MX2008006319A

MX2008006319A - Pharmaceutical composition

Info

Publication number: MX2008006319A
Application number: MXMX/A/2008/006319A
Authority: MX
Inventors: Edward Royce Alan; Li Shoufeng; Ashok Ghosh Anasuya; David Bateman Simon; Azria Moise
Original assignee: Azria Moise; David Bateman Simon; Ashok Ghosh Anasuya; Li Shoufeng; Novartis Ag; Novartis Pharma Gmbh; Edward Royce Alan
Priority date: 2005-11-17
Filing date: 2008-05-15
Publication date: 2008-10-03

Abstract

The present invention provides oral pharmaceutical compositions that enable the successful delivery of drugs in a pharmaceutically effective amount, particularly poly (amino acids) such as peptides, peptidomimetics and proteins, e.g. hormones to a subject via oral administration to accomplish the desired therapeutic effect. The oral pharmaceutical composition comprising a poly (amino acid) as the active ingredient, e.g. a peptide or protein, shows a rapid disintegration and/or dissolution such that the active ingredient is able to attain a therapeutic effect.

Description

PHARMACEUTICAL COMPOSITION The present invention relates to a novel pharmaceutical composition for the oral delivery of pharmaceutical compounds, in particular poly- (amino acids), including peptides or, in an alternative manner, peptidomimetics. In particular, the present invention relates, in one embodiment, to a novel oral pharmaceutical composition containing a poly- (amino acid), for the treatment of a disorder caused by abnormal bone resorption, and / or to the treatment of an arthritic condition, and another subject matter. Background of the Invention Hormones The poly- (amino acids) that have been used or proposed to be used for pharmaceutical or veterinary purposes include, but are not limited to, the following sources, including synthetic, natural or recombinant thereof: polypeptide hormones, such as calcitonins, for example, salmon calcitonin, growth hormone, including human growth hormones (hGH), recombinant human growth hormones (rhGH), bovine growth hormones, and porcine growth hormones; growth hormone-releasing hormones, and pituitary thyroid hormone. The parathyroid hormone or PTH can be the full-length form of 84 amino acids of the parathyroid hormone, by example, the human form, hPTH (1-84), or any polypeptide, protein, protein fragment, or modified fragment, ie, peptides related to the parathyroid hormone and parathyroid hormone analogs, capable of mimicking the activity of hPTH ( 1-84) in the control of calcium and phosphate metabolism, to build bone in the human body. In general terms, the parathyroid hormone fragments will incorporate at least the first 28 N-terminal residues, and will include, for example, PTH (1-28), PTH (1-31), PTH (1-34), PTH (1-37), PTH (1-38) and PTH (1-41) and analogs thereof, for example, PTS893. The parathyroid hormone can be a single parathyroid hormone or any combination of two or more parathyroid hormones. The preferred parathyroid hormone fragment is PTH (1-34). These parathyroid hormones are commercially available, or can be obtained in a recombinant manner, by peptide synthesis, or by extraction from the human fluid, by methods well established in the art. The amount of parathyroid hormone that is to be administered is generally an effective amount to stimulate the new bone formation, i.e., a therapeutically effective amount. This amount will necessarily vary with the age, size, sex, and condition of the subject to be treated, the nature and severity of the disorder to be treated, and the like. However, the unit amount may be less than the dosage described, when a plurality of the compositions, that is, the total effective amount can be administered in cumulative dosage units. The unit amount of parathyroid hormone may also be greater than the effective amount when the composition provides a sustained release of the pharmacologically active agent. The total amount of parathyroid hormone that should be used can be determined by methods known to those skilled in the art. However, in general, satisfactory results will be obtained systemically with daily dosages from about 0.001 microgram / kilogram to about 10 milligrams / kilogram of animal body weight, preferably from 1 microgram / kilogram to about 6 microgram / kilogram of body weight. The preferred pharmacologically active agent is a pharmacologically active peptide, in particular calcitonin. A known class of pharmacologically active agents, calcitonins, have variable pharmaceutical utility, and are commonly employed in the treatment, for example, of Paget's disease, hypercalcemia, and post-menopausal osteoporosis. Calcitonins, for example, from salmon, eel calcitonin- (Asu1 -7) or human, are compounds that are long-chain polypeptide hormones secreted by parafollicular cells of the thyroid gland in mammals, and by the ultimobranchial gland of birds and fish. Different calcitonins, including salmon, pork, and eel calcitonins, are commercially available, and They are commonly used for the treatment, for example, of Paget's disease, malignancy, and osteoporosis. Calcitonin can be any calcitonin, including natural, synthetic or recombinant sources thereof, as well as calcitonin derivatives, such as eel calcitonin-1,7-Asu. The compositions may comprise a single calcitonin or any combination of two or more calcitonins. The preferred calcitonin is synthetic salmon calcitonin. Calcitonins are commercially available, or can be synthesized by known methods. The amount of pharmacologically active agent is in general an amount effective to carry out the intended purpose, for example, a therapeutically effective amount. However, the unit amount may be less than the dosage described when a plurality of the compositions are to be administered, i.e., the total effective amount may be administered in cumulative dosage units. The unit amount of active agent may also be greater than the effective amount when the composition provides a sustained release of the pharmacologically active agent. The total amount of active agent to be used can be determined by methods known to those skilled in the art. However, because the compositions can deliver the active agent more efficiently than the above compositions, smaller amounts of the active agent than those used can be administered. in unit dosage forms or in prior delivery systems to a subject, while still achieving the same blood levels and / or therapeutic effects. The appropriate dosage of calcitonin to be administered, of course, will vary depending, for example, on the amount of calcitonin to be administered, and on the severity of the condition being treated. However, satisfactory results will generally be obtained through intranasal or injectable systemic administration in daily dosages from about 0.5 micrograms / kilogram to about 10 micrograms / kilogram of animal body weight, preferably from 1 microgram / kilogram to about 6 micrograms / kilogram of body weight. Human growth hormone (hGH) (or somatotropic hormone or somatotropin) is a polypeptide hormone secreted by the anterior lobe of the pituitary gland that promotes the growth of the body, especially by stimulating the release of somatomedin, and which has an influence on the metabolism of proteins, carbohydrates, and lipids Under the definition of human growth hormone can also be included any of different natural or synthetic substances that regulate the growth of animals or plants, such as growth hormone of pituitary in vertebrates, and auxins in plants.

Bone Disorders Many types of bone disorders are known. A first class of disorders fall in the class that is related to disorders caused by bone resorption. Examples of these disorders are osteoporosis, osteolysis, and Paget's disease. In a second class of disorders are the arthritic conditions. An example of these disorders is osteoarthritis. New Formulations Many attempts have been made to promote the absorption of poly- (amino acids), such as peptides and proteins, for example hormones. In general it is believed that peptides and proteins need to be protected from the gastric and intestinal environment, where there are many peptidases and significant degradation can occur. It has been proven that the enteric coating and the addition of peptidase inhibitors to the pharmaceutical compositions are effective in improving the absorption of poly (amino acids), for example proteins and peptides, by oral administration. However, these approaches alone do not offer sufficient protection to achieve a satisfactory plasma level of the peptides and proteins, and there still remains a need to provide alternative means to successfully deliver the peptide and protein drugs to a patient, while protect from chemical and enzymatic degradation, in order to make it possible for them to provide a therapeutic effect.

