WO2020012243A2 - Pharmaceutical composition containing a peptide - Google Patents
Pharmaceutical composition containing a peptide Download PDFInfo
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- WO2020012243A2 WO2020012243A2 PCT/IB2019/000716 IB2019000716W WO2020012243A2 WO 2020012243 A2 WO2020012243 A2 WO 2020012243A2 IB 2019000716 W IB2019000716 W IB 2019000716W WO 2020012243 A2 WO2020012243 A2 WO 2020012243A2
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- cys
- tyr
- carrier
- glu
- asn
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
Definitions
- the present invention relates generally to pharmaceutical compositions comprising a peptide.
- the invention relates to a composition comprising an adsorbate of a peptide on a carrier.
- aqueous solutions of polypeptides can be dried by freeze- drying, spray-drying or other methods, such dried formulations may also be unstable and have reduced activity relative to an aqueous solution of the polypeptide.
- Typical break-down mechanisms that occur both in aqueous solution and in dried formulations include aggregation and oxidative or hydrolytic degradation.
- Linaclotide is a tetradecapeptide having the amino acid sequence Cys-Cys-Glu-Tyr- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr that activates the guanylate cyclase-C (GC-C) receptor.
- Linaclotide which may be administered orally, is useful for the treatment of gastrointestinal disorders and conditions, including irritable bowel syndrome (IBS) and chronic constipation (CC).
- Formulations comprising Linaclotide are susceptible to degradation including moisture -driven degradation reactions such as hydrolysis, oxidation, deamidation, isomerization, and multimerization. The sensitivity of peptides to degradation due to oxidative or hydrolytic stress acts as a barrier to produce a stable drug formulation.
- W02007033427 discloses that proteins and peptides are susceptible to aggregation and/ or chemical degradation including oxidative or hydrolytic degradation.
- additives are required for peptide stabilization.
- additional drying steps such as lyophilization / freeze drying or spray drying are employed. Such freeze dried or spray dried products are very sensitive to moisture content and may need additional protective measures and such additional drying steps are very expensive.
- U.S patent 20150005241 discloses that peptides are often sensitive against degradation, for example, due to oxidative or hydrolytic stress. Such formulations require the addition of stabilizers like Ca 2+ ions and leucine to prevent hydrolytic and oxidative degradation of the peptide to achieve a stable drug product.
- a coating solution of Linaclotide is prepared by adding stabilizers such as leucine and Ca 2+ to the solution. After mixing, the solution is sprayed onto pellets made of microcrystalline cellulose (MCC). If stabilizers are not added, the impurities as well as multimers of the peptide increase substantially.
- WO/2017/024291 discloses the use of acesulfame to stabilize Linaclotide.
- the drawback of using such stabilizers is that the stabilizers may present potential incompatibility with certain peptides. Further, the use of stabilizers may cause unwanted side effects such as allergic reactions. In addition, there may be potential incompatibilities with antibiotics and inorganic ions like calcium ions.
- WO2010019266 describes that oxidation and hydrolysis occur in a significant manner if no stabilizers are added to the Linaclotide formulations.
- the formation of multimers and/or impurities reduce the amount of the active pharmaceutical ingredient required to enable the required pharmacodynamical effect in the respective therapy.
- Other stabilizers like trehalose, which are described in literature Jai K. Kaushik and Rajiv Bhat. J. Biol Chem. Vol. 278, No. 29, Issue of July 18, pp. 26458-26465, 2003
- a pharmaceutical composition comprising a peptide having the following amino acid sequence: Cys-Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys- Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein X is any amino acid.
- a process for preparing the composition as described herein comprising the steps of:(a) preparing an aqueous solution of a peptide; (b) combining the aqueous solution of the peptide with a carrier; (c) drying the mixture of peptide and carrier under reduced pressure at a temperature of from about 30 to about 50°C.
- a dosage form comprising the composition as described herein.
- compositions as described herein in the manufacture of a medicament for treating of chronic constipation or irritable bowel syndrome.
- a method of treating chronic constipation or irritable bowel syndrome comprising administering the composition as described herein or a dosage form as described herein, to a patient in need thereof.
- a composition as described herein in the manufacture of a medicament for treating a gastrointestinal disorder in a patient, wherein the composition further comprises a probiotic or a prebiotic or a mixture thereof.
- a method of treating a gastrointestinal disorder comprising administering the composition as described herein or a dosage form as described herein, to a patient in need thereof, wherein the composition or dosage form further comprises a probiotic or a prebiotic or a mixture thereof.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu-X- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 1 ) or a pharmaceutically acceptable salt thereof on at least one carrier, wherein X is any amino acid.
- the peptide Cys-Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr- Gly-Cys-Tyr may be Linadotide or a pharmaceutically acceptable salt thereof.
- amino acid refers to naturally occurring and non-naturally occurring amino acids, as well as amino acids such as proiine, amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids.
- amino acid refers to naturally occurring and synthetic a, b g or d amino acids.
- the backbone of the“amino acid” may be substituted with one or more groups selected from halogen, hydroxy, guanido, heterocyclic groups.
- amino acid also includes within its scope glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartatic acid, glutamic acid, lysine, arginine and histidine, taurine, betaine, N-methylalanine and the like.
- Naturally encoded amino acids include the common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proiine, serine, threonine, tryptophan, tyrosine, and valine) and the less common pyrroiysine and selenocysteine.
- common amino acids alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proiine, serine, threonine, tryptophan, tyrosine, and valine
- Naturally encoded amino acids include post-translational variants of the naturally occurring amino acids such as prenyiated amino acids, isoprenylated amino acids, myristoylated amino acids, palmitoylated amino acids, N-linked glycosylated amino acids, O-!inked glycosylated amino acids, phosphorylated amino acids and acylated amino acids.
- the amino acid may be in the L-configuration or D- configuration.
- the amino acid may be a derivative of a!anyi, vaiinyl, !euciny!, iso!euccinyl, prolinyl, pheny!a!aninyl, tryptophany!, methioninyl, glycinyl, serinyi, threoninyl, cysteinyl, tyrosinyl, asparaginyi, giutaminyl, aspartoyl, glutaroyl, lysinyi, argininyi, histidinyl, b-alanyl, b-valinyl, b-!eucinyl, b- isoleuccinyl, b-pro!inyl, b- pbenyialaninyl, b-tryptophanyl, b-methioninyl,
- polypeptide/' "peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. That is, a description directed to a polypeptide applies equally to a description of a peptide and a description of a protein, and vice versa. The terms apply to naturally occurring amino acid polymers as well as amino acid polymers in which one or more amino acid residues is a modified amino acid.
- the peptide may be a derivative or variant of Linaciotide.
- derivative or“variant” refers to a protein that differs from a related protein by substitutions in amino acid sequence. Such, substitutions may be conservative.
- variants also refers to a protein sequence that has one or more residues that differ in amino acid identity from another similar protein sequence. Said similar protein sequence may be the natural wild type protein sequence, or another variant of the wild type sequence. Variants include proteins that have one or more amino acid insertions, deletions or substitutions. Variants also include proteins that have one or more post-translationally modified amino acids.
- X may be selected from phenylalanine (Phe), Tyrosine (Tyr) or Tryptophan (Trp).
- the peptide according to the invention may comprise the following sequences: Cys-Cys-Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr- Gly-Cys-Tyr (SEQ ID NO.: 2), or Cys-Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly- Cys-Tyr (SEQ ID NO.: 3), or Cys-Cys-Glu-Trp-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly- Cys-Tyr (SEQ ID NO.: 4).
- the peptides have six Cys residues.
- the six Cys residues form three disulfide bonds in the mature and active form of the peptide when fully folded.
- the six Cys residues may be identified, from the amino to carboxy terminus of the peptide, as A, B, C, D, E, and F as follows: Cys(A)-Cys(B)-Glu-X-Cys(C)-Cys(D)-Asn-Pro-Ala-Cys(E)-Thr-Gly-Cys(F)-Tyr.
- the disulfide bonds form as follows: A-D, B-E, and C-F.
- one or both members of one or more pairs of Cys residues which normally form a disulfide bond can be replaced by homocysteine, 3- mercaptoproline; b, b dimethylcysteine or diaminopropionic acid to form alternative internal cross-links at the positions of the normal disulfide bonds.
- one or more disulfide bonds may be replaced by alternative covalent cross- links, e.g., an amide bond, an ester linkage, an alkyl linkage, a thio-ester linkage, a lactam bridge, a carbamoyl linkage, a urea linkage, a thiourea linkage, a phosphonate ester linkage, an alkyl linkage, and alkenyl linkage, an ether, a thioether linkage, or an amino linkage.
- alternative cross-links may require replacing the Cys residues with other residues such as Lys or Glu or non- naturally occurring amino acids.
- the peptide may be modified wherein at least one carboxyl group of an amino acid residue of the peptide is modified to an alkyl ester. In some embodiments, at least one carboxyl group of an amino acid of the peptide is an alkyl ester. Methods of producing alkyl esters from carboxyl groups are readily known in those skilled in the relevant art. In some embodiments, the carboxylic acid of the side chain of a glutamate amino acid in a peptide sequence is modified into an alkyl ester.
- alkyl includes within its meaning monovalent (“alkyl”) and divalent (“alkylene”) straight chain or branched chain saturated aliphatic groups having from 1 to 10 carbon atoms, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
- alkyl includes, but is not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, 2-butyl, isobutyl, tert-butyl, amyl, 1 ,2-dimethylpropyl, 1 ,1 -dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 1 ,2,2-thmethylpropyl, 1 ,1 ,2-trimethylpropyl, 2-ethylpentyl, 3- ethylpentyl, heptyl, 1 -methylhexyl, 2,2-dimethylpentyl
- the alkyl group is a fluorinated alkyl group.
- moieties with which the alkyl group can be substituted are selected from the group consisting of halogen (fluoro, chloro, bromo or iodo), hydroxyl, carbonyl, sulfany!, amino, alkyiamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art.
