were measured using an Ektachem DT slide (Johnson & Hohnson Clinical Diagnostics, Rochester, New York).
    [188] Results are shown in FIG. 11 for 0.1 mg of insulin with 7.5 mg / kg of sodium salt of carrier B (■), 0.1 mg / kg of insulin alone (●) and 7.5 mg / kg of sodium salt of carrier B alone (▲). It is explained.
    [189] Example 3b
    [190] The dosage composition was changed to 0.5 mg / kg of pig insulin and 7.5 mg / kg of sodium salt of Carrier B, and the procedure of Example 3a was repeated for the dosage composition with a pH of 6.6-6.9 in water. A control dosing composition of 0.5 mg / kg of pig insulin alone and 7.5 mg / kg of sodium salt of carrier B alone was also prepared.
    [191] Results are shown for 0.5 mg / kg of insulin with 7.5 mg / kg of sodium salt of carrier B (■), for 0.5 mg / kg of insulin alone (●) and 7.5 mg / kg of sodium salt of carrier B alone (▲). It is explained in 12.
    [192] Example 4 Insulin Lung Delivery
    [193] Carrier compound B, carrier compound C sodium salt and carrier compound D shown in Table 10 were examined as follows. Each rat was weighed, labeled with an indelible marker, and anesthetized by intramuscular injection of thorazine (3 mg / kg) and ketamine (44 mg / kg).
    [194] An endotracheal tube (a spray dropper purchased from Penn Century, Philadelphia, PA) with a Hamilton syringe was inserted using an optical fiber laryngoscope. A dropper syringe was used to drop 0.4 ml / kg of solution containing insulin (0.03 mg / kg) and carrier compound (16 mg / kg) into the lower portion of the airway. The endotracheal tube was removed after administration and the respiratory rate was monitored throughout the remainder of the study.
    [195] Blood samples (500 μl) were withdrawn through peripheral arteries at 0, 10, 30, 60, 90 and 120 minutes and analyzed according to the procedure outlined in the kit with DSL Insulin Kit # 10-1600. Serum insulin levels are illustrated in FIG. 13, and C max is described in Table 10 below.
    [196] carrier C max ( μU / ml) B44.6 ± 10.00 Sodium salt of C22.5 ± 4.0 D58.8 ± 12.0 none19.4 ± 4.3
    [197] The foregoing patents, applications, inspection methods and publications are hereby incorporated by reference in their entirety.
    [198] Many modifications of the invention will suggest themselves to those skilled in the art in light of the above detailed description. All such obvious variations are within the fully intended scope of the appended claims.
    权利要求:
    Claims (17)
    [1" claim-type="Currently amended] A method of administering a biologically active agent to an animal in need thereof, the method comprising (A) the active agent and (B) an acylated amino acid, a sulfonated amino acid, a polyamino acid comprising an acylated amino acid, a sulfonated amino acid A method comprising administering to the animal via a pulmonary route a composition comprising a carrier comprising any one of polyamino acids or combinations thereof.
    [2" claim-type="Currently amended] The method of claim 1, wherein the active agent is selected from the group consisting of biologically active agents, chemically active agents, and combinations thereof.
    [3" claim-type="Currently amended] The method of claim 2, wherein the biologically active agent comprises one or more peptides, mucopolysaccharides, carbohydrates, or fats.
    [4" claim-type="Currently amended] The method of claim 3 wherein the biologically active agent is a growth hormone, human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone, pig growth hormone, growth hormone releasing hormone, interferon, α-interferon, β-interferon , γ-interferon, interleukin-1, interleukin-II, insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfragmented heparin, heparinoids, dermatan, chondroitin, low Molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin, erythropoietin (EPO), atrial natureic facter, antigen, monoclonal antibody , Somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, luteinizing hormone releasing hormone, follicle stimulating hormone, glue Cerebrosidase, thrombopoietin, pilgrasstim, prostaglandin, cyclosporin, vasopressin, sodium chromoglycate, disodium chromoglycate, vancomycin, desferoxamine (DFO), parathyroid hormone (PTH) , A fragment of PTH, an antimicrobial agent, an antifungal agent, a homologue of the compound, a fragment, a mimetic and a polyethylene glycol (PEG) -modified derivative, and a combination of said compounds.
    [5" claim-type="Currently amended] The method according to claim 3, wherein the biologically active agent is human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone, growth hormone releasing hormone, interferon, α-interferon, β-interferon, γ-interferon, interleukin- 1, interleukin-II, insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfragmented heparin, heparinoid, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin , Calcitonin, salmon calcitonin, eel calcitonin, human calcitonin, erythropoietin (EPO), atrial natureic facter, antigen, monoclonal antibody, somatostatin, adrenocorticotropin, gonadotro Pin releasing hormone, oxytocin, luteinizing hormone releasing hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoietin, filgrastim, prostaglandin, cycl Rosporin, vasopressin, sodium chromoglycate, disodium chromoglycate, vancomycin, desferoxamine (DFO), parathyroid hormone (PTH), fragments of PTH, antimicrobial agents, antifungal agents, homologues of these compounds, fragments , Mimetics and polyethylene glycol (PEG) -modified derivatives, and combinations of the above compounds.
    [6" claim-type="Currently amended] 4. The method according to claim 3, wherein the biologically active agent is interferon, interleukin-II, insulin, insulin-like growth factor (IGF), IGF-1, heparin, low molecular weight heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, desfereri A method comprising oxamine, parathyroid hormone, and combinations thereof.
    [7" claim-type="Currently amended] The method of claim 2, wherein the biologically active agent is selected from the group consisting of insulin, insulin-like growth factor (IGF), IGF-1, or a combination thereof.
    [8" claim-type="Currently amended] The method of claim 1 wherein said carrier comprises a compound having the formula:

