JP2020512292A - Method for treating irritable bowel syndrome with modified or delayed release formulation of linaclotide - Google Patents

Abstract

The present invention provides a method for treating a patient having a condition, such as a GI disorder, or a GI or non-GI disorder, by administering a therapeutically effective amount of a delayed release pharmaceutical composition comprising linaclotide. . Despite the need for delayed release compositions of linaclotide, due to the inherent chemical instability of linaclotide, for example, moisture-induced degradation reactions such as hydrolysis, deamidation, isomerization and Due to multimerization, there are difficulties in preparing such formulations. The present application provides means for solving this problem.

Description

FIELD OF THE INVENTION The present invention treats various indications including gastrointestinal (GI) disorders such as irritable bowel syndrome constipation (IBS-c), and conditions associated with GI or non-GI disorders such as abdominal pain. For the use of a delayed release pharmaceutical composition comprising linaclotide.
Sequence listing

Claiming Priority This application claims priority under 35 U.S.C. 119 (e) to US Provisional Patent Application No. 62 / 437,566, filed December 21, 2016. The entire contents of this provisional patent application are hereby incorporated by reference.

Sequence Listing This application incorporates by reference in its entirety the Sequence Listing for the title “IW196PCT1_ST25.txt” (4,514 bytes), which was created on Dec. 20, 2017 and was submitted electronically with this specification.

BACKGROUND OF THE INVENTION In the United States, tens of millions of adults suffer from gastrointestinal (GI) disorders such as irritable bowel syndrome (IBS), chronic idiopathic constipation (CIC), diverticulitis and ulcerative colitis. . Many other people suffer from symptoms such as abdominal pain, discomfort and bloating associated with GI or non-GI disorders. An estimated 13 million adults in the United States have constipated irritable bowel syndrome (IBS-c). IBS-c is a chronic functional gastrointestinal disorder characterized by abdominal pain, discomfort and bloating associated with altered bowel habits. There are few currently available therapies to treat these disorders, and such therapies have a high rate of dissatisfaction. Patients suffering from GI disorders such as IBS-c can be physically, psychologically, socially and economically affected.

Roman III diagnostic criteria for irritable bowel syndrome (IBS) is associated with 2 or more of the following, starting at least 6 months prior to diagnosis and starting at 3 days per month for 3 months prior to diagnosis: Often include recurrent abdominal pain or discomfort:
a. Abdominal discomfort or pain is reduced by defecation;
b. Onset of symptoms is associated with changes in stool frequency;
c. Onset of symptoms is associated with changes in stool morphology or appearance.

  The Roman III diagnostic criteria are: Constipatory irritable bowel syndrome (IBS-c) in patients with hard or lumpy stools (Bristol stool quality scale 1-2) with at least 25% BM and less than 25% It is further defined as having soft or watery stools (Bristol stool quality scale 6-7) with BM.

  Patients with IBS-c report symptoms including (i) changes between constipation and normal stools, and (ii) lower abdominal cramps, pain or discomfort commonly induced by feeding There is also.

US Pat. Nos. 7,304,036 and 7,371,727, incorporated herein by reference, are guanylate cyclase C (GC-C) receptors for the treatment of gastrointestinal (GI) disorders. Disclosed are peptides that act as agonists of. One particular peptide disclosed is linaclotide, which consists of the following amino acid sequence: Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr. Linaclotide is
It has the chemical structure of

  Linaclotide is administered orally and is approved by the FDA for the treatment of constipated irritable bowel syndrome (IBS-c) and chronic idiopathic constipation (CIC) in the United States. In humans, linaclotide affects GI physiology, including reducing visceral pain, reducing bloating and accelerating GI transit, which increases stool frequency and improves stool consistency. Has been shown to be possible. Orally administered linaclotide acts locally by binding to and activating the GC-C receptor at the luminal surface of the intestine. The GC-C receptor is a key regulator of intestinal function in mammals and is found throughout the luminal surface of the GI tract. The GC-C receptor responds to the endogenous hormones guanillin and uroguanylin and to the enterobacterial peptide (ST peptide) from the thermostable enterotoxin family. Binding of linaclotide to the GC-C receptor results in intracellular elevation of the second messenger cyclic GMP (c-GMP) and an increase in chloride and bicarbonate secretion, which results in an increase in intestinal secretions. , Reduce abdominal pain.