- the carboxylic acid on the side chain of a glutamate amino acid may be modified into an ethyl ester.
- the C-terminus carboxylic acid of a tyrosine amino acid maybe modified into an alkyl ester.
- the C-terminus carboxylic acid of a tyrosine amino acid may be modified into an ethyl ester.
- the term ''pharmaceutically acceptable salt refers to any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Pharmaceutically acceptable salts further include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraaikylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids.
- the at least one carrier may have a high surface area.
- the term“high surface area”, as used herein, means that the carrier has a surface area of at least about 20 m 2 /g of carrier, at least about 30 m 2 /g, at least about 40 m 2 /g, at least about 50 m 2 /g, at least about 60 m 2 /g, at least about 70 m 2 /g, at least about 80 m 2 /g, at least about 90 m 2 /g, at least about 100 m 2 /g, at least about 110 m 2 /g, at least about 120 m 2 /g, at least about 130 m 2 /g, at least about 140 m 2 /g, at least about 150 m 2 /g, at least about 160 m 2 /g, at least about 170 m 2 /g, at least about 180 m 2 /g, at least about 190 m 2 /g, at least about 200 m 2 /g, at least about 210 m 2 /g, at least about 220
- the at least one carrier has a surface area of about 20 to about 320 m 2 /g or about 20 to about 350 m 2 /g. In another embodiment, the surface area may be from about 20 to about 700 m 2 /g of carrier. Preferably, the surface area may be about 300 to about 700 m 2 /g or about 320 to about 700 m 2 /g of carrier.
- the surface area of the carrier may be measured using standard procedures. Such standard procedures may include low-temperature nitrogen adsorption, based on the Brunauer, Emmett and Teller (BET) method which is well known in the art.
- the at least one carrier may be selected from one or more of metal oxides, metal silicates, metal phosphates, metal carbonates or zeolites.
- the carrier may be selected from an acetate co-polymer or cellulosic polymer.
- the acetate co-polymer may be a vinylpyrrolidone-vinyl acetate copolymer.
- the cellulosic polymer may be hydroxypropyl cellulose or a methylcellulose ether, for example, hydroxypropyl methylcellulose or carboxymethyl cellulose. It will be appreciated that combinations of acetate copolymers and cellulosic polymers may also be used in some embodiments as described herein.
- molecular sieves may also be used as a carrier.
- the at least one carrier is a porous carrier.
- the at least one carrier is a porous carrier comprising a metal oxide.
- metal oxides include silicon dioxide, titanium dioxide, zinc dioxide, zinc oxide and aluminium oxide.
- the metal oxide is silicon dioxide.
- the at least one carrier is porous silicon dioxide. It will be appreciated that the compositions described herein may contain at least one porous silicon dioxide carrier.
- Suitable commercially available examples of porous silicon dioxide are Syloid® XDP 3050 and Syloid® XDP 3150, characterized by a pore volume of >1.70 ml/g and an average particle size of about 48-66 microns and about 120-170 microns, respectively.
- the aforementioned silicas Syloid® XDP 3050 and Syloid® XDP 3150 have typical surface areas of about 320 m 2 /g.
- the Syloid XDP particles offer a relatively high surface area with many free silanol units to interact and attach to hydrophilic areas of the peptide to achieve stabilization and avoid any aggregation of peptide molecules with each other.
- the Syloid XDP particles provide a highly inner porous structure.
- the relatively small peptide molecules may be absorbed in the inner pore region during the wet granulation process and upon removal of the water the peptides remain in the inner pore structure attached by the polar regions and the silanol units.
- the geometrical and structural conditions of the Syloid particles permit a stabilizing interaction with the polar regions of the peptide as described herein.
- the high surface area and the excess availability of the stabilizing silanol units permit an interaction with the peptide molecules in a way that minimizes the risk of peptide aggregation or multimer formation as the peptide molecules are geometrically separated from each other.
- Other suitable commercially available examples of porous silicon dioxide are Syloid® 244 FP and Syloid AL-1 FP/63FP.
- Syloid® 244 FP has an average particle size of about 3.5 to about 5.5 microns and a surface area of about 300 m 2 /g.
- Syloid AL-1 FP/63FP has an average particle size of about 6.5 to 8.1 microns and a surface area of about 700 m 2 /g.
- average particle size refers to the particle size as measured using a Malvern Mastersizer. It will be appreciated that the term“average particle size” is intended to encompass particles sizes that are +/- 10% from the stated values.
- compositions as described herein may comprise one or more Syloid carriers.
- the composition may comprise one or more of Syloid® 244 FP, Syloid® XDP 3050, Syloid® XDP 3150 or Syloid® AL-1 FP/63FP as carriers.
- the composition may comprise any one or more of Syloid® 244 FP, Syloid® XDP 3050 or Syloid® XDP 3150 in combination with Syloid® AL-1 FP/63FP as carriers.
- the composition may comprise Syloid® 244 FP and Syloid® AL-1 FP/63FP as carriers, or Syloid® XDP 3050 and Syloid® AL-1 FP/63FP as carriers, or Syloid® XDP 3150 and Syloid® AL-1 FP/63FP as carriers. It will be appreciated that any combination of these carriers is intended to be encompassed within the scope of the invention.
- the at least one carrier, or at least one porous silicon dioxide carrier may be provided as a particle.
- the average particle size at least one carrier, or at least one porous silicon dioxide carrier, described herein may be about 2 to about 200 pm, about 2 to about 150 pm, about 4 to about 150 pm, about 5 to about 150 pm, about 10 to about 150 pm, about 25 to about 150 pm or about 50 to about 150 pm in diameter.
- the average particle size may be about 2 to about 195 pm, about 4 to about 195 pm , about 5 to about 195 pm , about 10 to about 195 pm , about 15 to about 190 pm, about 20 to about 185 pm, about 25 to about 180 pm, about 30 to about 175 pm, about 35 to about 170 pm, about 40 to about 170 pm, about 45 to about 170 pm, about 50 to about 170 pm, about 55 to about 170 pm, about 60 to about 170 pm, about 65 to about 170 pm, about 70 to about 170 pm, about 75 to about 170 pm, about 80 to about 170 pm, about 85 to about 170 pm, about 90 to about 170 pm, about 95 to about 170 pm, about 100 to about 170 pm, about 105 to about 170 pm, about 110 to about 170 pm, about 115 to about 170 pm or about 120 to about 170 pm in diameter.
- the average particle size may be about 2 to about 100 pm, about 4 to about 100 pm, about 5 to about 100 pm, about 10 to about
- the average particle size of the at least one carrier, or at least one porous silicon dioxide carrier may be about 3.0 pm to about 6.0 pm, about 3.1 pm to about 5.9 pm, about 3.2 pm to about 5.8 pm, about 3.3 pm to about 5.7 pm, about 3.4 pm to about 5.6 pm, and about 3.5 pm to about 5.5 pm.
- the average particle size of the at least one carrier, or at least one porous silicon dioxide carrier may be about 6.0 pm to about 8.5 pm, about 6.1 pm to about 8.4 pm, about 6.2 pm to about 8.3 pm, about 6.3 pm to about 8.2pm, about 6.4 pm to about 8.2 pm, and about 6.5 pm to about 8.1 pm.
- the average particle size of the at least one carrier, or at least one porous silicon dioxide carrier may be about 40 pm to about 74 pm, about 41 pm to about 73 m, about 42 pm to about 72 pm, about 43 pm to about 71 pm, about 44 pm to about 70 pm, about 45 pm to about 69 pm, about 46 pm to about 68 pm, about 47 pm to about 67 pm, about 46 pm to about 66 pm.
- the average particle size of the at least one carrier, or at least one porous silicon dioxide carrier may be about 110 pm to about 180pm, about 111 pm to about 179 pm, about 112 pm to about 178 pm, about 113 pm to about 177 pm, about 114 pm to about 176 pm, about 115 pm to about 175 pm, about 116 pm to about 174 pm, about 117 pm to about 173 pm, about 118 pm to about 172 pm, about 119 pm to about 171 pm, about 120 pm to about 170 pm.
- the average particle size of the at least one carrier, or at least one porous silicon dioxide carrier may be about 3.5, about 7.5, about 50 or about 150 pm.
- the ratio of the composition of the peptide to the at least one carrier ranges from about 0.1 to about 20 mg, about 0.2 to about 20 mg, about 0.3 to about 20 mg, about 0.4 to about 20 mg, about 0.5 to about 20 mg, about 0.6 to about 20 mg, about 0.7 to about 20 mg, about 0.8 to about 20 mg, about 0.9 to about 20 mg, about 1 to about 20 mg, about 1 to about 15 mg, about 2 to about 18 mg, about 3 to about 17 mg or about 4 to about 12 mg of peptide/g of the at least one carrier, or at least one porous carrier, or at least one porous silicon dioxide carrier.
- the ratio of the composition of the peptide to the at least one carrier ranges from about 0.1 to about 20 mg, about 0.1 to about 15 mg, about 0.1 to about 12 mg, about 0.1 to about 10 mg, about 0.1 to about 9 mg, about 0.1 to about 8 mg, about 0.1 to about 7 mg, about 0.1 to about 6 mg, about 0.1 to about 5 mg, about 0.1 to about 4 mg, about 0.1 to about 3 mg, about 0.1 to about 2 mg, about 0.1 to about 1 mg, about 0.1 to about 0.9 mg, about 0.1 to about 0.8 mg, about 0.1 to about 0.7 mg, about 0.1 to about 0.6 mg, about 0.5 to about 4 mg, about 0.3 to about 4 mg or about 0.1 to about 0.2 mg of peptide/g of the at least one carrier, or at least one porous carrier, or at least one porous silicon dioxide carrier.
- the composition may comprise about 4 mg of peptide, about 8 mg of peptide or about 12 mg of peptide/g of the at least one carrier, or at least one porous carrier, or at least one porous silicon dioxide carrier.