    Wherein R 1 is C 1 -C 7 alkyl, C 3 -C 10 cycloalkyl, cycloalkenyl, aryl, thienyl, phenyl, naphthyl, pyrrolo or pyridyl,
    R 1 is optionally one or more C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 6 -C 10 cycloalkyl, phenyl, phenoxy, F, Cl, Br, -OH , -SO 2 , -SO 3 H, -NO 2 , -SH, -PO 3 H, oxazolo, isoxazolo, alkoxy having the formula -OR 6 , -COOR 7 , -N (R 5 ) 2 ,- N + (R 5 ) 3 X - or a combination thereof, and

    X is halogen, hydroxide, sulfate, tetrafluoroborate or phosphate,
    R 2 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or-(CH 2 ) n -COOH (n = 1-10),
    R 3 is C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkyne, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, phenyl, naphthyl, (C 1 -C 10 alkyl) phenyl, (C 2 -C 10 alkenyl) phenyl, (C 1 -C 10 alkyl) naphthyl, (C 2 -C 10 alkenyl) naphthyl, phenyl (C 1 -C 10 alkyl) , Phenyl (C 2 -C 10 alkenyl), naphthyl (C 1 -C 10 alkyl) or naphthyl (C 2 -C 10 alkenyl),
    R 3 is optionally C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, -OH, SH, halogen, -NH 2 , -CO 2 R 4 , C 3 -C 10 cycloalkyl , C 3 -C 10 cycloalkenyl, heterocycle having 3-10 ring elements, wherein the hetero atom is any one or more of N, O, S or a combination thereof, aryl, (C 1 -C 10 alkyl) aryl , Aryl (C 1 -C 10 alkyl), or a combination thereof, and
    R 4 is hydrogen, C 1 -C 4 alkyl or C 2 -C 4 alkenyl,
    R 5 is hydrogen or C 1 -C 10 alkyl,
    R 6 is C 1 -C 10 alkyl, alkenyl, alkynyl, aryl or cycloalkyl,
    R 7 is hydrogen, C 1 -C 10 alkyl, alkenyl, alkynyl, aryl or cycloalkyl.
    [9" claim-type="Currently amended] The method of claim 8, wherein the active agent is selected from the group consisting of insulin, insulin-like growth factor (IGF), IGF-1, or a combination thereof.
    [10" claim-type="Currently amended] The method of claim 1, wherein the carrier comprises a compound having a formula such as Ar-Y- (R 8 ) n -OH;
    Here, Ar is substituted or unsubstituted phenyl or naphthyl, preferably Ar is substituted or unsubstituted 2-OH-phenyl,