  Under FDA approval, linaclotide is administered as an oral solid immediate release capsule formulation prepared by filling drug layered beads into gelatin capsules. Due to the high expression of GC-C receptors throughout the GI tract, linaclotide from immediate release formulations activates GC-C receptors starting in the upper GI tract and lowering significant amounts of intestinal fluid in the lower part. Bring to the GI tract. To reduce or mitigate this effect, delayed release compositions targeting the release of linaclotide in the distal or lower compartments of the gastrointestinal tract are needed. Targeting the lower GI for linaclotide release helps avoid excessive intestinal secretions, while at the same time maintaining or improving the efficacy of linaclotide for treating the abdominal and intestinal symptoms of GI disorders. Can help.

  Various formulation techniques, including the use of enteric coatings or pH-responsive polymers, have been used to develop delayed release compositions for pharmaceutically active agents. However, the specific components of these compositions will vary widely and will be highly dependent on the particular pharmaceutically active agent and the desired properties. For example, the formulation must be compatible with the pharmaceutically active agent and must also provide the required dissolution performance and stability characteristics.

  Linaclotide was previously demonstrated to reduce visceral pain in the GI tract, which is thought to be mediated by increased cGMP. Animal studies have shown that orally administered linaclotide can treat colon and hyperalgesia. However, due to the reducing environment of the intestinal tract, many of the oral linaclotide doses are known to be degraded before reaching the distal colon. In human volunteers treated with linaclotide, only about 5% of the oral dose is found in stool. A delayed release (“DR”) composition of linaclotide targeting the lower GI is directed towards reducing pain associated with various GI disorders by allowing delivery of higher doses of linaclotide to the colon. Can improve the efficacy of linaclotide. Such a DR composition of linaclotide has the potential to predominantly (or completely) release linaclotide in the lower GI. As a result, for example, a DR formulation or composition may have increased ability to treat lower GI-related disorders. Surprisingly, orally administered linaclotide has also been demonstrated to reduce visceral pain in non-GI tissues, and the mechanism of linaclotide-mediated visceral pain relief is mediated only by promoting secretion. It provides further evidence that it is not. This result suggests that cGMP modulators whose distribution is restricted to GI can reduce pain and can be used as a treatment to reduce pain in other parts of the body. However, for non-constipated patients, linaclotide may cause visceral pain in non-GI tissues (eg, ulcerative colitis, diverticulitis, IBS, overactive bladder syndrome, bladder hypersensitivity or colitis-induced bladder afferent hyperactivity). To be a useful therapy for the treatment of, it is necessary to reduce or eliminate the secretagogue effect of linaclotide. Thus, in one aspect, it is necessary to develop means to at least partially or completely separate the effect of promoting secretion from the effect of linaclotide on reducing visceral pain.

  Moreover, for example, it causes lower overall intestinal secretions by not activating the GC-C receptor in the upper GI, thus causing adverse events (eg, diarrhea) with a lower incidence than immediate release dosage forms. It may have the ability to cause. This is achieved while maintaining or even improving the efficacy of linaclotide for treating symptoms of GI disorders such as pain.

Despite the need for delayed release compositions of linaclotide, due to the inherent chemical instability of linaclotide, for example, moisture-induced decomposition reactions such as hydrolysis, deamidation, isomerization and Due to multimerization, there are difficulties in preparing such formulations. These difficulties can be exacerbated when producing formulations with lower dosages of linaclotide.
Therefore, there is a need for a delayed release composition that provides stable and reliable delivery of linaclotide to the targeted area of the gastrointestinal tract. There is also a need for methods of treating IBS-c by administering a delayed release composition of linaclotide.

US Pat. No. 7,304,036 US Pat. No. 7,371,727

SUMMARY OF THE INVENTION In general, the invention relates to methods of treating disorders such as gastrointestinal (GI) disorders (eg, IBS-c), or conditions associated with GI or non-GI disorders (eg, abdominal pain).

  One aspect of the invention is a method of reducing the incidence or severity of adverse events associated with administration of linaclotide, comprising the step of orally administering to a subject a delayed release pharmaceutical tablet composition comprising linaclotide, wherein the tablet comprises , A delayed release pharmaceutical tablet composition comprising an enteric coating comprising a pH sensitive polymer that releases linaclotide in the lower GI of a subject when compared to administration of an equal dose of linaclotide in an immediate release dosage form, wherein the delayed release pharmaceutical tablet composition is constipated and / or Alternatively, the method further comprises a therapeutically effective amount of linaclotide for treating pain.