This is in particular the case for calcitonins, wherein the preferred delivery route is oral administration, because it is convenient, relatively easy, and generally painless, which results in greater compliance of the patient relative to other modes of administration. supply. Brief Description of the Invention The present invention, therefore, provides a pharmaceutical composition that makes possible the successful delivery of drugs, in a pharmaceutically effective amount, in particular poly- (amino acids), such as peptides, peptidomimetics and proteins, by example, hormones, to a subject, by oral administration, to carry out the desired therapeutic effect. The present invention further provides an oral pharmaceutical composition comprising a poly- (amino acid) active ingredient, for example, a peptide or protein, wherein the disintegration time of the pharmaceutical composition and / or the rate of dissolution are rapid, such that the active ingredient is capable of achieving a therapeutic effect. In a particular aspect, the present invention provides pharmaceutical compositions comprising an active ingredient of peptide or protein, wherein the disintegration time of the pharmaceutical composition, for example the tablet, is up to ten minutes. The present invention also provides a composition pharmaceutical, for example, a tablet or capsule, which has a dissolution time of up to thirty minutes, for example up to twenty minutes, usually up to ten minutes. In particular, the present invention provides pharmaceutical compositions comprising a calcitonin as the active ingredient, together with the 5-CNAC delivery agent, wherein the pharmaceutical composition is manufactured in such a way that it provides a better oral bioavailability, for example, a bioavailability satisfactory or optimal oral for the active ingredient of calcitonin. By "bioavailability" is meant, within the scope of the present invention, the percentage of the dose that enters the systemic circulation after administration of a given dosage form. More explicitly, the ratio of the amount of drug "absorbed" from a test formulation to the amount of drug "absorbed" after administration of a conventional formulation. Frequently, the "conventional formulation" used in evaluating bioavailability is the aqueous solution of the drug, given intravenously. The amount of drug absorbed is taken as a measure of the ability of the formulation to deliver the drug to the sites of action of the drug; which depends on the disintegration and dissolution properties of the dosage form, and the rate of biotransformation in relation to the absorption rate. Dosage forms that contain identical amounts of active drug may differ markedly in its capabilities to make the drug available, and, consequently, in its capabilities to allow the drug to manifest its expected pharmacodynamic and therapeutic properties. It was within the scope of the present invention that it has been found in a surprising manner that the faster disintegration of the pharmaceutical compositions of the present invention in a subject, for example, in the stomach, provides the best absorption characteristics for the peptides and active proteins, where the greatest degradation of peptides or proteins occurs through pepsin or other enzymes. Therefore, the present invention further provides a pharmaceutical composition capable of delivering a peptide or protein by oral administration without the need for an enteric coating or a peptidase inhibitor. Accordingly, in the embodiments, the compositions of the invention are free of enteric coating or of peptidase inhibitors, or both. The calcitonin-containing pharmaceutical compositions of the present invention can be used to treat disorders related to abnormal bone resorption, or to treat arthritic conditions, as described herein. In one embodiment, the invention relates to an oral pharmaceutical composition in the solid phase, which comprises: i. a poly- (amino acid); ii. a supply agent, and, optionally, iii. a diluent; wherein the composition has a disintegration time of not more than 10 minutes, and a solution of > 80 percent at 20 minutes, in particular a disintegration time of no more than 6 minutes, and a dissolution of > 90 percent at 20 minutes. In particular, the composition according to the invention has a disintegration time of not more than 2 minutes. In another embodiment, the composition according to the invention additionally comprises a disintegrant, in particular a disintegrant selected from any super-disintegrant, such as a crospovidone or a povidone and / or another agent that decreases the disintegration time, for example , by effervescent means and / or other means. In yet another embodiment of the invention, a pharmaceutical composition having a dissolution time of > 80 percent to no more than 20 minutes in the gastric environment. The invention further relates to a pharmaceutical composition, which is in the form of a tablet, in particular a compressed tablet, wherein the tablet has a hardness of between 3 Kp and 20 Kp, in particular between 5 Kp and 15 Kp , more particularly, between 5 Kp and 7 Kp. In a specific embodiment, the composition according to the invention comprises a polypeptide hormone, in particular a calcitonin, more particularly, a salmon calcitonin. In particular, calcitonin is present in an amount Therapeutically effective, in free or salt form, which provides a peak plasma concentration (Cmax) of not less than 400 picograms / milliliter, in particular not less than 800 picograms / milliliter, more particularly, not less than 1,000 picograms / milliliter, and / or a reduction in the plasma calcium level of > 20 percent in 6 hours in primate animal models, particularly monkeys. In another embodiment of the invention, a composition is provided, which comprises a therapeutically effective amount of a calcitonin in free or salt form, in a dosage range of between 0.15 milligrams and 2.5 milligrams, in particular between 0.15 milligrams and 0.4 milligrams. milligrams The composition according to the invention may further comprise the delivery agent 5-CNAC and / or crospovidone and / or povidone as a disintegrant. Additionally, the composition may comprise one or more of a thickening agent, a stabilizer, and a dry binder. In one embodiment of the invention, the pharmaceutical composition is provided in the form of a tablet, which has a weight of 500 milligrams. In a specific embodiment of the invention, a pharmaceutical composition is provided, which comprises: a. Calcitonin from 0.03 to 0.5% by weight b. 5-CNAC micronized from 5 to 80% by weight c. Avicel PH 102 or 101 from 0 to 70% by weight d. Crospovidone, NF from 0 to 10% e. Magnesium stearate from 0 to 1.5% by weight f. Cab-o-sil from 0 to 1.5% where the total percentages add up to 100. In addition, a pharmaceutical combination is provided, which comprises: a. the composition according to the invention and as described hereinabove, and b. a co-agent, which is an inhibitor of bone resorption, or a cathepsin K inhibitor. In still another embodiment, a method for making an oral pharmaceutical composition is provided, which comprises the steps of: a. mixing a poly- (amino acid), a vehicle and a disintegrant, to make a first mixture; b. optionally mixing a dry binder with the first mixture to make a second mixture; c. optionally mixing a stabilizer with the second mixture to make a third mixture; d. Compress the third mixture on a tablet with a hardness of 5 Kp at 20 Kp. In still another embodiment, the invention relates to the use of the pharmaceutical composition according to the invention and as described hereinabove, for the manufacture of a medicament for the treatment of a disease caused by an abnormal bone resorption such as, for example, osteoporosis, an arthritic disease, or osteoarthritis. The invention further relates to a method for determining the absorption properties of a composition according to the invention and as described hereinabove, which comprises: a. determine the dispersion time, b. correlate the dispersion time with the dissolution time. In another embodiment, the invention relates to a method for pre-determining the peak plasma concentration (Cmax) of an active ingredient in a patient to be treated with an oral pharmaceutical composition comprising the aforementioned active ingredient, in particular calcitonin, more particularly, salmon calcitonin, and a delivery agent, which method comprises adjusting the disintegration time of the pharmaceutical composition and / or the dissolution time of the active ingredient, such as to provide a favorable micro-environment in the gastrointestinal tract for the dissolution of the active ingredient in the intestine, in order to optimize the absorption of the active ingredient and to reach a therapeutically effective peak plasma concentration of the active ingredient in the blood plasma, in particular a peak plasma concentration of not less than 400 picograms / milliliter. In particular, the favorable micro-environment in the tract Gastrointestinal for the dissolution of the active ingredient in the intestine can be provided by the addition of 5-CNAC to the composition. In a specific embodiment, a method is provided for pre-determining the peak plasma concentration (Cmax) of an active ingredient in a patient to be treated with an oral pharmaceutical composition, wherein the oral pharmaceutical composition is provided in the form of a tablet, and the disintegration time is adjusted by adapting the hardness of the tablet, in particular a tablet whose hardness is in the range of between 3 Kp and 20 Kp, and / or where the disintegration time is less than 10 minutes, in particular less than 1 minute. In yet another embodiment, the invention relates to the use, for the manufacture of an oral pharmaceutical composition having a disintegration time and / or a dissolution time of not more than 10 minutes, of: (i) a poly (amino acid) ); (ii) a supply agent; and (iii) a disintegrant. In particular, 5-CNAC can be used to provide a favorable micro-environment in the gastrointestinal tract, for the dissolution of salmon calcitonin. Detailed Description of the Invention The present invention provides an oral pharmaceutical composition, which comprises an active ingredient of poly (amino acid), for example, a peptide or a protein, wherein the disintegration time of the pharmaceutical composition is such that the active ingredient is capable of achieving an adequate therapeutic effect. The present invention further provides an oral pharmaceutical composition, which comprises a poly- (amino acid) active ingredient, for example, a peptide or a protein, wherein the dissolution rate of the pharmaceutical composition is such that the active ingredient is capable of to achieve an adequate therapeutic effect. The present invention further provides an oral pharmaceutical composition, which comprises a poly- (amino acid) active ingredient, for example, a peptide or a protein, wherein both the disintegration time and the dissolution rate of the pharmaceutical composition are such that the active ingredient is capable of achieving an adequate therapeutic effect. Considering that the speed of degradation is very fast, that is, it occurs in milliseconds, it was believed that this rapid degradation can not be compensated by means of dissolution. However, surprisingly, it was found, within the scope of the present invention, that a sufficiently high therapeutic level of the active ingredient can be achieved in a relatively fast time frame, which is capable of compensating for biochemical degradation (e.g. , in the gastrointestinal tract) of the active ingredient.