- At least one carrier, or at least one porous silicon dioxide carrier may be present in the pharmaceutical composition in an amount of about 50 to about 3000 mg by weight of the composition.
- the at least one carrier, or at least one porous silicon dioxide carrier may be present in the pharmaceutical composition in an amount of about 100 to about 3000 mg, about 150 to about 3000 mg, about 200 to about 3000 mg, about 250 to about 3000 mg, about 300 to about 3000 mg, about 350 to about 3000 mg, about 400 to about 3000 mg, about 450 to about 3000 mg, about 500 to about 3000 mg, about 550 to about 3000 mg, about 600 to about 3000 mg, about 650 to about 3000 mg, about 700 to about 3000 mg, about 750 to about 3000 mg, about 800 to about 3000 mg, about 850 to about 3000 mg, about 900 to about
- 3000 mg about 950 to about 3000 mg, about 1000 to about 3000 mg, about 1100 to about 3000 mg, about 1300 to about 3000 mg, about 1400 to about 3000 mg, about 1500 to about 3000 mg, about 1600 to about 3000 mg, about 1700 to about 3000 mg, about 1800 to about 3000 mg, about 1900 to about 3000 mg, about 2000 to about 3000 mg, about 2100 to about 3000 mg, about 2200 to about 3000 mg, about 2300 to about 3000 mg, about 2400 to about 3000 mg, about 2500 to about 3000 mg, about 2600 to about 3000 mg, about 2700 to about 3000 mg, about 2800 to about 3000 mg or about 2900 to about 3000 mg by weight of the composition.
- the at least one carrier, or at least one porous silicon dioxide carrier may be present in the pharmaceutical composition in an amount of about 100 to about 2900 mg, about 100 to about 2800 mg, about 100 to about 2700 mg, about 100 to about 2600 mg, about 100 to about 2500 mg, about 100 to about 2400 mg, about 100 to about 2300 mg, about 100 to about 2200 mg, about 100 to about 2100 mg, about 100 to about 2000 mg, about 100 to about 1900 mg, about 100 to about 1800 mg, about 100 to about 1700 mg, about 100 to about 1600 mg, about 100 to about 1500 mg, about 100 to about 1400 mg, about 100 to about 1300 mg, about 100 to about 1200 mg, about 100 to about 1100 mg, about 100 to about 1000 mg, about 100 to about 950 mg, about 100 to about 900 mg, about 100 to about 850 mg, about 100 to about 800 mg, about 100 to about 750 mg, about 100 to about 700 mg, about 100 to about 650 mg, about 100 to about 600 mg, about 100 to about a
- the pharmaceutical composition when in the form of a finished dosage form, may comprise about 10 to about 99.9 percent by weight of the composition of the carrier, or at least one porous silicon dioxide carrier. In some embodiments, the pharmaceutical composition, when in the form of a finished dosage form, may comprise about 10 to about 99.9, 15 to about 99.9, 20 to about 99.9, 30 to about 99.9, 35 to about 99.9, 40 to about 99.9, 45 to about 99.9, 50 to about 99.9, 55 to about 99.9, 60 to about 99.9, 65 to about 99.9, 70 to about 99.9, 75 to about 99.9,
- the pharmaceutical composition when in the form of a finished dosage form may comprise about 10 to about 95, 10 to about 90, 10 to about 85, 10 to about 80, 10 to about 75, 10 to about 70, 10 to about
- the pharmaceutical composition may have a moisture content of about 5% or less, about 4.5% or less, about 4% or less, about 3.5% or less, about 3% or less, about 2.5% or less, about 2% or less, about 1.5% or less, or about 1 % or less, inclusive of all ranges and subranges therebetween (i.e., any of about 1 % to about 5%, about 1.5% to about 5%, about 2% to about 5%, about 2.5% to about 5%, about 3% to about 5%, about 3.5% to about 5%, about 4% to about 5%, about
- compositions or dosage forms as described herein, maintained at low moisture content have been found to be substantially more stable compared to conventional compositions maintained at higher moisture contents, e.g. above about 5% or higher. It will be appreciated that a similar moisture content will also apply to any dosage forms as described herein.
- moisture content also referred to as“water content” means the amount of water that a composition contains.
- the moisture content can be expressed volumetrically (i.e. , by volume) as the ratio of the mass of moisture to the dry volume of the material.
- the moisture content can be expressed gravimetrically (i.e., by weight) as the mass of water removed upon drying per unit dry mass of the specimen. Determination of moisture content can be achieved by any of the conventional methods known in the art. For example, the moisture content can be determined by chemical titration, such as Karl Fischer titration, in which a sample is dissolved in an electrochemical titration cell.
- thermogravimetric methods such as“Loss on Drying” (LoD), in which the mass of a sample is measured prior to, and after controlled drying. The loss of mass after drying is attributed to loss of moisture.
- moisture analyzers e.g., available from Mettler Toledo, Sartorius AG, etc.
- the moisture content of the compositions or dosage forms of the present invention can be measured by any suitable method known in the art, for example LoD.
- accelerated stability testing or“accelerated storage testing” refers to test methods used to simulate the effects of relatively long-term storage conditions on enzyme activity, which can be carried out in a relatively short time. Accelerated stability testing methods are known in the art to be a reliable alternative to real-time stability testing, and can accurately predict the shelf-life of biological products. Such “accelerated stability testing” conditions are known in the art and are in accordance with the International Conference for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use: Stability Testing of New Drug Substances and Products Q1A, herein incorporated by reference in its entirety.
- the pharmaceutical composition as described herein, can be formulated in the substantial absence of other components such as glidants, lubricants, cations or amines and the like that have been previously required to stabilize peptide formulations and compositions.
- the use of at least one carrier having a high surface area results in a more stable formulation of peptides with a concomitant decrease in the formation of multimers compared to previous formulations.
- a pharmaceutical composition described herein does not comprise a stabilizer or other component for stabilizing a peptide formulation and/or composition.
- a stabilizer may be a cation, an amine, or the like.
- Non-limiting examples of stabilizers include Ca 2+ , Mg 2+ , Zn 2+ , polyvinyl pyrrolidone, polyvinyl alcohol, sucrose, cyclodextrin, xanthan, trehalose, sodium chloride, inulin, primary amines (for example, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, citrulline, taurine pyrrolysine, or a conjugate or a mixture thereof), L-histidine and acesulfame.
- primary amines for example, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine
- a pharmaceutical composition described herein may comprise a stabilizer to provide additional stability to the pharmaceutical composition.
- the invention also relates to a pharmaceutical composition consisting of an adsorbate of a peptide as described herein on at least one carrier having a surface area of about 300 m 2 /g.
- the invention also relates to a pharmaceutical composition consisting of an adsorbate of a peptide as described herein on at least one porous carrier having a surface area of about 300 m 2 /g.
- the invention also relates to a pharmaceutical composition consisting of an adsorbate of a peptide as described herein on at least one porous silicon dioxide carrier having a surface area of about 300 m 2 /g.
- the invention also further relates to a pharmaceutical composition consisting of an adsorbate of a peptide as described herein on at least one carrier having a surface area of about 300 m 2 /g to about 700 m 2 /g.
- the invention also relates to a pharmaceutical composition consisting of an adsorbate of a peptide as described herein on at least one porous carrier having a surface area of about 300 m 2 /g to about 700 m 2 /g.
- the invention also relates to a pharmaceutical composition consisting of an adsorbate of a peptide as described herein on at least one porous silicon dioxide carrier having a surface area of about 300 m 2 /g to about 700 m 2 /g.
- Compositions comprising SEQ ID NQ.1
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu-X- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu-X- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein the at least one porous carrier has an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu-X- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier has an average particle size of about 2 to about 200 pm.
- composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-
- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said composition has moisture content of less than about 5%.
- composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-
- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said composition has moisture content of less than about 5%.
- composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-
- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said composition has moisture content of less than about 5%.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 20 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said at least one porous carrier has a surface area of at least about 20 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said at least one porous silicon dioxide carrier has a surface area of at least about 20 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 300 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said at least one porous carrier has a surface area of at least about 300 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said at least one porous silicon dioxide carrier has a surface area of at least about 300 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a having the following amino acid sequence: Cys-Cys- Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said at least one porous carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said at least one porous silicon dioxide carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said at least one porous carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said at least one porous silicon dioxide carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said composition has moisture content of less than about 5%, and the at least one carrier has an average particle size of about 2 to about 200 pm.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous carrier has an average particle size of about 2 to about 200 pm.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous silicon dioxide carrier has an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 300 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein the at least one porous carrier has a surface area of at least about 300 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier has a surface area of at least about 300 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 20 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein the at least one porous carrier has a surface area of at least about 20 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier has a surface area of at least about 20 m 2 /g and an average particle size of about 2 to about 200 pm.
- composition comprising an adsorbate of a peptide peptide having the following amino acid sequence: Cys-Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO:
- X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200 pm.
- composition comprising an adsorbate of a peptide peptide having the following amino acid sequence: Cys-Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO:
- X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein the at least one porous carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide peptide having the following amino acid sequence: Cys-Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200 pm.