  Another aspect of the invention is a method of reducing the incidence or severity of adverse events associated with administration of linaclotide in a subject comprising the step of orally administering a delayed release pharmaceutical tablet composition comprising linaclotide. Wherein the method comprises an enteric coating comprising a pH sensitive polymer that releases a therapeutically effective amount of linaclotide for treating constipation and / or pain in a subject.

  Another aspect of the invention is a method of reducing the intestinal fluid secretagogue effect of linaclotide, comprising the step of orally administering to the subject a delayed release pharmaceutical tablet composition comprising linaclotide, the tablet comprising linaclotide in the lower GI of the subject. The method further comprises an enteric coating that comprises a pH-sensitive polymer that releases a.

  Yet another aspect of the invention is a method of treating visceral or abdominal pain in a non-constipated subject comprising the step of orally administering a delayed release pharmaceutical tablet composition comprising linaclotide, wherein the tablet is in the stomach of the subject. The method further comprises an enteric coating and a pH sensitive polymer that releases an amount of linaclotide that is less than the amount effective to induce secretion in the subject.

  Another aspect of the invention is a method of treating irritable bowel syndrome constipation (IBS-c), which comprises orally administering to a patient in need thereof a delayed release pharmaceutical tablet composition comprising a therapeutically effective amount of linaclotide. A method comprising the step of administering.

  Yet another aspect of the invention is a method of treating abdominal pain comprising orally administering to a patient in need thereof a delayed release pharmaceutical tablet composition comprising a therapeutically effective amount of linaclotide. is there.

FIG. 1 is a diagram of three separate time periods of the trial described in Example 18.

FIG. 2 is a plot of the primary efficacy parameters, 6/12 week APC + 1 responders, for the eight treatment groups as described in Example 20.

3A and 3B are plots of secondary efficacy parameters, weekly SBM frequency above baseline, for the eight treatment groups as described in Example 20.

FIG. 4 is a plot of the main efficacy parameters, weekly changes in abdominal pain from baseline for the eight treatment groups as described in Example 20.

FIG. 5 is a plot of secondary efficacy parameters, CSBM frequency above baseline at 12 weeks for the 8 treatment groups as described in Example 20.

6A and 6B are plots of secondary efficacy parameters, 6/12 and 9/12 CSBM responders, for the eight treatment groups as described in Example 20.

7A and 7B are plots of secondary efficacy parameters, 6/12 and 9/12 abdominal pain responders, for the eight treatment groups as described in Example 20.

FIG. 8 is a plot of secondary efficacy parameters, abdominal pain change from baseline at week 12 for the eight treatment groups as described in Example 20.

FIG. 9 is a plot of secondary efficacy parameters, SBM frequency above baseline at 12 weeks for the 8 treatment groups as described in Example 20.

FIG. 10 is a plot of secondary efficacy parameters, SBM frequency above weekly baseline, for the eight treatment groups as described in Example 20.

FIG. 11 is a plot of secondary efficacy parameters, change in stool stiffness from baseline (BSFS) at week 12 for the eight treatment groups as described in Example 20.

Figure 12: Secondary efficacy parameters for 8 treatment groups as described in Example 20, change in abdominal symptom score above baseline at 12 weeks, change in abdominal pain above baseline at 12 weeks, FIG. 9 is a plot of changes in abdominal discomfort above baseline at 12 weeks and changes in abdominal distension above baseline at 12 weeks.

FIG. 13 is a plot of secondary efficacy parameters, treatment satisfaction for eight treatment groups as described in Example 20.

FIG. 14 is a plot of total diarrhea TEAE rates for eight treatment groups as described in Example 20.

FIG. 15 is a plot of total diarrhea and diarrhea-induced dropout (ADO) rates for eight treatment groups as described in Example 20.

FIG. 16 is a plot of diarrhea TEAE by severity for eight treatment groups as described in Example 20.

17A, 17B, and 17C are plots of certain efficacy parameters compared to data from the Linzess® Phase III clinical trial. Same as above Same as above

FIG. 18 is a plot of the diarrhea TEAE rate compared to data from a Linzess® Phase III clinical trial.

FIG. 19 is a plot of diarrhea TEAE by severity compared to data from a Linzess® Phase III clinical trial.

FIG. 20A is a diagram showing the release profiles at various pHs of a delayed release composition containing 100 μg of linaclotide. FIG. 20B shows the effect of changing the ratio of pH sensitive polymer on the release profile.

FIG. 21 is a plot of percent change from baseline in weekly abdominal pain at Week 12 for DR1 composition, IR composition and placebo.