    R 8 has the formula

    R 9 is C 1 -C 24 alkyl, C 1 -C 24 alkenyl, phenyl. Naphthyl, (C 1 -C 10 alkyl) phenyl, (C 1 -C 10 alkenyl) phenyl, (C 1 -C 10 alkyl) naphthyl, (C 1 -C 10 alkenyl) naphthyl, phenyl (C 1 -C 10 alkyl), phenyl (C 1 -C 10 alkenyl), naphthyl (C 1 -C 10 alkyl) and naphthyl (C 1 -C 10 alkenyl),
    R 9 is optionally C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkoxy, -OH, -SH, CO 2 R 11 , cycloalkyl, cycloalkenyl, heterocyclic alkyl, alkylaryl , Heteroaryl, heteroalkylaryl, or a combination thereof,
    R 9 is optionally interrupted by any one of oxygen, nitrogen, sulfur, or a combination thereof,
    R 10 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkenyl,
    R 11 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkenyl.
    [11" claim-type="Currently amended] The method of claim 10, wherein the active agent is selected from the group consisting of insulin, insulin-like growth factor (IGF), IGF-1, or a combination thereof.
    [12" claim-type="Currently amended] The method of claim 1 wherein said carrier comprises a compound having the formula: and a salt of said compound.

    [13" claim-type="Currently amended] The method of claim 12, wherein the active agent is selected from the group consisting of insulin, insulin-like growth factor (IGF), IGF-1, or a combination thereof.
    [14" claim-type="Currently amended] The method of claim 1 wherein said carrier comprises a compound having the formula: and a salt of said compound.

    [15" claim-type="Currently amended] The method of claim 14, wherein the active agent is selected from the group consisting of insulin, insulin-like growth factor (IGF), IGF-1, or a combination thereof.
    [16" claim-type="Currently amended] The method of claim 1 wherein said carrier comprises a compound having the formula: and a salt of said compound.

    [17" claim-type="Currently amended] The method of claim 16, wherein the active agent is selected from the group consisting of insulin, insulin-like growth factor (IGF), IGF-1, or a combination thereof.
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    同族专利:
    公开号 | 公开日
    CA2338358C|2009-04-21|
    HU0103318A2|2002-01-28|
    WO2000006534A1|2000-02-10|
    NZ509238A|2003-07-25|
    CA2338419A1|2000-02-10|
    HK1036970A1|2005-09-30|
    DE69925276D1|2005-06-16|
    CA2338358A1|2000-02-10|
    NZ509239A|2002-10-25|
    JP2002521455A|2002-07-16|
    JP2003517438A|2003-05-27|
    ES2242412T3|2005-11-01|
    CZ2001331A3|2001-08-15|
    AU5321099A|2000-02-21|
    JP5144861B2|2013-02-13|
    WO2000006534A9|2000-07-13|
    AU745290B2|2002-03-21|
    TR200100922T2|2001-09-21|
    WO2000006184A1|2000-02-10|
    CN1311686A|2001-09-05|
    JP4675481B2|2011-04-20|
    BR9912694A|2002-01-02|
    EP1100522A1|2001-05-23|
    EP1100522B1|2016-12-07|
    EP1100771B1|2005-05-11|
    IL140710D0|2002-02-10|
    AU5323799A|2000-02-21|
    EP1100522A4|2003-01-08|
    US6642411B1|2003-11-04|
    CN1205994C|2005-06-15|
    IL140710A|2006-12-31|
    AU751612B2|2002-08-22|
    EP1100771A1|2001-05-23|
    AT295347T|2005-05-15|
    DE69925276T2|2005-10-06|
    CA2338419C|2011-06-14|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-07-27|Priority to US9426798P
    1998-07-27|Priority to US60/094,267
    1998-10-16|Priority to US10446698P
    1998-10-16|Priority to US60/104,466
    1999-07-27|Application filed by 추후제출, 에미스페어 테크놀로지스, 인코포레이티드
    1999-07-27|Priority to PCT/US1999/016957
    2001-08-09|Publication of KR20010074777A
    优先权:
    申请号 | 申请日 | 专利标题
    US9426798P| true| 1998-07-27|1998-07-27|
    US60/094,267|1998-07-27|
    US10446698P| true| 1998-10-16|1998-10-16|
    US60/104,466|1998-10-16|
    PCT/US1999/016957|WO2000006184A1|1998-07-27|1999-07-27|Pulmonary delivery of active agents|
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