As a result of the higher plasma concentration of the therapeutically active ingredients, it will be appreciated that the compositions of the present invention may not require that both active ingredient be present, compared to the compositions without the properties of the compositions described herein. Of course, this will not only have the benefit of reducing the production costs of the resulting medicinal products, but also reduces the risk of forming undesired, or even toxic, metabolites of the active ingredient in the patient. In addition, the compositions of the present invention can provide a method by which the therapeutic level of the active ingredient can be controlled, for example, the plasma concentration of an active ingredient. In other words, when there is a linear, or nearly linear, relationship between the disintegration, dissolution, and / or plasma concentration of an active ingredient, the desired plasma concentration can be determined in advance at any given time by the choice of a particular composition with a particular disintegration time and / or a particular dissolution time. For this purpose, the present invention also includes a library of compositions, each having different properties of disintegration and / or dissolution by the means described herein. A particular library of compositions comprises a library of tablets, each having a different hardness, for example, from 3 Kp to 20 Kp, in particular from 5 Kp to 20 Kp, more particularly from 5 Kp to 15 Kp, but especially from 5 Kp to 7 Kp. In a sub-library, each tablet of each hardness may also differ in the amount of active ingredient, vehicle, diluent, lubricant, skimmer, or disintegrant, for example. The present invention also includes a library of compositions, wherein the absence of lubricant can contribute to a faster establishment of disintegration and dissolution. In one aspect, the present invention provides an oral pharmaceutical composition having one or both of a dissolution time or a disintegration time of up to ten minutes. The present invention provides compositions for which the degree of dissolution is between 20 percent and 100 percent using the USP II paddle method in a dissolution medium of 0.1 N HCl and 0.01 percent Tween-80 during a prescribed period of time. In particular, the compositions of the invention have a degree of dissolution of between 20 percent and 100 percent, for example, 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, and 100 percent, for a period of 0 to 60 minutes, for example 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55 and 60 minutes. In a preferred aspect of the present invention, the dissolution times and the degree of dissolution, as mentioned previously, they correlate with compositions having a disintegration time of less than ten minutes. In one embodiment of the invention, the composition has a disintegration time of not more than 10 minutes and a solution of > 80 percent in no more than 20 minutes, in particular, a disintegration time of no more than 6 minutes, and a dissolution of > 90 percent in no more than 20 minutes, particularly in the gastric environment. In yet another embodiment, the composition has a disintegration time of not more than 10 minutes and a solution of > 80 percent in 20 minutes, in particular a disintegration time of no more than 6 minutes and a dissolution of > 90 percent in 20 minutes, particularly in the gastric environment. The skilled person will be aware that a number of different parameters have an influence on the disintegration time or dissolution time of an oral solid phase formulation, including: • The dosage form (eg, capsule or tablet), • The identity of the active agent, • The identity of the additional ingredients, for example, the delivery agent, the disintegrant, the skimmer, the lubricant, the diluent, • The amounts (proportions) of the ingredients, • The particle sizes , · The hardness of the tablets.

Accordingly, it is not possible to stipulate a universal parameter set that defines all compositions that have a specified disintegration and / or dissolution time, but that exclude all other compositions. However, the skilled person has the appropriate knowledge and ability to make compositions having the dissolution time and disintegration time disclosed herein. For the avoidance of doubt, this descriptive memory includes guidance regarding the scope and measurement of disintegration time and dissolution time. The dissolution time of a compound can directly affect the plasma concentration of an active ingredient at any given time. Accordingly, the present invention includes a pharmaceutical composition in the solid phase, which comprises: a poly- (amino acid); a supply agent; and if necessary, a diluent; wherein the composition has a disintegration time of not more than 10 minutes. In particular, the present invention includes: a pharmaceutical composition for the oral delivery of poly (amino acids), which comprises: (i) a poly- (amino acid), (ii) a delivery agent, (iii) a diluent, wherein the composition has a dissolution time of not more than 10 minutes. The present invention also includes: a solid pharmaceutical composition for the oral delivery of poly (amino acids), which comprises: (i) a poly- (amino acid), (ii) a delivery agent, (ii) a disintegrant, (iv) a diluent, wherein the composition has a disintegration time of not more than 10 minutes. The solid composition can be in the form of a tablet. The tablet can be compressed in a manner as described herein. The poly- (amino acid) can be any poly- (amino acid) drug, for example, comprising a protein or a protein fragment. It can be any poly- (amino acid) described above under the heading "Background of the Invention". In a particular class of pharmaceutical compositions, the poly- (amino acid) is a hormone, for example a polypeptide hormone, such as a calcitonin, for example salmon calcitonin, a growth hormone, including human growth hormones (hGH), human growth hormones recombinants (rhGH), bovine growth hormones, and porcine growth hormones; growth hormone-releasing hormones, and a pituitary thyroid hormone, for example. The poly- (amino acid) is preferably a pharmaceutically active ingredient. Contrary to popular belief, it has surprisingly been found that the faster disintegration of the pharmaceutical compositions of the present invention in a subject, for example in the stomach, provides the best absorption characteristics for peptides and active proteins, in where the greatest degradation of peptides or proteins occurs through pepsin or other enzymes. A particularly preferred class of pharmaceutical compositions comprises salmon calcitonin as an active ingredient. The poly- (amino acid) may be in free or salt form. The poly (amino acid), such as, for example, calcitonin, may preferably be present in an amount of between 0.03 weight percent and 1 weight percent, in particular between 0.05 weight percent and 1 percent by weight, more particularly between 0.03 percent by weight and 0.5 percent by weight of the total mass of the pharmaceutical composition. In particular, the poly (amino acid), such as, for example, calcitonin, may be present in an amount of between 0.05 and 0.5 percent by weight, for example, between 0.1 and 0.2 percent by weight. weight. For ele, when the weight of the final pharmaceutical composition is 500 milligrams, this is equal to amounts of the poly- (amino acid), for ele calcitonin, from 0.25 milligrams to 5 milligrams. The delivery agent can be any suitable delivery agent for delivering poly (amino acids) by oral administration. The delivery agents useful in the formulation, for ele in the oral formulation, are any agents useful for delivering the particular pharmacologically active agent. Suitable delivery agents are any of the modified amino acids disclosed in the aforementioned U.S. Patent No. 5,866,536, or any of the modified amino acids described in the aforementioned US Patent No. 5,773,647. , or any combination thereof. The contents of the aforementioned Patents of the United States of North America Nos. 5,773,647 and 5,866,536 are hereby incorporated by reference in their entirety. In addition, the delivery agent may be the disodium salt of any of the aforementioned modified amino acids, as well as the ethanol solvates and hydrates thereof. Suitable compounds include the compounds of the following formula I: Formula I wherein: R1, R2, R3, and R4 are independently hydrogen, -OH, -NR6R7, halogen, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms; R5 is an alkylene of 2 to 16 carbon atoms substituted or unsubstituted, alkenylene of 2 to 16 carbon atoms substituted or unsubstituted, alkyl of 1 to 12 carbon atoms- (arylene) substituted or unsubstituted, or aryl- (1-alkylene) to 12 carbon atoms) substituted or unsubstituted; and R6 and R7 are independently hydrogen, oxygen, or alkyl of 1 to 4 carbon atoms; and the alcohol hydrates and solvates thereof. The compounds of the formula I, as well as their disodium salts and the alcohol solvates and hydrates thereof, are described in International Publication Number WO 00/059863, together with the methods for their preparation. In addition, the delivery agent may be the disodium salt of any of the aforementioned modified amino acids, as well as the solvates of ethane and hydrates thereof.