Detailed Description of the Invention A. Method of treatment

  One aspect comprises orally administering a delayed release composition comprising linaclotide used to treat any number of diseases, disorders or conditions including constipation and / or pain (eg, visceral pain, abdominal pain). Methods of treatment are generally described herein. For example, a method of treatment, as described herein, comprising the step of orally administering a delayed release pharmaceutical tablet composition comprising linaclotide provides constipation irritable bowel syndrome (IBS-c) in a patient in need thereof. Used to treat. A patient can be diagnosed with IBS-c according to Roman criteria (eg, Rome III). In another embodiment, the method of treatment described herein comprising the step of orally administering a delayed release pharmaceutical tablet composition comprising linaclotide is used to treat abdominal pain in a patient in need thereof. To be done.

  One aspect of the invention is a method of reducing the incidence or severity of adverse events associated with administration of linaclotide, comprising the step of orally administering to a subject a delayed release pharmaceutical tablet composition comprising linaclotide, wherein the tablet comprises , A delayed release pharmaceutical tablet composition comprising an enteric coating comprising a pH sensitive polymer that releases linaclotide in the lower GI of a subject when compared to administration of an equal dose of linaclotide in an immediate release dosage form, wherein the delayed release pharmaceutical tablet composition is constipated and / or Alternatively, the method further comprises a therapeutically effective amount of linaclotide for treating pain.

  Another aspect of the invention is a method of reducing the incidence or severity of adverse events associated with administration of linaclotide in a subject comprising the step of orally administering a delayed release pharmaceutical tablet composition comprising linaclotide. Wherein the method comprises an enteric coating comprising a pH sensitive polymer that releases a therapeutically effective amount of linaclotide for treating constipation and / or pain in a subject.

  In some embodiments, the reduction in incidence or severity of adverse events is a reduction in incidence or severity of adverse events as compared to administration of equal doses of linaclotide in immediate release dosage form. In some embodiments, the adverse event is diarrhea. In some embodiments, the incidence of adverse events is reduced. In some embodiments, the severity of adverse events is reduced.

  Another aspect of the invention is a method of reducing the intestinal fluid secretagogue effect of linaclotide, comprising the step of orally administering to the subject a delayed release pharmaceutical tablet composition comprising linaclotide, the tablet comprising linaclotide in the lower GI of the subject. The method further comprises an enteric coating that comprises a pH-sensitive polymer that releases a.

  Yet another aspect of the invention is a method of treating visceral or abdominal pain in a non-constipated subject comprising the step of orally administering a delayed release pharmaceutical tablet composition comprising linaclotide, wherein the tablet is in the stomach of the subject. The method further comprises an enteric coating and a pH sensitive polymer that releases an amount of linaclotide that is less than the amount effective to induce secretion in the subject.

  Another aspect of the invention is a method of treating irritable bowel syndrome constipation (IBS-c), which comprises orally administering to a patient in need thereof a delayed release pharmaceutical tablet composition comprising a therapeutically effective amount of linaclotide. A method comprising the step of administering.

  Yet another aspect of the invention is a method of treating abdominal pain comprising orally administering to a patient in need thereof a delayed release pharmaceutical tablet composition comprising a therapeutically effective amount of linaclotide. is there.

  In some embodiments, the delayed release pharmaceutical tablet composition comprises a therapeutically effective amount of linaclotide to reduce, prevent or reduce pain or constipation in a subject. In some embodiments, the delayed release pharmaceutical composition comprises a therapeutically effective amount of linaclotide that reduces, prevents or reduces pain in a subject but does not affect bowel habits. In some embodiments, the delayed release pharmaceutical composition provides less than an effective amount of linaclotide to substantially affect bowel habits. In some embodiments, the bowel habit is selected from CSBM rate, SBM rate or stool consistency.

  In some embodiments, the subject is diagnosed with constipated irritable bowel syndrome (IBS-c).

  In some embodiments, the delayed release pharmaceutical tablet composition comprising linaclotide releases less than 50%, less than 40%, less than 25% or less than 10% of linaclotide in the stomach.

  In some embodiments, the delayed release pharmaceutical tablet composition is administered once daily. In some embodiments, the delayed release pharmaceutical tablet composition is administered once daily in the morning. In some embodiments, the delayed release pharmaceutical tablet composition is administered once a day in the morning, at least 30 minutes before breakfast. In some embodiments, the delayed release pharmaceutical tablet composition is administered after the patient has fasted for at least 2 hours. In some embodiments, the delayed release pharmaceutical tablet composition is administered for at least 12 weeks.