- composition comprising an adsorbate of a peptide peptide having the following amino acid sequence: Cys-Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO:
- X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein the at least one porous carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide peptide having the following amino acid sequence: Cys-Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein the at least one porous carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide peptide having the following amino
- X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200 pm.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said composition has moisture content of less than about 5%, and the at least one carrier has an average particle size of about 2 to about 200 pm, and a surface area of at least about 20 m 2 /g.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous carrier has an average particle size of about 2 to about 200 pm, and a surface area of at least about 20 m 2 /g.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous silicon dioxide carrier has an average particle size of about 2 to about 200 pm, and a surface area of at least about 20 m 2 /g.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said composition has moisture content of less than about 5%, and the at least one carrier has an average particle size of about 2 to about 200 pm, and a surface area of at least about 300 m 2 /g.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous carrier has an average particle size of about 2 to about 200 pm, and a surface area of at least about 300 m 2 /g.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous silicon dioxide carrier has an average particle size of about 2 to about 200 pm, and a surface area of at least about 300 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier selected from Syloid® XDP 3050, Syloid® XDP 3150, Syloid® 244 FP, Syloid AL-1 FP/63FP or any combination thereof.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier selected from Syloid® XDP 3050, Syloid® XDP 3150, Syloid® 244 FP, Syloid AL-1 FP/63FP or any combination thereof, wherein the at least one porous silicon dioxide carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier selected from Syloid® XDP 3050, Syloid® XDP 3150, Syloid® 244 FP, Syloid AL-1 FP/63FP or any combination thereof.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier selected from Syloid® XDP 3050, Syloid® XDP 3150, Syloid® 244 FP, Syloid AL-1 FP/63FP or any combination thereof, wherein the at least one porous silicon dioxide carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200 pm.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier is Syloid® XDP 3150.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-X-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier is Syloid® XDP 3150, wherein said composition has moisture content of less than about 5%.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu-X- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carrier selected from an acetate co-polymer carrier, a cellulosic polymer carrier or a combination thereof.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu-X- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one vinylpyrrolidone- vinyl acetate copolymer carrier.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu-X- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one hydroxypropyl cellulose carrier.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu-X- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one methylcellulose carrier.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu-X- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one hydroxypropyl methylcellulose carrier.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu-X- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one carboxymethyl cellulose carrier.
- compositions comprising SEQ ID Nos.2, 3 and 4
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys-Glu-Phe- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu-Tyr-Cys- Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp-Cys-Cys- Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys-Glu-Phe- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu-Tyr-Cys- Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp-Cys-Cys- Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein the at least one porous carrier has an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu-X- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.1 ), wherein X is any amino acid, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier has an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said composition has moisture content of less than about 5%.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said composition has moisture content of less than about 5%.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said composition has moisture content of less than about 5%.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 20 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said at least one porous carrier has a surface area of at least about 20 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said at least one porous silicon dioxide carrier has a surface area of at least about 20 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 300 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said at least one porous carrier has a surface area of at least about 300 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said at least one porous silicon dioxide carrier has a surface area of at least about 300 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said at least one porous carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said at least one porous silicon dioxide carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said at least one porous carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said at least one porous silicon dioxide carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said composition has moisture content of less than about 5%, and the at least one carrier has an average particle size of about 2 to about 200 pm.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous carrier has an average particle size of about 2 to about 200 pm.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous silicon dioxide carrier has an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 300 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein the at least one porous carrier has a surface area of at least about 300 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier has a surface area of at least about 300 m 2 /g and an average particle size of about 2 to about 200 pm
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 20 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein the at least one porous carrier has a surface area of at least about 20 m 2 /g and an average particle size of about 2 to about 200 pm.
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier has a surface area of at least about 20 m 2 /g and an average particle size of about 2 to about 200 pm
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein the at least one porous carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g and an average particle size of about
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier has a surface area of at least about 300 m 2 /g to about 700 m 2 /g and an average
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g and an average particle size of about 2 to about 200
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein the at least one porous carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g and an average particle size of about
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier has a surface area of at least about 20 m 2 /g to about 700 m 2 /g and an average
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said composition has moisture content of less than about 5%, and the at least one carrier has an average particle size of about 2 to about 200 pm, and a surface area of at least about 20 .
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous carrier has an average particle size of about 2 to about 200 pm, and a surface area of at
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous silicon dioxide carrier has an average particle size of about 2 to about 200 pm, and a
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said composition has moisture content of less than about 5%, and the at least one carrier has an average particle size of about 2 to about 200 pm, and a surface area of at least about 300 .
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous carrier has an average particle size of about 2 to about 200 pm, and a surface area of at
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein said composition has moisture content of less than about 5%, and the at least one porous silicon dioxide carrier has an average particle size of about 2 to about 200 pm, and a
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier selected from Syloid® XDP 3050, Syloid® XDP 3150, Syloid® 244 FP, Syloid AL-1 FP/63FP or any combination
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier selected from Syloid® XDP 3050, Syloid® XDP 3150, Syloid® 244 FP, Syloid AL-1 FP/63FP or any combination
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 20 m 2
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein said at least one carrier has a surface area of at least about 300 m 2
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 20 m 2
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one carrier, wherein the at least one carrier has a surface area of at least about 300 m 2
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier selected from Syloid® XDP 3050, Syloid® XDP 3
- a pharmaceutical composition comprising an adsorbate of a peptide comprising a sequence selected from: Cys-Cys- Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu- Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), wherein at least one carboxyl group of the peptide is an alkyl ester, or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier selected from Syloid® XDP 3050, Syloid® XDP 3
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys- Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys- Glu-Trp-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier is Syloid® XDP 3150.
- the pharmaceutical composition as described herein may comprise an adsorbate of a peptide having the following amino acid sequence: Cys- Cys-Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys- Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys- Glu-Trp-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one porous silicon dioxide carrier, wherein the at least one porous silicon dioxide carrier is Syloid® XDP 3150, wherein said composition has moisture content of less than about 5%.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu- Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu-Tyr- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp-Cys- Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carrier selected from an acetate co-polymer carrier, a cellulosic polymer carrier or a combination thereof.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu- Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu-Tyr- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp-Cys- Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one vinylpyrrolidone-vinyl acetate copolymer carrier.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu- Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu-Tyr- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp-Cys- Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one hydroxypropyl cellulose carrier.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu- Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu-Tyr- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp-Cys- Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one methylcellulose carrier.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu- Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu-Tyr- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp-Cys- Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one hydroxypropyl methylcellulose carrier.
- a pharmaceutical composition comprising an adsorbate of a peptide having the following amino acid sequence: Cys-Cys-Glu- Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 2) or Cys-Cys-Glu-Tyr- Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 3) or Cys-Cys-Glu-Trp-Cys- Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr (SEQ ID NO.: 4), or a pharmaceutically acceptable salt thereof, on at least one carboxymethyl cellulose carrier.
- the pharmaceutical composition in accordance with the present invention is in the form of a free-flowing powder, with excellent handling properties.
- the adsorbate is very suitable to be used for the preparation of dosage forms.
- Dosage forms contemplated in the present disclosure include a tablet, a powder filled capsule or a powder filled sachet.
- Dosage form as used herein may refer to physically discrete units suited as unitary dosages for the individual to be treated; each unit containing a predetermined quantity of the composition, as described herein, is calculated to produce the desired therapeutic effect.
- the composition may be formulated for convenient and effective administration in effective amounts in an acceptable dosage unit.
- compositions containing supplementary active ingredients are determined by reference to the usual dose and manner of administration of the said ingredients.
- the pharmaceutical composition or dosage forms as described herein may be administered orally.
- the free-flowing powder may be enclosed in a hard or soft-shell gelatin capsule, tablets, or incorporated directly into an individual's diet.
- the dosage form comprising the pharmaceutical composition as described herein may be used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like
- a pharmaceutical composition is a dosage form formulated as enterically coated granules, tablets or capsules suitable for oral administration. Also included in the scope of this invention are delayed release formulations. Suitable pharmaceutical compositions in accordance with the invention will generally include an amount of the active compound(s) with an acceptable pharmaceutical diluent or excipient, such as a sterile aqueous solution, to give a range of final concentrations, depending on the intended use.
- an acceptable pharmaceutical diluent or excipient such as a sterile aqueous solution
- the techniques of preparation are generally well known in the art, as exemplified by Remington's Pharmaceutical Sciences (18th Edition, Mack Publishing Company, 1995).
- the composition may comprise capsules/tablets/sachets that comprise about 20-600 meg of Linaclotide to be taken orally once daily on an empty stomach.
- the Linaclotide composition comprises capsules/tablets/sachets that comprise at least about 20, about 25, about 30, about 35, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 100, about 145 or about 290 meg which are to be taken orally once daily on an empty stomach for treating IBS-C (IBS with constipation).
- the Linaclotide composition comprises capsules/tablets/sachets that comprise at least about 20, about 25, about 30, about 35, about 45, about 50, about 55, about 60, about 65, about 70, about 72, about 75, about 80, about 85, about 90, about 100, about 145 or about 290 meg which are to be taken orally once daily on an empty stomach for treating chronic idiopathic constipation.
- the Linaclotide composition comprises capsules/tablets/sachets that comprise at least about 30 meg to 1500 meg of Linaclotide, or 10mg to 500mg of Linaclotide.
- the Linaclotide composition may include additional ingredients or excipients.
- one or more therapeutic agents of the dosage unit may exist in an extended or control release formulation and additional therapeutic agents may not exist in extended release formulation.
- a peptide described herein may exist in a controlled release formulation or extended release formulation in the same dosage unit with another agent that may or may not be in either a controlled release or extended release formulation.
- the aqueous solution of the peptide is acidic with a pH in the range of about 1 to about 3, about 1 to about 2.9, about 1 to about 2.8, about 1 to about 2.7, about 1 to about 2.6, about 1 to about 2.5, about 1 to about 2.4, about 1 to about 2.3, about 1 to about 2.2.
- the pH may be in the range of about 1.1 to about 3, about 1.2 to about 3, about 1.3 to about 3, about 1.4 to about 3, about
- the combining step (step B) may comprise spraying or rinsing the aqueous solution of peptide onto a carrier powder.
- the drying step (step C) may be performed in a vacuum dryer, spray drier or a fluidized bed dryer. Examples of equipment that can be used are fluid bed, high shear mixed and spray drying.
- the dried powder may be further milled or granulated.
- the dried powder or granulated powder may be encapsulated in HPMC or gelatin or hard gelatin capsules.