The disodium salt can be prepared from the ethanol solvate, by evaporation or drying of the ethanol solvate, by methods known in the art to form the anhydrous disodium salt. The drying is generally carried out at a temperature of about 80 ° C to about 120 ° C, preferably about 85 ° C to about 90 ° C, and most preferably about 85 ° C. The drying step is generally carried out at a pressure of 26"Hg (66cmHg) or greater.The anhydrous disodium salt generally contains less than about 5 weight percent ethanol, and preferably less than about 2 weight percent. percent by weight of ethanol, based on 100 percent of the total weight of the anhydrous disodium salt The disodium salt of the delivery agent can also be prepared by making a paste of the delivery agent in water, and adding two molar equivalents of hydroxide of aqueous sodium, sodium alkoxide, or the like The suitable sodium alkoxide includes, but is not limited to, sodium methoxide, sodium ethoxide, and combinations thereof.An yet additional method for the preparation of the disodium salt is by the reaction of the delivery agent with a molar equivalent of sodium hydroxide, to provide the disodium salt.The disodium salt can be isolated as a solid by the concentration of the e contain the disodium salt until a thick paste is obtained by vacuum distillation. This paste can be dried in a vacuum oven to obtain the disodium salt of the Supply as a solid. The solid can also be isolated by spray drying an aqueous solution of the disodium salt. The delivery agents can be prepared by methods known in the art, for example as mentioned above, by the methods described in the Patents of the United States of North America Nos. 5,773,647 and 5,866,536. Ethanol solvates, as described in International Publication Number WO 00/059863, mentioned above, include, but are not limited to, a molecular or ionic complex of molecules or ions of ethanol solvent with molecules or ions of the disodium salt of the supply agent. Typically, the ethanol solvate contains about one molecule or ethanol ion per each disodium salt molecule of the delivery agent. The ethanol solvate of the disodium salt of the delivery agent can be prepared by dissolving the delivery agent in ethanol. Typically, each gram of the delivery agent is dissolved in from about 1 to about 50 milliliters of ethanol, and in general from about 2 to about 10 milliliters of ethanol. Then the supply agent / ethanol solution is reacted with a molar excess of a sodium-containing salt, such as a salt containing monosodium, in relation to the delivery agent, ie, for each mole of delivery agent, There is more than one mole of sodium cations, producing the ethanol solvate. Suitable monosodium salts include, but are not limited to, sodium hydroxide; sodium alkoxide, such as sodium methoxide and sodium ethoxide; and any combination of the above. Preferably, at least about two molar equivalents of the monosodium-containing salt are added to the ethanol solution, ie, for each mole of delivery agent, there are at least about two moles of sodium cations. Generally speaking, the reaction is carried out at or below the reflux temperature of the mixture, such as at room temperature. Then the ethanol solvate is recovered by methods known in the art, such as concentration of the resulting paste with atmospheric distillation, cooling of the concentrated paste, and filtration of the solid. The recovered solid can then be dried under vacuum to obtain the ethanol solvate. The hydrates of the disodium salts of the delivery agents can be prepared by drying the ethanol solvate from an anhydrous disodium salt, as described above, and hydrating the anhydrous disodium salt. Preferably, the monohydrate of the disodium salt is formed. Because the anhydrous disodium salt is very hydroscopic, the hydrate is formed after exposure to atmospheric moisture. In general, the hydration step is carried out from about room temperature to about 50 ° C, preferably from room temperature to about 30 ° C, and in an environment having a relative humidity of at least 50 ° C. hundred. In an alternative way, the anhydrous disodium salt can be hydrated with steam.

Preferred delivery agents can be selected from: N- (5-chloro-salicyloyl) -8-amino-caprylic acid (5-CNAC), N- (10- [2-hydroxy-benzoyl] -amino) -decanoic (SNAD), N- (8- [2-hydroxy-benzoyl] -amino) -caprylic acid (SNAC), and its mono- and di-salts, for example its monosodium and disodium salts, the ethanol solvates of their salts, and the monohydrates of their salts, and any combinations thereof, such as the ethanol solvates of their sodium salts and the monohydrates of their sodium salts, and any combinations thereof, for example. Other salts, such as potassium, lithium, and calcium are also contemplated. The agents of supply of 5-CNAC, SNAD, and SNAC are very soluble in water, especially in the alkaline conditions of the intestine, and are absorbed almost completely, ie, by more than 90 percent, in the gastrointestinal tract, such like the duodenum, for example, whether ingested in a micronized or coarse form. Conversely, the delivery agents can form precipitates in an acidic environment, for example in the stomach. Preferably, the delivery agent is in a micronized form. A particularly surprising aspect of the present invention is the effect that the selected delivery agent can have on the dissolution time of the active ingredient. For example, when the vehicle is 5-CNAC, the transformation of an insoluble form, for example the solid form of the sodium salt or the free acid of 5-CNAC in a particular environment, for example the intestinal environment, to a soluble form, for example the -CNAC in solution, provides a mechanism by which the active ingredient has a high rate of dissolution, for example, no more than ten minutes. Accordingly, it is hypothesized that any insoluble form of a delivery agent, which becomes a soluble entity after its contact with the gastrointestinal environment (such as that of the duodenum environment, for example), can provide a mechanism for a high dissolution speed of an active ingredient. Accordingly, the delivery agent, such as 5-CNAC for example, or its salts, can provide a satisfactory or optimum micro-environment for the satisfactory or optimum rate of dissolution and / or absorption of an active ingredient of poly ( amino acid). In particular, the disodium salt of 5-CNAC can provide a satisfactory or optimal micro-environment for the absorption of salmon calcitonin. The absorption of calcitonin and salmon can be measured by plasma concentration, for example. In a particularly preferred class of pharmaceutical compositions, the delivery agent is 5-CNAC. The 5-CNAC may be in free or salt form, or it may consist of a wide range of particle sizes, for example in the range of average particle sizes of 50 to 5 microns. Preferably, the delivery agent is in a micronized form.

The average particle size of the micronized delivery agent, for example 5-CNAC, can be measured by grinding the coarse 5-CNAC, and periodically sampling with measurements of reference particle sizes, to identify when the desired average particle size is reached. A process for micronizing 5-CNAC is described in International Publication Number WO 2005/014031, which is incorporated herein by reference; see in particular page 10 and example 1, which describe the effects of 5-CNAC particles of different sizes. The preferred delivery agent is present in an amount of between 5 percent by weight and 80 percent by weight, in particular between 10 percent by weight and 70 percent by weight, more particularly from 20 percent by weight and 60 percent by weight, still more particularly between 40 percent by weight and 60 percent by weight of the total mass of the pharmaceutical composition, eg, 50 percent by weight. When the weight of the final pharmaceutical composition is 500 milligrams, this equals amounts of 2.5 to 400 milligrams of the delivery agent present in the final pharmaceutical composition.

In addition, when the delivery agent is 5-CNAC or a salt thereof, its salt form is preferably present in an amount of more than 90 weight percent by the total weight of 5-CNAC present in the composition; this applies particularly when the disodium salt of 5-CNAC is present.