  In some embodiments, the administering step increases the number of spontaneous defecation (CSBM) without stool sensation by the patient. In some embodiments, the administering step reduces abdominal pain in the patient. In some embodiments, the administering step increases the number of spontaneous defecation (CSBM) by the patient from baseline at least once per week for at least 6 out of 12 weeks. Let In some embodiments, the administering step reduces abdominal pain in the patient by at least 30% from baseline for at least 6 out of 12 weeks. In some embodiments, the administering step increases the number of spontaneous defecation (CSBM) without stool deficiency by the patient from baseline at least once per week for at least 6 out of 12 weeks. The method according to any of the preceding claims, wherein the administering step reduces abdominal pain in the patient by at least 30% from baseline for at least 6 out of 12 weeks.

  In some embodiments, the administering step improves one or more (eg, two or more) of the following: abdominal pain, CSBM frequency rate, SBM frequency rate, stool consistency, Stomach abdomen, abdominal discomfort, abdominal distention, abdominal symptom score, constipation severity, IBS symptom severity, days of use of per protocol rescue medication, treatment satisfaction, and appropriate relief assessment.

  In some embodiments, the administering step results in improvement in one or more (eg, two or more) of the following efficacy parameters: Weekly change from baseline in abdominal pain. , Weekly change from baseline in CSBM frequency, 6/12 week APC + 1 responders, 6/12 week CSBM + 1 responders, 9/12 week CSBM + 1 responders, 6/12 week abdominal pain responders, 9/12 week Abdominal pain responders, weekly CSBM + 1 responders, weekly abdominal pain responders, weekly APC + 1 responders, change from baseline in 12-week abdominal pain, change from baseline in 12-week CSBM frequency rate, 12 From baseline in weekly SBM frequency , Change from baseline in 12-week stool hardness, change from baseline in 12-week stomach belly, change from baseline in 12-week abdominal discomfort, baseline in 12-week abdominal distention Change from baseline in 12-week abdominal symptom score, change from baseline in 12-week constipation severity, change from baseline in 12-week IBS symptom severity, use of per protocol rescue medication Assessment of change from baseline in 12-week percent of days, treatment satisfaction, and appropriate relief.

  In some embodiments, the administering step ameliorates one or more of the following as compared to treatment with the immediate release composition of linaclotide: abdominal pain, CSBM frequency rate, SBM frequency rate, stool consistency. Severity, abdominal discomfort, abdominal discomfort, abdominal distension, abdominal symptom score, constipation severity, IBS symptom severity, days of use of per protocol rescue medication, treatment satisfaction, and appropriate relief assessment.

  In some embodiments, the administering step results in an improvement in one or more of the following efficacy parameters as compared to treatment with the immediate release composition of linaclotide: Weekly from baseline in abdominal pain. Change from baseline to week in CSBM frequency, 6/12 week AP + 1 responders, 6/12 week CSBM + 1 responders, 9/12 week CSBM + 1 responders, 6/12 week abdominal pain responders, 9 / 12 Week Abdominal Pain Responder, Weekly CSBM + 1 Responder, Weekly Abdominal Pain Responder, Weekly APC + 1 Responder, 12 Week Abdominal Pain Change From Baseline, 12 Week CSBM Frequency Rate Change From Baseline , Base on 12-week SBM frequency Change from in, change from baseline in stool hardness at 12 weeks, change from baseline at 12 weeks swelling abdomen, change from baseline in abdominal discomfort at 12 weeks, abdominal distension at 12 weeks From baseline, change from baseline in 12-week abdominal symptom score, change from baseline in 12-week constipation severity, change from baseline in 12-week IBS symptom severity, per protocol rescue Assessment of change from baseline in 12-week percent drug use, treatment satisfaction, and appropriate relief.

  In some embodiments, the administering step results in a reduction in the risk of an adverse event in the patient as compared to treatment with the immediate release composition of linaclotide. In some embodiments, the administering step results in a reduction in the risk of diarrhea in the patient as compared to treatment with the immediate release composition of linaclotide. In some embodiments, the administering step results in at least a 20% reduction in the risk of diarrhea in the patient as compared to treatment with the immediate release composition of linaclotide. In some embodiments, the administering step results in a reduction in the risk of severe diarrhea in the patient as compared to treatment with the immediate release composition of linaclotide.

  Another aspect of the invention is a method of treating or alleviating pain, comprising the step of administering a therapeutically effective amount of a delayed release pharmaceutical tablet composition described herein to a patient in need thereof. Is the way.