- the carrier is a porous carrier.
- the porous carrier is porous silicon dioxide. It will be appreciated that the methods and equipment to carry out the process to form the adsorbate are well known in the art.
- composition may be formed by an extrusion process, for example by twin screw extrusion.
- compositions as described herein in the manufacture of a medicament for treating a gastrointestinal disorder in a patient in need thereof.
- a method of treating a gastrointestinal disorder comprising administering the composition, as described herein, or a dosage form, as described herein, to a patient in need thereof.
- a patient diagnosed with a gastrointestinal disorder may be provided with the composition described herein, wherein the gastrointestinal disorder may be selected from the group consisting of irritable bowel syndrome (IBS) (such as constipation-predominant IBS), constipation (such as chronic idiopathic constipation), a functional gastrointestinal disorder, gastroesophageal reflux disease, functional heartburn, dyspepsia, visceral pain, gastroparesis, chronic intestinal pseudo- obstruction, colonic pseudo-obstruction, Crohn's disease, ulcerative colitis, and inflammatory bowel disease, chronic constipation or irritable bowel syndrome (IBS).
- IBS irritable bowel syndrome
- the gastrointestinal disorder may be constipation.
- the constipation may be chronic idiopathic constipation, idiopathic constipation, due to post-operative ileus, or caused by opiate use.
- Clinically accepted criteria that define constipation include the frequency of bowel movements, the consistency of feces and the ease of bowel movement.
- Constipation may be idiopathic (functional constipation or slow transit constipation) or secondary to other causes including neurologic, metabolic or endocrine disorders.
- Constipation may also be the result of surgery (postoperative ileus) or due to the use of drugs such as analgesics (like opioids), antihypertensives, anticonvulsants, antidepressants, antispasmodics and antipsychotics.
- the gastrointestinal disorder may be irritable bowel syndrome (IBS).
- the irritable bowel syndrome can be constipation-predominant irritable bowel syndrome (IBS-C), diarrhea-predominant irritable bowel syndrome (IBS-D) or alternating between the two irritable bowel syndromes (IBS-A).
- the gastrointestinal disorder may be dyspepsia.
- the gastrointestinal disorder may be gastroparesis.
- the gastroparesis may be selected from idiopathic, diabetic or post-surgical gastroparesis.
- the gastrointestinal disorder may be chronic intestinal pseudo obstruction.
- the gastrointestinal disorder may be Crohn's disease.
- the gastrointestinal disorder may be ulcerative colitis.
- the gastrointestinal disorder may be selected from IBS or chronic constipation. More preferably, the IBS is IBS-C (IBS with predominant constipation).
- IBS IBS-C
- the use of a composition as described herein in the manufacture of a medicament for treating IBS-C (IBS with predominant constipation) or chronic constipation comprising administering the composition, as described herein, or a dosage form, as described herein, to a patient in need thereof.
- composition as described may further comprise one or more supplementary active ingredients or medicaments useful for the treatment of gastrointestinal disorders.
- composition as described herein may be administered in combination with a supplementary active ingredient or medicament, either separately, sequentially or simultaneously.
- the supplementary active ingredient or medicament may be a probiotic or a prebiotic or a mixture thereof.
- probiotic refers to live bacteria (also referred to as microflora or microorganisms) that confer a beneficial effect when introduced into the gastrointestinal tract of a mammal.
- prebiotic refers to any substance that may be consumed by a relevant probiotic, or that otherwise assists in keeping the relevant probiotic alive or stimulates its growth, and may include mucopolysaccharides, oligosaccharides, polysaccharides, amino acids, vitamins, nutrient precursors and proteins.
- gastrointestinal tract refers to the tract from the mouth to the anus and includes the stomach and intestines (including the ileum, duodenum, jejunum, caecum, crassum (large intestine), rectum, and ska (small intestine, which includes the intestinum *** mesenteriale). Accordingly, in one aspect, there is provided use of a composition as described herein in the manufacture of a medicament for treating a gastrointestinal disorder in a patient in need thereof, wherein the composition further comprises a probiotic, a prebiotic or a mixture thereof.
- a method of treating a gastrointestinal disorder comprising administering the composition as described herein or a dosage form as described herein, to a patient in need thereof, wherein the composition or dosage form further comprises a probiotic, a prebiotic or a mixture thereof.
- the probiotic may comprise lactic acid bacteria, including Lactobacilli (abbreviated to “L” herein), Bifidobacteria (abbreviated to“B.” herein), and Streptococci (abbreviated to“S.” herein); anaerobic bacteria; or aerobic bacteria or mixtures thereof.
- Lactobacilli abbreviated to “L” herein
- Bifidobacteria abbreviated to“B.” herein
- Streptococci abbreviated to“S.” herein
- anaerobic bacteria or aerobic bacteria or mixtures thereof.
- Non- limiting examples of probiotics include, but are not limited to, one or more of L acidophilus, L reuteri, L curvatus, L bulgaricus, L grasseri, L casei, L ferment um, L caveasicus, L helveticus, L lactis, L salivarius, L rhamnosus, L brevis, L leichmanni, L plantarum, L cellobiosus, L buchneri, B. laterosporus, B. breve, B.
- subtilus L sporogenes (also known as Bacillus coagulans), pediococcus acidilactici, pediococcus pentosaceus, enterococcus faecium, B. adolescentis, B. infantis, B. longum, B. thermophilum, B. animalis, and B. bifidum and S thermphilius.
- Other probiotics include Lactococcus lactis cremoris, S. diacetylactis and S. intermedius.
- the prebiotic may comprise one or more of the following (a) a mucopolysaccharide or glycosaminoglycan, e.g.
- hyaluronic acid agar, carrageenan or chitin or the like
- an oligosaccharide a fructo-oligosaccharide (“FOS”), such as a soy fructo-oligosaccharide, inulin or banana fiber
- FOS fructo-oligosaccharide
- pectin or pectic polysaccharide a mannan, such as guar gum, locust bean gum, konjac, orxanthan gum
- the prebiotic may be selected to be complementary to the probiotic (for example, a complimentary prebiotic is consumed by, or otherwise assists in keeping alive or stimulates the growth of, a relevant probiotic).
- a complimentary prebiotic is consumed by, or otherwise assists in keeping alive or stimulates the growth of, a relevant probiotic.
- the term "about”, in the context of concentrations of components of the formulations typically means +/- 5% of the stated value, more typically +/- 4% of the stated value, more typically +/- 3% of the stated value, more typically, +/- 2% of the stated value, even more typically +/- 1 % of the stated value, and even more typically +/- 0.5% of the stated value.
- certain embodiments may be disclosed in a range format.
- range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
- Linaclotide carrier compositions were prepared at 4, 8 and 12 mg/g of carrier.
- Linaclotide carrier compositions were prepared using a Diosna laboratory mixer. Briefly, 1 kg Syloid (either Syloid® XDP 3150 or Syloid® FP 244 or Syloid® XDP 3050) was weighted in a steel box and transferred into the 10 L container of the Diosna mixer. Linaclotide was then added to a hydrochloric acid (HCI) solution at a pH of from 1.7-2.2 to form an acidic Linaclotide solution. 1 kg of Linaclotide solution was sprayed on the Syloid® for approximately 6 minutes. The mixture was then stirred for a further 5 minutes to form a wet granulate. The resulting wet granulate was then dried using a vacuum dryer.
- HCI hydrochloric acid
- Dried Linaclotide carrier composition granules were then encapsulated into hard gelatin (HG) capsules under controlled humidity conditions below 40%, or formed into tablets, using techniques well known to those in the art and packed in HDPE (high-density polyethylene) bottles under nitrogen either with or without a desiccant, for example MiniPax®.
- HG hard gelatin
- HDPE high-density polyethylene
- Tables 1 to 5 show the specific compositions of the granulate Linaclotide carrier composition produced in accordance with the invention as described herein.
- Table 1 shows the composition of Linaclotide formulated as an absorbate on Syloid®3150.
- Table 2 shows the composition of Linaclotide formulated as an absorbate on Syloid®3150 and including Syloid®AL as an additional Syloid.
- Table 3 shows the composition of Linaclotide formulated as an absorbate on Syloid®244.
- Table 4 shows the composition of Linaclotide formulated as an absorbate on Syloid®XDP3050.
- Table 2 Linaclotide formulated as an absorbate on Syloid®3150 and including Syloid®AL.
- Table 4 Linaclotide formulated as an absorbate on Syloid®3050.
- Linaclotide aggregate and multimer formation in the compositions and formulations as described herein and a commercially available preparation of Linaclotide were determined.
- the pellets of 10 capsules from each of the formulations prepared as described in Example 1 and those of the commercially available formulation were pooled and homogenized.
- the pellets in the pellet pool were placed into a glass beaker and weighed. A solvent was then added to the beaker to achieve a target concentration of 250pg Linaclotide per ml. The pellets were then stirred for 15 minutes until a suspension was obtained. The suspension was then centrifuged for 3 min at 21380 ref (15000 rpm) until a clear supernatant was obtained. The clear supernatant was subsequently decanted and used for further analysis. Size exclusion chromatography (SEC) was used to analyze Linaclotide multimers. Briefly, the sample supernatant was added to a 100 A SEC column.
- SEC Size exclusion chromatography
- Linaclotide multimers were then isocratically eluted using 0.017 M Na2HP04 as the eluent. The elution was monitored by UV absorption at a wavelength of 220 nm. Evaluation was performed using data collected from the peaks of the chromatogram obtained and then analyzing these using the area% method which is well known in the art.
- A Linaclotide 290 pg HG Capsules in HDPE bottle with 2 g desiccant in lid of HDPE container.
- B Linaclotide 290 pg HG Capsules in HDPE bottle with 3 x 2g desiccant.
- D Linaclotide 290 pg HG tablets in HDPE bottle in twist-off glass without desiccant.
- the commercially available Linaclotide formulation comprises 290 pg Linaclotide in hard gelatin capsules.