The preferred delivery agent is the disodium salt of 5-CNAC. The ratio of the active ingredient to the delivery agent is preferably between 1/25 and 1/400, in particular between 1/50 and 1/300, more particularly between 1/100 and 1/200, the most preferred proportion being the case of the sCT / 5-CNAC compositions of 0.5 mg'1 mg sCT for 200 milligrams to 300 milligrams of the disodium salt of 5-CNAC. The disintegrant may be selected from any super-disintegrant, for example, synthetic polymers capable of swelling through the absorption of water, of which mention may be made in particular of crospovidones and povidones. The most specific examples of the disintegrants are crospovidone, povidone, Explotab, or AC-Di-Sol. In a referred class of pharmaceutical compositions, the disintegrant is Crospovidone. Crospovidone is a synthetic cross-linked homopolymer of N-vinyl-2-pyrrolidone, also referred to as 1-ethenyl-2-pyrrolidinone, having a molecular weight of 1,000,000 or greater. The super-disintegrants are agents that can absorb water and swell to a significant degree, either by the wicking effect or by hydration. They are more efficient than the conventional disintegrant, due to their water absorption and their swelling capacity. Other agents that decrease the disintegration time by effervescent means and / or other means can also be used. The preferred disintegrant is present in an amount from 0.02 weight percent to 10 weight percent, in particular from 0.2 weight percent to 10 weight percent, more particularly from 1.0 weight percent to 8 weight percent, for example, 3 percent by weight at 7 percent by weight of the total mass of the pharmaceutical composition, for example 5 percent by weight. When the weight of the final pharmaceutical composition is 500 milligrams, this is equal to amounts of the disintegrant of between 0.1 milligrams and 50 milligrams. Commercially available crospovidones include Poliplasdone XL, Poliplasdone XL-10, Poliplasdone INF-10 available from ISP, Kollidon CL, available from BASF Corporation. The preferred crospovidone is Poliplasdone XL. L povidone is a synthetic polymer consisting of linear 1-vinyl-2-pyrrolidinone groups having a molecular weight of generally between 2,500 and 3,000,000. Commercially available povidones include Kollidon K-30, Kollidon K-90F available from BASF Corporation, and Plasdona K-30 and Plasdona K-29/32, available at ISP. In an alternative way, they can be synthesized by known processes. The diluent may be, for example, Avicel PH 102 or 101. The diluent may be present in the pharmaceutical composition up to 90 weight percent, based on the total composition, or it may be used to make any difference between the mass of the final desired and actual pharmaceutical composition, which may be, for example, up to 600 milligrams, for example 500 milligrams. Preferably, the binder is present in an amount of between and 70 percent by weight, based on the total composition, for example 40 to 60 percent by weight, for example 50 percent by weight. When the weight of the final pharmaceutical composition is 500 milligrams, this is equal to amounts, for example, from 100 milligrams to 350 milligrams. In a preferred embodiment of the present invention, the diluent is a microcrystalline cellulose. The addition of a diluent will decrease the disintegration times of a tablet. The dissolution times of an active agent may be independent of the diluent. The addition of a skimmer or lubricant to a tablet can increase the dissolution rate of an active ingredient, and this is known to the person skilled in the art, due to the hydrophobicity of the lubricant, ie, magnesium stearate, stearyl fumarate of sodium, calcium stearate, etc. Disintegration and Dissolution The terms "disintegration" and "dissolution" can be defined in the USP < 701 > and < 711 > , which are incorporated herein by reference. It should be understood that the "dissolution time", according to the present invention, is the time that is required for a given amount (or fraction) of a drug in a solution to be released from a solid dosage form. The dissolution time is measured in vitro, under conditions simulating those that are present in vivo, in experiments where the amount of drug in solution is determined as a function of time. For example, the solution can be determined by the USP XXIII Palette Method, using a USP dissolution test apparatus of 2 to 50 revolutions per minute. It should be understood that the "disintegration time" (DT) according to the present invention is the time it takes for the formulated drug product (i.e., a capsule or tablet) to decompose in the primary particles, under carefully specified test conditions. The conditions of the laboratory test, in vitro, are established to simulate those that occur in vivo. For example, when the composition is in the form of a tablet, the disintegration time is the time it takes for a tablet to break down into granules of a specified size. Factors such as the class and amount of tablet binders, and the degree of compression employed in the compaction of the tablet ingredients, determine the disintegration time. The disintegration time of the pharmaceutical composition according to the present invention is not greater than 10 minutes, for example, it may not be more than 9 minutes. Preferably, the disintegration time is up to 8 minutes, for example 6 minutes, for example it may be less than 8 minutes, as in the case of 7 minutes. In an additional class of pharmaceutical compositions, the disintegration time is up to 5 minutes for example between 1 and 4 minutes, such as 2 minutes, for example. In still a further class of pharmaceutical compositions, the disintegration times are less than two minutes, for example 1 minute or less. Accordingly, a further aspect of the present invention is that the compositions have a dissolution time of up to ten minutes. In summary, the disintegration times of the compositions of the present invention are any of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 minutes or any fraction thereof, such as, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 130, 140, 150, 160, 170, 180 seconds, etc. Disintegration refers here to the physical process by which a tablet is broken down into fine particles, for example less than 0.065 centimeters in diameter. This process is monitored visually, and belongs to the physical integrity of the tablet alone. Typically, disintegration is carried out by monitoring the time it takes for 100 percent of the dispersed particles to pass through a coarse-mesh cylinder, eg, 7.75 centimeters long, with an internal diameter of 21.5 millimeters, and a wall of approximately 2 millimeters thick, in a water bath maintained at 37 ° C (+ 2 ° C), according to USP < 701 > . The disintegration time of a composition can be linked at the time of dissolution. The dissolution time is the time in which an active ingredient is dissolved in a liquid medium. The solution is monitored by means of UV or HPLC analysis, and provides the approximate time required for the complete release of a drug. The active ingredients in a disintegrated composition, such as, for example, a tablet, are not necessarily in solution and available for absorption. A long disintegration time is incompatible with the rapid absorption of the drug; a short disintegration time, by itself, does not ensure rapid absorption. Typically, there is some relationship between disintegration and dissolution. For the compositions of the present invention, a linear relationship could be established between the dissolution time and the disintegration time. In the current example, it could be shown that the shorter disintegration time corresponds to a faster dissolution, while the longer disintegration time is related to a slower dissolution. More specifically, a disintegration time of 6 minutes and less, corresponds to a dissolution of > 90 percent in 20 minutes, a disintegration time of 9 minutes corresponds to a dissolution of approximately 30 percent in 20 minutes. In a specific embodiment of the invention, the dissolution time of the compositions has a linear relationship with the dispersion time of the compositions. As such, in yet another As an aspect of the present invention, the disintegration time of the composition can be used to predict the dissolution time of the composition. Likewise, when the dissolution time of the composition is known, the disintegration time of the composition can be calculated. The use of the relationship between the disintegration time and the dissolution time is particularly effective when the composition is in a tablet form. Here, the disintegration time will be the disintegration time of the tablet in the stomach. Accordingly, factors that have an effect on the disintegration time of the tablet, for example the hardness of the tablet, can also be used to predict the dissolution time of an active ingredient. The degree of dissolution can be reflected in the degree of absorption. Accordingly, a successful dissolution parameter is one in which a therapeutically effective amount of the active substance or substances reaches the blood plasma. In a monkey pharmacokinetic study, a formulation containing 0.8 milligram of calcitonin should provide a peak plasma concentration (Cmax) of not less than 400 picograms / milliliter, and / or a reduction in plasma calcium level of > 20 percent in 6 hours. Accordingly, it is contemplated that, by adjusting the disintegration time of the compositions of the invention, the speed and / or amount of absorption can be optimized and / or change as required. As an example, when the composition is in the form of a tablet, the bioavailability can be adjusted by adjusting the hardness of the tablet, for example. As such, the ingredients (excipients / vehicles) of a tablet, and the degree of compression in tablet formation, can influence the bioavailability of an active ingredient in a composition of the present invention. In yet another class of compounds according to the present invention, the pharmaceutical composition is in the form of a compressed tablet. In this form, the tablet preferably has a hardness of between 5 and 10 kilopascals. In this class of compounds, the hardness of the tablet can be used to further determine the disintegration time of the pharmaceutical composition. The present inventors have found that, using the same pharmaceutical composition, the hardness of the tablet has a linear relationship with the disintegration time. ThereforeIt is another aspect of the present invention that the disintegration time of the pharmaceutical composition depends on the hardness of the tablet. More specifically, a certain disintegration time can be achieved by controlling the hardness of the compressed tablets. Tablet Hardness A tablet of a preferred dough with the preferred formulation having a hardness of between 5 and 20 Kp would typically have a disintegration time of less than 6 minutes.

The hardness of a tablet is directly related to the disintegration time of the tablet, as shown in the following Tables 1 and 2, and in Figures 3 and 4. Table 1 Table 2 Where: RSD is the relative standard deviation; and DT is the time of disintegration. Accordingly, the compression force applied to a particular composition when a tablet is manufactured, can determine the disintegration time of the pharmaceutical composition. Additional Ingredients In the additional classes of compositions, the pharmaceutical composition additionally comprises a skimmer and / or a stabilizer and / or a dry binder. Therefore, in a class of pharmaceutical compositions, the pharmaceutical composition comprises a further skim agent. The skid agent is, for example, cab-o-sil. The skimmer may be present in an amount of up to 1.5 weight percent, for example 0.02 to 0.5 weight percent, based on the total composition, for example, 0.3 weight percent. When the weight of the final pharmaceutical composition is 500 milligrams, this is equal to amounts of up to 7.5 milligrams. In a further class of pharmaceutical compositions, the pharmaceutical composition additionally comprises a lubricant. The lubricant is, for example, magnesium stearate. The lubricant may be present in an amount, for example, 0.5 to 1.5 percent by weight, based on the total composition, for example from 0.75 to 1.25 weight percent, for example, of 1 weight percent. When the weight of the final pharmaceutical composition is 500 milligrams, this equals amounts of 2.5 milligram to 7.5 milligrams. In addition to the specific ingredients mentioned herein, the compositions of the present invention, which have the disintegration and / or dissolution properties mentioned herein, may also be combined with other technologies, such as those described in Patent Numbers WO 94/26778; US 5,359,030; US 5,438,040; US 5,681,811; US 6,191,105; US 6,309,633; US 6,380,405; US 6,436,990; US 6,458,776; WO 97/33531; US 5,912,014; US 608,618 and US 6,479,692 (the content thereof is hereby incorporated by reference in its entirety). Methods The present invention includes methods for the preparation of the formulations and compositions described herein. In particular, the present invention relates to a method for making a tablet having a disintegration time of not more than 10 minutes, the method comprising: a. Mix a poly- (amino acid), a delivery agent, and a disintegrant with each other, to form a mixture. b. Add to the mix a diluent, and mix. c. Compress the product. Optionally, the method can comprise in a additional any of the following: 1. Tamper the mixture of the cloth. 2. Add a disintegrant, and mix after step b. 3. Add a lubricant and / or skid before step c. Next, in Scheme 1, an exemplary method is shown: Step 1: Mix by 50 Mix 1 Calcitonin from salmon revolutions Recombinant diffusion mixer + 5-CNAC (I) in weight ratio of 1: 6 Step 2: Sieve the material together through the sieve of sieve 1 0.25 millimeters (60 mesh). Frewitt Oscillator The sieve is rinsed with 5-CNAC end Crospovidone + 5-CNAC Step 3: Place the (III) + Aerosil 200 PH + Mix II ingredients in a mixAvicel 101 (I), sieve diffusers, and mix the diffusion mixer together through a sieve for 150 revolutions of 0.85 millimeters (mesh) Step 4: Sift the material 20) + Avicel 101 (II) Sieve II mixed through a Oscillator Frewitt sieve of 0.85 millimeters (20 mesh) Step 5: Mix the final mixture Mg stearate sieved material by 50 or Mixer Sifted diffusion (mesh of 0.85 100 or 150 revolutions millimeters) Compression Step 6: Compression Fette 3090 Beveled edge with round flat face of 12 millimeters with relief NVR / 984 Temporary storage in polyethylene bags in fiber drums. Diagram 1 Final packaging: HDPE bottles.