  In some embodiments, the pain is selected from visceral pain; diverticulitis pain; pelvic pain; abdominal pain; or pain associated with gastrointestinal disorders, sexually transmitted diseases, bladder pain syndrome or interstitial cystitis. In some embodiments, the pain is whole abdominal pain, diverticulous disease, pain associated with irritable bowel syndrome (IBS), chronic or acute radiation rectal disease (also called radiation proctitis), rectal pain, chronic anus. Peripheral pain, transient rectal pain, anal pain, chronic anal fissure, postoperative anal pain, overactive bladder syndrome, stress incontinence, interstitial cystitis, bladder pain syndrome, cancer-related pain, gastrointestinal neoplasm Associated pain, pelvic pain, endometriosis, vulva, chronic prostatitis, prostatic pain, vulvar pain, urethral syndrome, penile pain, perianal pain, and ulcerative colitis, ulcerative rectus Selected from pain associated with enteritis or Crohn's disease.

  In some embodiments, the method of treating a patient comprises administering a once-daily delayed release composition comprising a therapeutically effective amount of linaclotide. In some embodiments, the composition is administered once daily in the morning. In some embodiments, the composition is administered at least 30 minutes prior to ingestion of food once daily, for example, at least 30 minutes before breakfast, once daily in the morning. In some embodiments, the composition is administered after the patient has fasted, eg, after the patient has fasted for at least 2 hours, at least 4 hours, at least 8 hours or at least 10 hours.

  In certain aspects of the methods of the invention, the composition is administered for a period greater than 4 weeks (eg, at least 8 weeks, at least 12 weeks or at least 26 weeks). In some aspects of the methods of the invention, linaclotide is administered at least once per week, at least twice per week, at least three times per week, at least four times per week, for one week each day of the week. At least 5 times or at least 6 times a week.

  In one aspect, a method of treating a patient comprises orally administering a delayed release composition comprising a therapeutically effective amount of linaclotide, wherein the administering step comprises the frequency of spontaneous defecation (CSBM) without sensation of residual stool by the patient. To increase. In some embodiments, the CSBM frequency rate increases up to 3 or more CSBMs per week. In some embodiments, the CSBM frequency rate is increased by one or more CSBMs per week as compared to baseline levels of CSBM prior to treatment with the delayed release composition of linaclotide. In some embodiments, the frequency of CSBM by the patient is increased compared to treatment with the immediate release composition of linaclotide. In some aspects, the administering step increases the spontaneous defecation (SBM) frequency rate for the patient. In some embodiments, the frequency of SBM is increased compared to treatment with an immediate release composition of linaclotide.

  In another aspect, a method of treating a patient comprises administering a delayed release composition comprising a therapeutically effective amount of linaclotide, the administering step reducing abdominal pain in the patient. In some embodiments, abdominal pain is reduced by at least 30% (eg, at least 40%, at least 50%) compared to baseline levels of abdominal pain prior to treatment with the delayed release composition of linaclotide. In some embodiments, abdominal pain in the patient is reduced as compared to treatment with the immediate release composition of linaclotide. In some embodiments, abdominal pain is reduced by at least 30% (eg, at least 40%, at least 50%) at 12 weeks after administration for 12 weeks.

  In another aspect, a method of treating a patient comprises administering a delayed release composition comprising a therapeutically effective amount of linaclotide, the administering the step comprising: And reduce abdominal pain in the patient.

  In another aspect, a method of treating a patient comprises administering a delayed release composition comprising a therapeutically effective amount of linaclotide, the administering step comprising: a patient with abdominal pain above moderate; In patients with severe abdominal pain, or patients with severe to very severe abdominal pain, abdominal symptoms (eg, pain, discomfort, bloating) and / or bowel symptoms (eg, CSBM per week, 1 week). SBM per hit, stool hardness, swelling belly).

  Importantly, administration of the delayed release composition comprising linaclotide described herein has the following advantages: increased in number of CSBM, reduced in abdominal pain or discomfort, reduced in bloating, in constipation severity. Decrease, improvement in stool consistency, increase in SBM frequency, increase in BM frequency, decrease in stomach belly during defecation, improvement in abdominal symptom score, improvement in IBS symptom severity, decrease in use of per protocol rescue medication , And the improvement is a patient assessment of quality of life, treatment satisfaction or appropriate relief. The improvement may be an improvement compared to treatment with an immediate release composition of linaclotide.