- the capsules also generally contain microcrystalline cellulose, hypromellose, calcium chloride dihydrate and leucine.
- the capsule shell comprises red iron oxide, titanium dioxide, yellow iron oxide and gelatin.
- the commercially available Linaclotide formulation is packed in a white HDPE bottle with a tamper evident seal and a child resistant screw cap, together with one or more desiccant canisters containing silica gel. Calcium chloride dihydrate and leucine are present as additional stabilizers which are not present in the Linaclotide formulations according to the present invention as prepared in Example 1.
- the level of multimer formation is shown in the bottom row of Table 5 as Area% (multimers).
- the commercially available Linaclotide formulation is shown in Batch E.
- the level of multimers in the commercially available formulation is shown to be from 1.6% to 1.8% over 4 weeks.
- the composition in accordance with the present invention is shown in batches A-D.
- Batches A and B show the multimer content for the composition in HG capsules to be from 1.1 % to 1.2% in Batch A and from 0.9% to 1.0% in Batch B.
- the compositions in the form of tablets shown in batches C and D had higher concentrations of multimers than the commercially available Linaclotide formulation.
- Linaclotide carrier composition using a different Syloid was also tested (see Table 6 below). This composition was tested in the absence of a desiccant. As was to be expected, the multimer formation (see Area% (Multimers) in last row of Table 6) was slightly higher than that of the Syloid formulations tested with a desiccant. However, the level of multimer in this Linaclotide composition (1.7% to 1.8%) is still comparable to the commercially available Linaclotide formulation (1.6 to
- F Linaclotide 290 pg HG capsules HDPE bottle in twist-off glass without desiccant.
- Example 3 Determination of Moisture Content in Linaclotide Carrier Compositions and Formulations
- the moisture content in the Linaclotide carrier compositions and formulations as described herein was determined using the Karl-Fischer Oven-Method with coulometric detection.
- the compositions were prepared as previously described in Example 1.
- the determination of the moisture content of the Linaclotide carrier composition as described herein was performed on samples ranging from 10-350 mg.
- Samples of the composition or pellets were added to sample vials.
- the sample vials were then placed into a Karl Fischer autosampler.
- the samples were then automatically transferred to an oven on the sampler. Water located in the vial and within the sample was heated in the oven at a defined temperature and the water vapour transferred to a measuring cell using nitrogen gas.
- the mass of the transferred water vapor was determined coulometrically in the measuring cell that had been preconditioned with the Karl Fischer reagent and methanol.
- the measurement was automatically carried out with a Stopdrift (pg water/m in) and the moisture content of the sample in % (w/w) was then calculated.
- A Linaclotide 290 pg HG Capsules in HDPE bottle with 2 g desiccant in lid of HDPE container.
- B Linaclotide 290 pg HG Capsules in HDPE bottle with 3 x 2g desiccant.
- D Linaclotide 290 pg HG tablets in HDPE bottle in twist-off glass without desiccant.
- the commercially available Linaclotide formulation comprises 290 pg Linaclotide in hard gelatin capsules.
- the capsules also generally contain microcrystalline cellulose, hypromellose, calcium chloride dihydrate and leucine.
- the capsule shell comprises red iron oxide, titanium dioxide, yellow iron oxide and gelatin.
- the commercially available Linaclotide formulation is packed in a white HDPE bottle with a tamper evident seal and a child resistant screw cap, together with one or more desiccant canisters containing silica gel. Calcium chloride dihydrate and leucine are present as additional stabilizers which are not present in the Linaclotide formulations according to the present invention as prepared in Example 1. The percentage of moisture content is shown in the last row of Table 7, above.
- the commercially available Linaclotide formulation is shown in Batch E.
- the moisture content in the commercially available formulation is shown to be 2.7% over a four- week period of testing.
- the composition in accordance with the present invention is shown in batches A-D.
- Batches A and B show the moisture content for the composition in HG capsules to be from 3.1 % to 2.7% in Batch A and from 1.9% to 2.6% in Batch B.
- This demonstrates that the Linaclotide carrier compositions of the present invention have a comparable level of moisture content, and in some cases a lower degradation product content, to that found in the commercially available formulation over the same period of testing, in the absence of additional stabilizers.
- the compositions in the form of tablets shown in batches C and D.
- Batch C also demonstrates a comparable level of moisture content to the commercially available Linaclotide formulation over the same period of testing.
- Example 4 Determination of Impurity/Degradation Product Content by RP- HPLC-UV in Linaclotide Carrier Compositions and Formulations
- the content of Linaclotide and any impurities in the Linaclotide carrier compositions and formulations was determined by RP-HPLC-UV.
- the level of impurities and degradation products, distinct from multimer content, in the Linaclotide carrier compositions and a commercially available Linaclotide formulation was analyzed.
- the compositions for testing were prepared as described in Example 1.
- Linaclotide was eluted by applying distinct organic solvent concentrations. A gradient with an increasing amount of acetonitrile was used for the separation on a C18 column. The protein elution was monitored by UV absorption at a wavelength of 227 nm. Quantitation was carried out using external standard method. Single point calibration was performed using the mean of 4 injections.
- TFA 0,5 ml TFA was added to 800 ml acetonitrile in a volumetric flask and filled up to 1000 ml.
- Linaclotide test solution was prepared by dissolving Linaclotide (content of reference substance was taken into account) in an ice-cold solvent to a final concentration of 100 pg/mL (e.g. weigh approx. 2.5 mg Linaclotide into a 25 ml volumetric flask and filled up to the required volume with solvent).
- Linaclotide carrier formulations were weighed into a beaker, after addition of ice-cold solvent to a target concentration of 100 pg Linaclotide per mL the samples were extracted on a magnetic stirrer for 15 minutes. The obtained suspension was centrifuged at 22 °C for 3 min at 21380 ref using 2ml Eppendorf Tubes (PP, disposal). The clear supernatant was used for analysis.
- the pellets of not less than five capsules were pooled and homogenized.
- Drug product pellets out of the pellet pool were weighed into a beaker, after addition of ice cold solvent to a target concentration of 100 pg Linaclotide per mL the samples were extracted on a magnetic stirrer for 15 minutes. The obtained suspension was centrifuged at 22 °C for 3 min at 21380 ref using 2ml Eppendorf Tubes (PP, disposal). The clear supernatant was used for subsequent analysis.
- A Linaclotide 290 pg HG Capsules in HDPE bottle with 2 g desiccant in lid of HDPE container.
- B Linaclotide 290 pg HG Capsules in HDPE bottle with 3 x 2g desiccant.
- D Linaclotide 290 pg HG tablets in HDPE bottle in twist-off glass without desiccant.
- the commercially available Linaclotide formulation comprises 290 pg Linaclotide in hard gelatin capsules.
- the capsules also generally contain microcrystalline cellulose, hypromellose, calcium chloride dihydrate and leucine.
- the capsule shell comprises red iron oxide, titanium dioxide, yellow iron oxide and gelatin.
- the commercially available Linaclotide formulation is packed in a white HDPE bottle with a tamper evident seal and a child resistant screw cap, together with one or more desiccant canisters containing silica gel. Calcium chloride dihydrate and leucine are present as additional stabilizers which are not present in the Linaclotide formulations according to the present invention as prepared in Example 1.
- the level of impurities and degradation products is shown in the bottom row of Table 8 as Sum of Degradation Products (distinct from multimers) Area%.
- the commercially available Linaclotide formulation is shown in Batch E.
- the level of impurities and degradation products in the commercially available formulation is shown to be from 2.2% to 3.1 % over 4 weeks.
- the composition in accordance with the present invention is shown in batches A-D.
- Batches A and B show the level of impurities and degradation products for the composition in HG capsules to be from 0.8% to 2.0% in Batch A and from 0.9% to 1.5% in Batch B.
- This clearly demonstrates that the compositions provided by the present invention have a significantly lower multimer content than the commercially available Linaclotide formulation over the same period of testing.
- the compositions in the form of tablets shown in batches C and D had higher concentrations of multimers than the commercially available Linaclotide formulation over the same period of testing.
- Example 5 Dissolution of Linaclotide Carrier Formulations
- the dissolution of Linaclotide was performed according to FDA recommendations.
- the dissolution testing of the HG capsules comprising granules of the Linaclotide carrier composition in accordance with the present invention were tested according to the USP (United States Pharmacopeia) basket method.
- Linaclotide carrier dosage form as prepared in accordance with Example 1 was added to a dissolution medium comprising 50mM phosphate buffer at pH 4.5. The solution was then stirred at 50 rpm and samples were taken at 5, 10, 15 and 20 minute time intervals.
- the dosage forms were stored at 40°C at 75% relative humidity for 0 and 4 weeks prior to the dissolution testing.
- Sample analysis was performed using high pressure liquid chromatograph (HPLC). Linaclotide was eluted by applying distinct organic solvent concentrations. A gradient with an increasing amount of acetonitrile was used for the elution on a C18 column. The protein elution was monitored by UV absorption at a wavelength of 208 nm. Quantitation was carried out using an external standard method. Four-point calibration was performed.
- the relatively high surface area Linaclotide carrier compositions provided by the present invention were compared to a relatively low surface area Suglet carrier.
- Table 9 shows a comparison of surface area between Group 1 comprising Linaclotide on Suglets, a relatively low surface area carrier, and Group 2, the Linaclotide-Syloid carrier compositions in accordance with the present invention, which provide a relatively higher surface area.
- the Suglets used in this example have a particle size of from about 500-600 microns.
- the surface area of Suglets 500/600 is generally in the region of 0.015 m 2 /g to 0.010 m 2 /g, which is substantially lower than the surface area of the syloids used in this example.
- the Linaclotide-Syloid carrier compositions as provided by the present invention, provide clear advantages with respect to impurities and degradation product levels and multimer formation compared to the use of lower surface area carriers such as Suglets.