In one embodiment of the above method, compression of the mixture in a tablet provides a tablet having a hardness of between 5 and 20 pa, and to which the tablet has a disintegration time of not more than 10 minutes. As mentioned above, when the poly- (amino acid) is calcitonin, the formulation of the present invention can be used to treat a bone resorption disorder, such as osteoporosis, osteolysis, or Paget's disease, for example, or an arthritic condition , such as osteoarthritis, for example. For this purpose, a method is provided for preventing and / or treating a bone resorption disorder and / or an arthritic condition in a patient in need thereof, which comprises administering to this patient a therapeutically effective amount of the pharmaceutical composition in accordance with the present invention, wherein the poly- (amino acid) is calcitonin, for example salmon calcitonin, in free form or in salt form, and the disintegration time of the pharmaceutical composition is up to 10 minutes. In addition, the pharmaceutical composition can be used, when it contains the required poly- (amino acid), for example calcitonin, in the following: 1. A method to inhibit resorption and normalize subchondral bone change in a patient who need, which comprises administering to this patient a therapeutically effective amount of the pharmaceutical composition according to the present invention. 2. A method for preserving and stimulating cartilage by means of a direct or indirect effect on chondrocytes in a patient in need thereof, which comprises administering to this patient a therapeutically effective amount of the pharmaceutical composition according to the present invention. 3. A method for inhibiting the activity of phospholipase A2 and / or collagenase in a patient in need thereof, which comprises administering to this patient a therapeutically effective amount of the pharmaceutical composition according to the present invention. 4. A method for obtaining a stimulatory effect on the synthesis of glycosaminoglycan and / or proteoglycan in a patient in need, which comprises administering to this patient a therapeutically effective amount of the pharmaceutical composition according to the present invention. 5. A method for acting upon the lack of homogeneity in the density or stiffness of subchondral bone in a patient in need thereof, which comprises administering to this patient a therapeutically effective amount of the pharmaceutical composition according to the present invention. 6. A method for acting on the inflammatory process, which leads to attenuations on pain in movement and related symptoms (e.g., knee circumference, knee flexion angle, rigidity with swelling) in a patient who need, which includes administering to this patient a therapeutically effective amount of the pharmaceutical composition according to the present invention. 7. A method for reducing degenerative change in the joint in a patient in need, which comprises administering to this patient a therapeutically effective amount of the pharmaceutical composition according to the present invention. Combinations In another aspect of the invention, the pharmaceutical composition according to the present invention, can be administered with, for example, it can include, a second drug substance, wherein this second drug substance is, for example, a second inhibitor. of bone resorption, a bone-forming drug, or a pain-reducing drug. When the pharmaceutical composition according to the invention is administered with a second, third, or fourth drug substance, each substance can be administered independently in a simultaneous, separate, or sequential manner, relative to the composition of the present invention. The second suitable drug substances may include a calcitonin of different origin, for example salmon calcitonin, eel- (Asu 1 -7), or human, a calcitonin analog or a derivative thereof, a steroid hormone, for example a estrogen, a partial estrogen agonist or a combination of estrogen-gestagen, a SERM (Selective Receptor Modulator of Estrogen), for example raloxifene, lasofoxifene, TSE-424, FC1271, Tibolone (Livial O), vitamin D or an analogue thereof, or parathyroid hormone, a parathyroid hormone fragment or a parathyroid hormone derivative, for example, PTH (1-84), PTH (1-34), PTH (1-36), PTH (1-38), PTH (1-31) NH2 or PTS 893, bisphosphonates (eg, alendronate, risedronate, zoledronic acid , ibandronate); protease inhibitors, for example cathepsin inhibitor, preferably a cathepsin K inhibitor; parathyroid hormone releases; SARMs (Selective Androgen Receptor Molecules); Inhibitors of MMP (metalloprotease inhibitors), related to strontium, COX-2 inhibitors, for example lumiracoxib (Prexige (E)), celecoxib (CelebrexO), rofecoxib (Vioxx (D)), valdecoxib (BextraS)), etoricoxib ( ArcoxiaG)), or mixed inhibitors of COX-1 and COX-2, for example, diclofenac. Accordingly, according to this aspect of the invention, there is provided a pharmaceutical combination, which comprises: a) a first agent, which comprises a pharmaceutical composition comprising calcitonin, for example salmon calcitonin, eel-like (Asu 1 -7), or human, in free form or in salt form, in a pharmaceutically acceptable oral delivery form, a delivery agent, and a disintegrant, this pharmaceutical composition having a disintegration time of up to 10 minutes; and b) a co-agent that is an inhibitor of bone resorption, a bone-forming drug, or a pain-reducing agent, for example, as disclosed above. The term "pharmaceutical combination", as used herein, means a product resulting from the mixture or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, for example salmon calcitonin and a co-agent, are both administered to a patient in a simultaneous manner in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, for example salmon calcitonin and a co-agent, are both administered to a patient as separate entities, either concurrently, concurrently, or in sequence, without limits of specific times, wherein this administration provides therapeutically effective levels of the two compounds in the patient's body. Preferably, calcitonin, for example salmon calcitonin, in free form or in pharmaceutically acceptable salt form, is co-administered with a protease inhibitor, for example a cathepsin inhibitor, for example a cathepsin K inhibitor. As part of the above aspect of the invention, a kit of parts is also provided for use in the prevention and / or treatment of a bone resorption disorder and / or an arthritic condition, this kit comprising: a) a first agent that is a calcitonin, for example salmon calcitonin, eel- (Asu 1-7), or human, in free form or in salt form, in a pharmaceutical composition having: (i) a poly- (amino acid), (ii) a delivery agent , (iii) a disintegrant; and a disintegration time of up to 10 minutes; and b) a co-agent that is an inhibitor of bone resorption, a bone formation drug, or a pain reducing agent, for example, as disclosed above. In addition, co-administration methods are also provided for each of the methods (i) to (vii) above, wherein the methods comprise the co-administration of a therapeutically effective amount of the pharmaceutical composition according to the present invention, by example a pharmaceutical composition containing calcitonin, for example salmon calcitonin, in free form or in salt form, in a pharmaceutical composition having a disintegration time of up to 10 minutes, and a second drug substance, this second substance being drug an inhibitor of bone resorption, a bone-forming drug, or a pain-reducing drug, in free form or in salt form. The terms "co-administration" or "combined administration", or the like, as used herein, are intended to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens wherein the Agents are not necessarily administered by the same route of administration or at the same time. Dosages When the pharmacologically active agent is salmon calcitonin, the appropriate dosage will, of course, vary depending on, for example, the host and the nature and severity of the condition it is treating. However, in general, satisfactory results will be obtained systemically with daily dosages of about 0.5 micrograms / kilogram to about 10 micrograms / kilogram of animal body weight, preferably from 1 microgram / kilogram to about 6 micrograms / kilogram of body weight. The pharmaceutically acceptable inactive excipients that are used in the calcitonin pharmaceutical composition, for example, in the oral pharmaceutical composition of calcitonin, may include polymers and inactive compounds that, for example, aid the pharmaceutical composition or manufacture of the dosage form oral solid contemplated by the present invention, and which may aid in the release of the solid oral composition in the gastrointestinal environment. The disclosure provides the provision of a particular dosage range for a calcitonin, in particular a calcitonin in free or salt form, for example salmon calcitonin, which is effective and well tolerated, i.e., safe for a patient to take. .