  In some embodiments, a method of treating a patient is irritable bowel syndrome (IBS), constipation, constipated irritable bowel syndrome (IBS-c), diarrhea irritable bowel syndrome in a patient in need thereof. (IBS-d), mixed IBS (IBS-m), unclassifiable IBS (IBS-u), chronic idiopathic constipation (CIC), colon cancer, diverticulitis, ulcerative colitis, functional gastrointestinal disorder, Gastroesophageal reflux disease, functional heartburn, dyspepsia, visceral pain, abdominal pain, gastroparesis, chronic pseudointestinal obstruction, pseudocolonic obstruction, Crohn's disease, inflammatory bowel disease, overactive bladder syndrome, bladder hypersensitivity Or treating a disorder selected from colitis-induced colitis-induced bladder afferent hyperactivity. In some embodiments, the method of treating a patient comprises treating a condition in a patient in need thereof, such as a GI disorder, or alternatively a non-GI disorder. For example, the treatment can be for abdominal pain, discomfort or bloating, or visceral pain associated with a disorder (GI or non-GI). For example, the patient can be a non-constipated patient.

  In a further embodiment, the disorder or condition treated is selected from visceral pain; diverticulitis pain; pelvic pain; abdominal pain; or pain associated with gastrointestinal disorders, sexually transmitted diseases, bladder pain syndrome or interstitial cystitis. In a further embodiment, the disorder or condition treated is pain in the entire abdomen, diverticulopathy, pain associated with irritable bowel syndrome (IBS), chronic or acute proctopathy (also called radiation proctitis). Associated with rectal pain, chronic perianal pain, transient rectal pain, anal pain, anal fissure, postoperative anal pain, overactive bladder syndrome, stress incontinence, interstitial cystitis, bladder pain syndrome, cancer Pain, pain associated with gastrointestinal neoplasms, pelvic pain, endometriosis, pudendal pain, chronic prostatitis, prostatic pain, vulvar pain, urethral syndrome, penile pain, perianal pain, and ulcerative It is a pain selected from pain associated with colitis, ulcerative proctitis or Crohn's disease. In further embodiments, the disorder or condition treated is constipation, such as chronic constipation, opioid-induced constipation, post-operative constipation (postoperative ileus), and a combination of constipation or symptoms thereof associated with a neuropathic disorder ( Disorders or conditions associated with, for example, a combination of irritable bowel syndrome and chronic constipation), constipation associated with neuropathic disorders (eg, constipation associated with Parkinson's disease), constipation associated with cystic fibrosis or thyroid disease, Is.

  In some embodiments, the disorder or condition treated is a disorder or condition associated with lower GI (eg, lower GI disorder).

  In some embodiments, the methods of treatment described herein include whole abdominal pain, diverticulopathy, pain associated with irritable bowel syndrome (IBS), chronic or acute radiation rectal disorders (radiation proctitis). Also called), rectal pain, chronic perianal pain, transient rectal pain, anal pain, chronic anal fissure, postoperative anal pain, overactive bladder syndrome, stress incontinence, interstitial cystitis, bladder pain syndrome, cancer Pain associated with, gastrointestinal neoplastic pain, pelvic pain, endometriosis, pudendal pain, chronic prostatitis, prostatic pain, vulvar pain, urethral syndrome, penile pain, perianal pain, Useful for the treatment of a disease or condition associated with visceral pain selected from the group consisting of ulcerative colitis, ulcerative proctitis and Crohn's disease. In one particular embodiment, the compositions described herein are useful for treating bladder pain syndrome. In another specific embodiment, the compositions described herein are useful for the treatment of overactive bladder syndrome, including, for example, bladder hypersensitivity or colitis-induced bladder afferent hyperactivity. Is.

  In yet another embodiment, the methods of treatment described herein are useful for treating interstitial cystitis. In yet another embodiment, the compositions described herein are useful for treating endometriosis. In another embodiment, the compositions described herein are useful for the treatment of anal pain.

  In some embodiments, there is provided a method of treating a disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a composition described herein. In some embodiments, the disorder is colorectal / locally metastasized colorectal cancer, intestinal polyp, Barrett's esophagus, gastrointestinal tract cancer, lung cancer, cancer of epithelial cells or pre-cancerous or metastatic growth, It is a cancer selected from polyps, breast, colorectal, lung, ovary, pancreas, prostate, kidney, stomach, bladder, liver, esophagus and testicular cancer.