- Linaclotide-Syloid compositions The stability of Linaclotide-Syloid compositions was investigated. Dried granules comprising the Linaclotide-Syloid composition as described herein were prepared as previously described in Example 1 and subsequently tested after 6 months of storage.
- Table 10 shows the results of stability testing over 6 months using three batches of dried granules comprising the Linaclotide compositions in accordance with the present invention. An assessment between the two groups was made on the basis of the following parameters: 1 ) multimer content, 2) impurity and degradation product levels. These two parameters were tested and analysed as described previously in examples 2 and 4 above.
- Example 8 Comparison of Linaclotide carrier compositions comprising Syloid® XDP 3150 or Syloid® XDP 3050
- Table 11 shows the results of a comparison between two Syloid formulations. Linaclotide was adsorbed on either Syloid® XDP 3150 or Syloid® XDP 3050 and either prepared as dried granules or encapsulated in HG capsules. The comparison between the formulations was made using the following parameters: 1 ) multimer content, 2) impurity and degradation product levels. These two parameters were tested and analysed as described previously in examples 2 and 4 above.
- Batch 1 comprising Linaclotide adsorbed on Syloid® XDP 3050 and Batch 2, comprising Linaclotide adsorbed on Syloid® XDP 3150 demonstrate comparable levels of multimer formation at 1 month (1.4% vs. 1.9%). These batches also show comparable levels of impurities and degradation products (2.2% vs. 1.7%) over the same period of testing.
- Linaclotide carrier compositions encapsulated in HG capsule and stored in HDPE bottles under nitrogen with and without desiccant was performed.
- the encapsulated compositions were compared against dried granules. The results are presented in Table 12 below.
- Table 12 shows the results of a comparison of Linaclotide carrier compositions.
- Batch 4 represents an encapsulated Linaclotide carrier composition in HG capsules stored in HDPE bottles under nitrogen with a desiccant.
- Batch 5 represents an encapsulated Linaclotide carrier composition in HG capsules stored in HDPE bottles under nitrogen without a desiccant.
- Batches 1 -3 are dried granules comprising an equivalent Linaclotide carrier composition.
- the encapsulated Linaclotide carrier compositions demonstrate comparable levels of degradation products, multimer formation and moisture content.
- Batch 4 and Batch 5 do not differ significantly in multimer content (1.2% vs. 1.6%), degradation products (0.9% vs. 1.0%) or moisture content (3.7% vs. 4.6%) over a 7 day period, showing that the encapsulated compositions either with or without desiccant are comparable.
- batches 4 and 5 demonstrate comparable, and in some cases, lower degradation product levels than the dried granule preparations (0.9% and 1.0%, for batches 3 and 4, vs 1.8%, 1.3% and 0.8% for batches 1 to 3).
- Linaclotide carrier compositions are stable even when encapsulated in the absence of a desiccant. This is advantageous, as such compositions in accordance with the present invention may be used in sachets or the like.
- a Linaclotide combination comprising Syloid® AL-1 FP and Syloid® XDP 3150 was also prepared, as described previously in Example 1 , and subsequently analysed. The results can be seen in Table 13.
- Table 13 shows a comparison of Linaclotide compositions containing either Syloid® XDP 3150 (batches 1 , 2 and 3) or a combination of Syloid® XDP 3150 and Syloid® AL-1 FP (batch 4 and 5), in a composition in accordance with the present invention.
- Batches 6 and 7 show a comparison of a Linaclotide composition containing a combination of Syloid® XDP 3150 and Syloid® AL-1 FP encapsulated in HG Capsules and packaged in HDPE bottles without desiccant under nitrogen as previously described in Example 1.
- Batch 6 and 7 comprise 5% or 67% of Syloid® AL-1 FP, respectively.
- the results from batch 6 and 7 suggest that a lower content (5%) of Syloid® AL-1 FP is preferable, with respect to degradation products (0.6% vs. 3.0%) and multimer formation (0.5% vs. 0.7%).
- the presence of a combination of Syloid® AL-1 FP 5% and Syloid® XDP 3150 as in batches 4 and 5 has no significant effect on the degradation product level or multimer formation, when compared to compositions comprising a single Syloid carrier (batches 1 , 2 or 3), with all batches 1 to 5 having comparable levels of degradation products and multimer content.
- Batch 4 has a degradation product level and multimer content of 0.7% and 0.6%, respectively.
- Batch 5 has a degradation product level and multimer content of 0.5% and 0.6%, respectively.
- Batch 1 has a degradation product level and multimer content of 0.5% and 0.6%, respectively.
- Batch 2 has a degradation product level and multimer content of 0.2% and 0.3%, respectively.
- Batch 3 has a degradation product level and multimer content of 0.2% and 0.4%, respectively.
- Linaclotide carrier compositions were prepared at 4, 8 and 12 mg/g of carrier.
- a Linaclotide stock solution was prepared by adding 0.5g linaclotide into a 500mL Schott flask and 200g of HCI solution (pH 1.7) was then added. The solution was stirred using a magnetic stirrer for 30 minutes until the linaclotide had dissolved and the solution was clear.
- Linaclotide stock solution was sprayed onto the Kollidon VA 64 for about 60 seconds using a 0.4 mm spray nozzle. The mixture was stirred (mixer 500 rpm, chopper 750 rpm) for approximately five minutes. The resulting slight reddish liquid material was transferred to a metal dish. All three batches (813392, 813393 and 813395) were dried in a vaccum dryer at 40°C and 10 mbar pressure overnight. All three batches were removed from their respective dishes and subsequently milled for 5 minutes in a plastic mortar. A 5g sample of each batch was taken for a LOD measurement - the remaining material was filled into a 125 ml twist-off glassflask for subsequent analytical testing.
- Table 14 shows the specific compositions of the alternative granulate Linaclotide carrier composition produced in accordance with the invention as described herein. Table 14 shows the composition of Linaclotide formulated on HPC-SSL, CompactCel P204 and Kollidon VA 64.
- a Linaclotide stock solution was prepared by adding 0.220g linaclotide into a Schott flask and 24g of HCI solution (pH 1.7) was then added. The solution was stirred using a magnetic stirrer for 30 minutes until the linaclotide had dissolved and the solution was clear.
- a Linaclotide stock solution was prepared by adding 0.220g Linaclotide into a Schott flask and 20g of HCI solution (pH 1.7) was then added. The solution was stirred using a magnetic stirrer for 30 minutes until the Linaclotide had dissolved and the solution was clear. Preparation of Batch 813479
- Copovidon VA 64 25 g Copovidon VA 64 was weighed into the 250 mL bin of a Mini-Diosna mixer. 5 g of Linaclotide stock solution was sprayed onto the Copovidon VA 64 for about 30 seconds using a 0.4 mm spray nozzle. During spraying the mixture was stirred. The mixture was then stirred (mixer 500 rpm, chopper 750 rpm) for approximately five minutes after all water was introduced by spraying. The resulting white sticky material was transferred to a glass dish.
- All three batches (813476, 813477 and 813479) were dried in a vaccum dryer at 40°C and 10 mbar pressure overnight. All three batches were removed from their respective dishes and subsequently milled for 5 minutes in a plastic mortar. A 2g sample of each batch was taken for a LOD measurement. All three batches were filled into size 1 capsules using an Aponorn capsule filling device.
- Table 15 shows the composition of Linaclotide formulated on CompactCel P204 (813476 and 813477) and Kollidon VA 64 (813479).
- Table 16 shows the details of the size 1 capsules filled with batches of linaclotide formulation (813476, 813477 and 813479) using the Aponorm capsule filling device.
- This example relates to the use of an external desiccant on stability of the Linaclotide carrier compositions together with a further investigation on the use of an additional Syloid (AL-1 FP) in the Linaclotide carrier compositions described herein.
- Linaclotide was weighed in a 0.2 L Schott bottle. A magnetic stir bar and 60 g
- Linaclotide capsules batch 812959 (batch 812899 + 10% Syloid AL-1 FP)
- HG capsules size 1 120 HG capsules size 1 were filled completely with batch 812959 with the semi- automated encapsulation system CAPIII. 5 HG capsules size 1 were filled manually with batch 812959. The capsules were filled under controlled humidity conditions in 5 HDPE bottles (20 pcs.) and 2 Twist-off glasses (5 pcs. and 20 pcs.). All container systems were flushed with nitrogen.
- 125 HG capsules size 1 were filled completely with batch 812968 with the semi- automated encapsulation system CAPIII.
- the capsules were filled under controlled humidity conditions in 5 HDPE bottles (20 pcs.) and 2 Twist-off glasses (5 pcs. and 20 pcs.).
- a 1.5 g desiccant pouch were placed in all HDPE bottles. All container systems were flushed with nitrogen.
- HG capsules size 1 were filled completely with batch 812968 with the semi- automated encapsulation system CAP III.
- the capsules were filled under controlled humidity conditions in 5 HDPE bottles (20 pcs.) and 1 Twist-off glass (20 pcs.).
- a 3.0 g desiccant pouch was placed in all HDPE bottles. All container systems were flushed with nitrogen.
- HG capsules size 1 120 HG capsules size 1 were filled for 73% (target 93.6 mg) manually with batch 812969.
- the capsules were filled under controlled humidity conditions in 5 HDPE bottles (20 pcs.) and 2 Twist-off glasses (5 pcs. and 15 pcs.).
- a 2.0 g desiccant pouch was placed in all HDPE bottles. All container systems were flushed with nitrogen.
- HG capsules size 2 were filled completely with batch 812969 with the semi- automated encapsulation system CAPIII. 5 HG capsules size 2 were filled manually with batch 812969. The capsules were filled under controlled humidity conditions in 5 HDPE bottles (20 pcs.) and 2 Twist-off glasses (5 pcs. and 15 pcs.). A 2.0 g desiccant pouch was placed in all HDPE bottles. All container systems were flushed with nitrogen.