A range of 0.15 milligrams to 2.5 milligrams, in particular 0.4 milligrams to 2.5 milligrams of salmon calcitonin, is preferred for a patient, eg, human, eg, an average human of approximately 70 kilograms. More preferred are doses of about 1 milligram, for example, from 0.8 milligrams to 1.2 milligrams. Doses of n more than 1 milligram but at least 0.4 milligrams are also preferred. More preferred is a dose of about 1 milligram, for example, 1 milligram. More preferred is a dose of between 0.5 milligrams and 1.1 milligrams, in particular, from 0.6 milligrams to 0.8 milligrams, more particularly a dose of 0.15 milligrams to 0.4 milligrams, but especially a dose of 0.15 milligrams. Doses can be administered once a day to a patient in need. For this purpose, the pharmaceutical compositions of the present invention can be used for the following: • A method for preventing and / or treating osteoarthritis in a patient in need thereof, which comprises administering to this patient, a pharmaceutical composition, which comprises between 0.4 and 2.5 milligrams, preferably between 0.8 and 1.2 milligrams, and most preferably about 1 milligram of a calcitonin, for example, salmon calcitonin, and with a disintegration time of up to 10 minutes. • A pharmaceutical composition, which comprises between 0.4 and 2.5 milligrams, preferably between 0.8 and 1.2 milligrams, and most preferably about 1 milligram of a calcitonin, for example, salmon calcitonin. • The use of a calcitonin, eg, salmon calcitonin, in the manufacture of a medicament for the treatment and / or prevention of a bone resorption disorder and / or an arthritic condition, wherein this medicament comprises calcitonin in an amount from 0.4 to 2.5 milligrams, preferably from 0.8 to 1.2 milligrams, and most preferably from about 1 milligram of a calcitonin, eg, salmon calcitonin, wherein this pharmaceutical composition has a disintegration time of up to 10 minutes . This oral form of delivery is, for example, a pharmaceutical composition for the oral delivery of salmon calcitonin, which comprises: (A) a therapeutically effective amount of said salmon calcitonin; (B) at least one effective absorption enhancer for promoting the bioavailability of this salmon calcitonin, this composition having a disintegration time of up to 10 minutes. Examples of the enhancers include 5-CNAC, SNAC, and fatty acids, such as Na Caprate, Na Capralate. Pharmaceutical compositions demonstrating the usefulness of calcitonin in the treatment of osteoarthritis can be provided as a capsule, including a soft gel capsule, tablet, caplet, suppository, or other oral dosage form solid, all of which can be prepared by methods well known in the art, provided that the composition has a disintegration time of up to 10 minutes. In a particularly preferred formulation of the present invention, the compositions have a disintegration time of up to 10 minutes. Or, if tested under appropriate conditions, it has more than 90 percent of the content dissolved in 20 minutes. In an overview of the process of the present invention, the solid pharmaceutical compositions can be prepared by first grinding either the delivery agent or the delivery agent with any combination of the additional ingredients of the present composition, up to a particle size. micronized The micronized delivery agent, or the micronized delivery agent plus the additional micronized ingredients of the present invention, can then be further processed by conventional methods, for example by the combination of a mixture of the active agent or the active agents, the agent of delivery, crospovidone or povidone and / or other ingredients, kneading, and filling into capsules, or, instead of filling in capsules, molding followed by additional tabletting, or compression molding to give tablets. In addition, a solid dispersion can be formed by known methods, followed by further processing to form a tablet or capsule. Throughout the description and the claims of this descriptive memory, the words "comprise" and "contain", and the variations of the words, for example "comprising" and "comprises", mean "including, but not limited to", and this is not intended to exclude (and does not exclude) ) to other fractions, additives, components, integers, or steps. Throughout the description and claims of this specification, the singular encompasses the plural, unless the context otherwise requires. In particular, when the indefinite article is used, it should be understood that the descriptive memory contemplates plurality as well as singularity, unless the context otherwise requires it. The features, integers, features, compounds, fractions, or chemical groups described in conjunction with a particular aspect, embodiment, or example of the invention, are to be understood as being applicable to any other aspect, embodiment, or example described herein, unless that is incompatible with it.

EXAMPLES The following examples serve to further illustrate the invention, and will be readily understood by one of ordinary skill in the art. The examples are not intended to be limiting of the present invention in any way.

EXAMPLE 1: Pharmaceutical Composition 1 Ingredient Quantity (mg) Percentage Calcitonin salmon 0.8 0.16 5-CNAC micronized 228 45.6 Avicel PH 102 (E) 241 47.94 Crospovidone, NF 25 5 Magnesium stearate 5 0.3 Total 500 Calcitonin from salmon, 5-CNAC, and crospovidone were mixed together in a first step of mixing. The Avicel PH 102 was sieved, and added to the mixture, and mixed in a second mixing step. Magnesium stearate was then added, and the mixture was further combined in a final mixing step. The final mixture was compressed into a 500-milligram tablet, and evaluated in a Rhesus monkey. The results are shown in Figure 5.

EXAMPLE 2: Alternative Pharmaceutical Composition (3 Lots) The same composition as in Example 1 was made, that is, composition comprising: Ingredient Quantity (mg) Percentage Calcitonin of salmon 0.8 0.16 5-CNAC micronized 228 45.6 Avicel PH 102 (E) 241 47.94 Crospovidone, NF 25 5 Magnesium stearate 5 0.3 However, in contrast to Example 1, salmon Calcitonin and Avicel PH 102 were mixed in a first mixing step. Then 5-CNAC and crospovidone were added to the first mixture, in a second mixing step. Finally, the magnesium stearate was added in a final mixing step. Then the final mixture was compressed into 3 different compression levels, to obtain 3 different batches of tablets, each having a different hardness, in order to provide 3 different disintegration times: (i) Disintegration time of 1 minute 10 seconds . (ii) Disintegration time of 5 minutes 40 seconds. (iii) Disintegration time of 8 minutes 51 seconds.

EXAMPLE 3: Alternative Pharmaceutical Composition A mixture similar to that of Example 1 was made, except that an amount of Cab-o-sil was added to form a composition comprising: Ingredient Quantity (mg) Percentage Calcitonin of salmon 0.6 0.12 5-CNAC micronized 228 45.6 Avicel PH 102 (E) 241 47.94 Crospovidone, NF 25 5 Cab-o-sil 1.5 0.3 Magnesium stearate 5 1 Total 500 The salmon calcitonin, 5-CNAC, and crospovidone were mixed in a first mixing step. The Avicel and the Cab-o-sil were sieved and added in a second mixing step. Finally, the magnesium stearate was added in a final mixing step. The final mixture was compressed to a 500 milligram tablet. The incorporation of Cab-o-sil improved the compression profile of the tablet. EXAMPLE 4: Alternative Pharmaceutical Composition A composition was made as described in Example 3, except that the composition comprised: Ingredient Amount (mg) Percentage Calcitonin salmon 0.8 0.16 5-CNAC micronized 228 45.6 Avicel PH 102 (E) 241 47.94 Crospovidone, NF 25 5 Cab-o-sil 1.5 0.3 Magnesium stearate 5 1 Total 500 EXAMPLE 5: Pharmaceutical composition Alternative Ingredient Quantity (mg) Percentage Calcitonin of recombinant salmon 0.6 0.12 5-CNAC (I) 1.2 0.24a -CNAC (II) 226.8 45.36b Avicel PH 101 (I) 15.a 3a Avicel PH 101 (II) 224.9b 44.9b Crospovidone 25 5 Aerosil 200 PH 1.5 0.3 Magnesium Stearate 5 1.0 Total Weight of the Tablet (mg) 500 100 Unit weight (a + b) listed as the disodium salt of 5-CNAC, which corresponds to the combined weight of 200 milligrams of the 5-CNAC free acid. The unit weight (a + b) of Avicel PH 101 (I) and (II) corresponds to the combined weight of Avicel PH 101. EXAMPLE 6: Pharmaceutical composition Alternative Ingredient Quantity (mg) Percentage Calcitonin of recombinant salmon 0.8 0.16 5-CNAC (I) 4.8a 2.1a 5-CNAC (II) 4.8b 2.1b 5-CNAC (III) 218.4c 41.4c Avicel PH 101 (I) 15.a 3a Avicel PH 101 ( II) 224.7b 44.9b Crospovidone 25 5 Aerosil 200 PH 1.5 0.3 Magnesium Stearate 5 1.0 Total Weight of the Tablet (mg) 500 100 Unit weight (a + b + c) listed as the disodium salt of 5-CNAC, which corresponds to the combined weight of 200 milligrams of acid free of 5-CNAC. The unit weight (a + b) of Avicel PH 101 (I) and (II) corresponds to the combined weight of Avicel PH 101. 1. 0.25 grams of sCT DS are weighed; 2. Mix with Part I of 5-CNAC; 3. The mixed material from Step 2 is sifted through the # 60 (0.25 mm) screen; 4. Rinse the sieve from Step 3 with Part II of 5- CNAC; 5. The Aerosil 200PH and Part I of Avicel PH 101 are sifted through the # 20 mesh screen (0.85 millimeters); 6. Add the Avicel PH 101 (Part II), sift the material from Step 5, 5-CNAC (Part III), sift the material from Step 4, Crospovidona, into the diffusion mixer, and mix it by 150 revolutions; 7. The mixed material is sifted through a # 20 mesh screen (0.85 millimeters); 8. Magnesium stearate is sieved through a # 20 mesh screen (0.85 millimeters), and added to the mixture from Step 7; 9. Lubrication for 50 revolutions; 10. Compress the mixture into 12-millimeter flat-faced bevelled edge embossed tablets. All the equipment used is the same as that described in Example 1.