- composition and batch overview can be seen in tables 17 and 18.
- Table 18 Composition and Batch overview of Linaclotide Granules mixed with Syloid AL and Hard Gelatine Capsules 290 pg/cps.
- Granules batch 812959 was manufactured using an already existing granule batch having a Linaclotide API content of 2.49 mg/g formulation.
- the water content was 2.8 %, 3.9 % and 4.7 % (w/w) for batches 812968, 812969 and 812959 respectively.
- Multimers levels were measured with 0.9, 1.0 and 1.2 % for batches 812968, 812969 and 812959 respectively.
- the purity was about 99.4 % for batches without Syloid AL (812968, 812969) with a recovery between 101.3 and 102.0 whereas the purity for batch 812959 (with 10 % Syloid AL) was 98.8 % and the recovery with 98.4 %.
- Table 19 Granules with different API load (2.38 mg/g; 3.26 mg/g; 2.27 mg/g) in TOG (Twist-off glass)
- Batches 812968, 812975, 812976 (all HG 1 ; all 100 % fill; 1.5, 2.0, 3.0 g desiccant in pouches)
- Batches 812969, 812977 (HG 1 and HG 2; 73 % and 100 % fill; all 2.0 g desiccant in pouches)
- Batch 812959 (HG 1 ; 100 % fill; 10 % Syloid AL, no desiccant in pouches)
- Water content 812968, 812975, 812976 (all HG 1 ; all 100 % fill; 1.5, 2.0, 3.0 g desiccant in pouches):
- the initial water content was 3.8 % (w/w).
- the water content decreased after 4 weeks of storage at 40°C/75% RH up to 2.5 % (w/w) using the maximum amount of desiccant (3.0 g) in pouches.
- the water content increased for two batches (812968 and 812975) and stayed the same for 812976 (3.0 g desiccant).
- the highest water content was detected using the minimum amount of desiccant (1.5 g) with 4.4 % (w/w) after 26 weeks of storage at 40°C/75% RH.
- the initial multimer level was about 0.5 %. After 26 weeks of storage at 40°C/75% RH multimers increased to 8.1 %, 6.0 % and 4.0 % depending on the amount of desiccant in pouches used.
- the initial multimer level was about 0.5 %. After 26 weeks of storage at 40°C/75% RH multimers increased to 6.7 % for batch 812969 and 6.3 % for batch 812977.
- the initial multimer level was 0.6 %. However, after 26 weeks of storage at 40°C/75% RH multimers increased to 18.1 % due to high water content within the granules.
- the initial impurity level was about 0.4 %, hence a purity of 99.6 %.
- RH impurities increased to 4.3 %, 3.9 % and 3.2 % depending on the amount of desiccant in pouches used.
- the initial recovery of label claim was about 109.6 %, 109.9 % and 108.5 %, respectively batch 812968, 812975 and 812976.
- RH recovery of label claim decreased to 86.7 %, 91.1 % and 92.0 % depending on the amount of desiccant in pouches used.
- the initial impurity level was about 0.6 %, hence a purity of 99.4 %.
- RH impurities increased to 5.1 % and 4.0 %.
- the initial recovery of label claim was about 109.0 % and 118.5 %, respectively batch 812969 and 812977. For batch 812969 this was unexpected, since we have aimed for about 105 % of label claim.
- After 26 weeks of storage at 40°C/75% RH recovery of label claim decreased to 88.7 % and 97.8 %.
- the initial impurity level was 0.7 %, hence a purity of 99.3 %. After 26 weeks of storage at 40°C/75% RH impurities increased to 16.4 %.
- the initial recovery of label claim was about 107.6 %. After 26 weeks of storage at 40°C/75% RH recovery of label claim decreased to 65.5 %.
- Table 20 HG Capsules size 1 in HDPE bottles with different amount of desiccant (1.5, 2.0 and 3.0 g)
- Table 21 Granules in HG Capsules size 1 (73% filled) and size 2 (100% filled) in HDPE bottles with 2.0g desiccant
- Table 22 Granules + 10% Syloid AL-1 FP in HG Capsules size 1 in HDPE bottles without desiccant, initial in TOG
- This example relates to the use of an external desiccant on stability of the Linaclotide carrier compositions together with a further investigation on the use of an additional Syloid (AL-1 FP).
- FIG capsules size 1 were filled completely with batch 813253 with the semi-automated encapsulation system CAPIII.
- 20 capsules per bottle were each filled into 35 ml FIDPE bottles under controlled humidity conditions.
- 2 Twist-off glass were each filled with 20 capsules (cps). without nitrogen flushing.
- Table 23 Composition and Batch overview of Linaclotide Granules and Hard
- the integrity of the capsules were checked visually for integrity and the absence of any defects. The outcome of this initial assessment was then noted and reported (I).
- the capsules were taken between thumb and index finger applying moderate mechanical stress whilst rolling between these fingers. This aims to mimic the handling of a capsule by a patient. Afterwards, the closed capsules were visually checked for integrity and the absence of any defects. The outcome of this assessment was then noted and reported (II).
- the coulometric determination of water is an absolute method and it is based on a quantitative reaction of water with an anhydrous solution of sulphur dioxide and iodine in the presence of a buffer, which in turn captures hydronium ions:
- Iodine (I2) is generated electrochemically from iodide (L).
- iodine (I2) encounters the water in the sample, water is titrated according to the above-mentioned reaction scheme. Once all the water available has reacted, the reaction is complete. The amount of water in the sample is calculated by measuring the current needed for the electrochemical generation of iodine (I2) from iodide (L). Titration was performed with a modified Karl-Fischer (KF)-solution using biampero- metric indication (dead-stop-method).
- KF Karl-Fischer
- Linaclotide and Linaclotide related compounds were eluted by applying distinct organic solvent concentrations.
- a gradient with an increasing amount of acetonitrile was used for the separation on a C18 column.
- the protein elution was monitored by UV absorption at a wavelength of 227 nm. Quantitation was carried out using external standard method.
- Linaclotide multimers were eluted isocratic with 0.017 M Na2HP0 4 as eluent on a 100 A SEC column. The protein elution was monitored by UV absorption at a wavelength of 220 nm. Quantitation was carried out using area% method. Dissolution
- the dissolution testing was performed using a basket apparatus, 500 ml potassium phosphate buffer at pH 4.5 with 50 rpm at 37°C. A dissolution profile was generated up to 20 min. Samples were analyzed a gradient HPLC method.
- Multimers level was measured at 0.9 %
- the purity was 99.4 % with a recovery of 98.7 %.
- Table 24 Granules with API load (2.38 mg/g) in TOG
- the initial water content was 3.9 % (w/w). After 26 weeks of storage at 30°C/65% RH all three batches (just desiccant in pouches) decreased to 3.4 %, 3.1 % and 3.1 % (w/w) depending on the amount of desiccant used.
- the initial impurity level was about 0.4 %, hence a purity of 99.6 %.
- the initial recovery of label claim was about 104.3 %. After 26 weeks of storage at 30°C/65% RH a decrease in recovery for all three batches (just desiccant in pouches) to about 97.0 - 99.6 % could be observed.
- Table 25 Granules (API load 2.38 mg/g) in HG Capsules size 1 in HDPE bottles with different amount of desiccant in pouches (1.5, 2.0 and 2.5 g), initial in TOG, Intermediate Condition 30°C/65% RH, closed) Group 3
- the initial water content was 3.4 % (w/w). No significant decrease or increase of water content could be observed over the course of the stability for 30°C/65% RH.
- the initial multimer level was about 1 .0 %. After 26 weeks of storage at 30°C/65% RH a slight increase to 1 .4 % could be observed.
- the initial impurity level was about 1 .6 %, hence a purity of 98.4 %.
- the initial recovery of label claim was about 103.4 %. After 26 weeks of storage at 30°C/65% RH no significant change occurred. However, after 14 weeks an increase of recovery to 1 1 1.6 % could be observed.
- Table 26 Originator in FIG Capsules size 2 in FIDPE bottles with about 3.3g desiccant in cylindric can, Intermediate Condition 30°C/65% RH , closed)
- the Linaclotide carrier compositions having Syloid 3150 as a carrier demonstrate comparable product qualities compared to the originator formulation with respect to impurities (Fig. 3), multimer content (Fig. 4), water content (Fig.5), recovery of label claim (Fig. 6) and dissolution profiles (Fig. 7).
- the linaclotide formulation demonstrates a lower impurity content than the originator formulation at 0 to 14 weeks and a comparable impurity level at 26 weeks (Fig. 3).
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WO2007033427A1 (en) | 2005-09-23 | 2007-03-29 | Metabolic Pharmaceuticals Limited | Stabilisation of peptides with basic amino acids |
WO2010019266A2 (en) | 2008-08-15 | 2010-02-18 | Ironwood Pharmaceuticals, Inc. | Stable solid formulation of a gc-c receptor agonist polypeptide suitable for oral administration |
US20150005241A1 (en) | 2012-07-12 | 2015-01-01 | Forest Laboratories Holdings Ltd. | Linaclotide compositions |
WO2016024291A1 (en) | 2014-08-11 | 2016-02-18 | Sun Pharmaceutical Industries Ltd. | Linaclotide stable composition |
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WO2007033427A1 (en) | 2005-09-23 | 2007-03-29 | Metabolic Pharmaceuticals Limited | Stabilisation of peptides with basic amino acids |
WO2010019266A2 (en) | 2008-08-15 | 2010-02-18 | Ironwood Pharmaceuticals, Inc. | Stable solid formulation of a gc-c receptor agonist polypeptide suitable for oral administration |
US20150005241A1 (en) | 2012-07-12 | 2015-01-01 | Forest Laboratories Holdings Ltd. | Linaclotide compositions |
WO2016024291A1 (en) | 2014-08-11 | 2016-02-18 | Sun Pharmaceutical Industries Ltd. | Linaclotide stable composition |
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