EXAMPLE 7: Administration to Primates The following tables were prepared by the methods described hereinabove, and were tested in Rhesus monkeys. Lot A 1. 0.8 mg, DT 2m35s, Strength 8.5 kN 2. 0.8 mg, DT 5m40s, Strength 11.2 kN 3. 0.8 mg, DT 8m34s, Strength 12.1 kN Lot B 1. 0.6 mg, DT 3m40s-5m35s, Strength 8kN 2 0.6 mg, DT 6m15s-7m55s, Force 9kN 3. 0.6 mg, DT 9m, Force 10.2 kN Lot C 1. 0.8 mg, DT 2m, Force 8.2 kN Rhesus monkeys are fasted during the night before dosing, and are restrained in fully conscious chairs, for the duration of the study period. One tablet of each Lot is administered to each monkey by oral intubation, followed by 10 milliliters of water. Blood samples are collected from the Rhesus monkeys immediately before administration, and at 0.25, 0.5, 0.75, 1.1. 5.2, 3.4, 5, and 6 hours after its administration. The resulting plasma salmon calcitonin for each dose and for each monkey is determined by radioimmunoassay.

For each monkey, the salmon calcitonin in primate plasma (SCt) is calculated for a batch and a period of time, plasma SCt concentrations for all monkeys for a batch and a period of time, the standard deviation (SD ) of SCt concentrations in plasma for a batch and a period of time, and the standard error of the average (SEM) for SCt concentrations in plasma for all monkeys for a batch and a period of time, and are reported in Figure 5

Claims

1. An oral pharmaceutical composition in solid phase, which comprises: iv. a poly- (amino acid); v. a supply agent; and, optionally, vi. a diluent; wherein the composition has a disintegration time of not more than 10 minutes and a solution of > 80 percent in 20 minutes.

2. A solid phase oral pharmaceutical composition, which comprises: vii. a poly- (amino acid); viii. a supply agent; and, optionally, ix. a diluent; wherein the composition has a disintegration time of no more than 6 minutes and a solution of > 90 percent in 20 minutes.

3. The composition of claim 1, which has a disintegration time of not more than 2 minutes.

4. The composition of any one of claims 1 to 3, which further comprises a disintegrant, in particular a disintegrant selected from any super-disintegrant, such as a crospovidone or a povidone.

5. The composition of any of claims 1 to 3, which additionally comprises an agent that decreases the disintegration time by effervescent means and / or other means.

6. The pharmaceutical composition of any of claims 1 to 5, which has a dissolution time of > 80 percent in no more than 20 minutes in the gastric environment.

7. The pharmaceutical composition of any of claims 1 to 6, which is in the form of a compressed tablet, wherein the tablet has a hardness of between 3 Kp and 20 Kp.

8. The pharmaceutical composition of claim 7, which is in the form of a compressed tablet, wherein the tablet has a hardness of between 5 Kp and 15 Kp.

9. The pharmaceutical composition of claim 8, which has a disintegration time of less than 1 minute, and a hardness of between 5 Kp and 7 Kp.

The composition of any of claims 1 to 9, wherein the poly- (amino acid) is a polypeptide hormone.

The composition of claim 10, wherein the hormone is calcitonin.

The composition of claim 5, wherein the calcitonin is salmon calcitonin.

The composition of any of claims 11 to 12, which comprises a calcitonin in a therapeutically effective amount in free or salt form, which provides a peak plasma concentration (Cmax) of not less than 400 picogram / milliliter and / or a reduction in the plasma calcium level of > 20 percent in 6 hours in primate animal models, particularly monkeys.

The composition of claim 13, wherein the Cmax is not less than 800 picograms / milliliter.

15. The composition of claim 13, wherein the Cmax is not less than 1,000 picograms / milliliter.

16. The composition of any one of claims 11 to 15, which comprises a therapeutically effective amount of a calcitonin in free or salt form, in a dosage range of between 0.15 milligrams and 2.5 milligrams.

17. The composition according to claim 16, wherein the dosage range is between 0.15 milligrams and 0.4 milligrams.

The composition of any of the preceding claims, wherein the delivery agent is 5-CNAC.

19. The composition of any of the preceding claims, wherein the disintegrant is crospovidone and / or povidone.

20. The composition of any one of the preceding claims, wherein the composition additionally comprises one or more of a thickening agent, a stabilizer, and a dry binder.

21. The pharmaceutical composition of any of claims 7 to 9, wherein the tablet has a weight of 500 milligrams.

22. The pharmaceutical composition of any of the preceding claims, which comprises: x. Calcitonin from 0.03 to 0.5% by weight xi. 5-CNAC micronized from 5 to 80% by weight xii. Avicel PH 102 or 101 from 0 to 70% by weight xiii. Crospovidona, NF from 0 to 10% xiv. Magnesium stearate from 0 to 1.5% by weight xv. Cab-o-sil from 0 to 1.5% where the total percentages add up to 100.

23. A pharmaceutical combination, which includes xvi. the composition of any of claims 1 to 22. xvii. a co-agent, which is an inhibitor of bone resorption.

The combination of claim 23, wherein the coagent is a cathepsin K inhibitor.

25. A method for making an oral pharmaceutical composition, which comprises the steps of: xviii. Mix a poly- (amino acid), a vehicle, and a disintegrant, to make a first mixture. xix. Optionally mix a dry binder with the first mix to make a second mix. xx. Optionally mix a stabilizer with the second mixture to make a third mixture. xxi. Compress the third mixture to a tablet with a hardness of 5 Kp at 20 Kp.

26. The use of the pharmaceutical composition of any of claims 1 to 22, for the manufacture of a medicament for the treatment of a disease caused by abnormal bone resorption.

27. The use of claim 26, wherein the disease is osteoporosis.

28. The use of the pharmaceutical composition of any of claims 1 to 22, for the manufacture of a medicament for the treatment of an arthritic disease.

29. The use of claim 28, wherein the disease is osteoarthritis.

30. A method for determining the absorption properties of a composition according to any of claims 1 to 22, which comprises: xxii. determine the dispersion time, xxiii. correlate the dispersion time with the dissolution time.

31. A method for pre-determining the peak plasma concentration (Cmax) of an active ingredient in a patient to be treated with an oral pharmaceutical composition, which comprises said active ingredient, and a delivery agent, which method comprises adjust the disintegration time of the pharmaceutical composition and / or the time of dissolution of the active ingredient, such as to provide a favorable micro-environment in the gastrointestinal tract, for the dissolution of the active ingredient in the intestine, in order to optimize the absorption of the active ingredient, and to achieve a peak plasma concentration therapeutically effective of the active ingredient in the blood plasma.

32. A method according to claim 31, wherein the active ingredient is calcitonin, in particular salmon calcitonin.

33. A method according to claim 32, wherein the concentration in peak plasma is not less than 400 p i cog rams / thousand liter.

34. A method according to any of claims 31 to 33, wherein the oral pharmaceutical composition is provided in the form of a tablet, and the disintegration time is adjusted by adding the hardness of the tablet.

35. A method according to claim 34, wherein the hardness is in the range of between 3 Kp and 20 Kp.

36. A method according to claims 34 or 35, wherein the disintegration time is less than 10 minutes.

37. A method according to claim 36, wherein the disintegration time is less than 1 minute.

38. A method according to claim 31, wherein the favorable micro-environment in the gastrointestinal tract for the dissolution of the active ingredient in the intestine, is provided by the addition of 5-CNAC to the composition.

39. The use, to manufacture an oral pharmaceutical composition, having a disintegration time of not more than 10 minutes, of: (i) a poly- (amino acid); (ii) a supply agent; and (iii) a disintegrant.

40. The use, to manufacture an oral pharmaceutical composition, having a dissolution time of not more than 10 minutes, of: (iv) a poly- (amino acid); (v) a supply agent; and (vi) a disintegrant.

41. The use of 5-CNAC to provide a favorable micro-environment in the gastrointestinal tract for the dissolution of salmon calcitonin.

42. A pharmaceutical composition substantially as described hereinabove, with reference to the Examples.

43. A method substantially as described hereinabove, with reference to the Examples.