  In some embodiments, a method for preventing gastrointestinal cancer or hyperplasia or recurrence of gastrointestinal cancer or hyperplasia in a patient in need thereof, comprising: A method is provided that includes administering to a patient an amount of a composition or oral dosage form. In some embodiments, the cancer or hyperplasia is colorectal cancer, intestinal polyps, or precancerous or metastatic growth of gastrointestinal epithelial cells. In some embodiments, the composition or oral dosage form is administered concurrently or sequentially with an effective amount of a COX-2 inhibitor. Examples of highly selective and selective COX-2 inhibitors include etoricoxib, rofecoxib, lumiracoxib, valdecoxib, celecoxib (Celebrex®), sulindac, diclofenac, meloxicam and etodolac. Non-selective NSAIDs that inhibit COX-2 include naproxen, ibuprofen, sodium salicylate and diflunisal. As used herein, the term "prevent" or "preventing" refers to, as compared to a patient who has not been treated with the compositions described herein. Cancer or hyperplasia, delaying the onset of cancer or hyperplasia (ie, the period before the clinical manifestation of the disease) or recurrence, and / or reducing the risk of developing cancer or hyperplasia. Means that.

  In some embodiments, methods are provided for treating gastrointestinal disorders in pediatric patients using the compositions and oral dosage forms described herein. In some embodiments, a method for treating a gastrointestinal disorder in a pediatric patient diagnosed with one or more gastrointestinal disorders or conditions, the method comprising administering to the patient an effective amount of a composition or oral dosage form. A method including is provided. In some embodiments, GI motility disorder, irritable bowel syndrome, constipated irritable bowel syndrome (IBS-c), mixed irritable bowel syndrome (IBS-m), chronic constipation, chronic idiopathic constipation, opioid induction. Sexual constipation, postoperative constipation (postoperative ileus), constipation associated with neuropathic disorders, constipation associated with cystic fibrosis or thyroid disease, dyspepsia (including functional dyspepsia or non-ulcer dyspepsia), stomach Paresis, gastrointestinal motility, functional gastrointestinal disorder, gastroesophageal reflux disease (GERD), inflammatory bowel disease, Crohn's disease, ulcerative colitis, functional heartburn, chronic pseudoileus (or pseudocolon obstruction) ), Visceral pain, abdominal pain, pelvic pain, anal fissure pain, pain associated with vulvar pain, pain associated with endometriosis, pain associated with fibromyalgia, functional abdominal pain, interstitial bladder Flame pain , Diverticulitis, a method of using the compositions and oral dosage forms to but includes pain associated with diverticulitis associated pain, and the celiac sprue treating gastrointestinal disorders including but not limited to be provided. In some embodiments, the compositions and oral dosage forms described herein are used to treat IBS-c, IBS-m or chronic constipation (eg, chronic idiopathic constipation) in pediatric patients. A method is provided. In some embodiments, a method for treating IBS-c in a pediatric patient in need thereof is provided. In some embodiments, methods are provided for treating chronic idiopathic constipation in a pediatric patient in need thereof.

  In some embodiments, the method is a method for treating or alleviating pain, comprising administering to a patient in need thereof a therapeutically effective amount of the composition described herein. In some embodiments, the pain is visceral pain; abdominal pain; pelvic pain; or gastrointestinal disorders, sexually transmitted diseases, bladder pain syndrome, diverticulitis pain, prostatitis, testicular pain, endometriosis, vulvar pain, rectal pain. Or selected from pain associated with interstitial cystitis. In some embodiments, the pain is pelvic pain, proctitis-related pain, anal fissure pain, vulvar pain-related pain, endometriosis-related pain, fibromyalgia-related pain, function. Abdominal pain, interstitial cystitis pain, pain associated with sexually transmitted disease, diverticulitis, pain associated with diverticulitis, and pain associated with celiac sprue.

  In some embodiments, the effective dose range of linaclotide for an adult human is 25 μg to 6 mg orally per day.

  In some embodiments, the dosage range is 15 μg to 2 mg orally per day. In some embodiments, the dose range for adult humans is 15 μg to 1 mg orally per day (e.g., 15 μg, 30 μg, 50 μg, 72 μg, 100 μg, 145 μg, 150 μg, 200 μg, 250 μg, 290 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 550 μg, 579 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg or 1 mg). In some embodiments, the dose range for adult humans is 30 μg to 300 μg orally per day. In some embodiments, the dosage range is 100 μg to 600 μg orally per day. In some embodiments, the dose is 30 μg, 100 μg, 150 μg, 200 μg, 300 μg, 400 μg, 500 μg or 600 μg linaclotide orally per day. In some embodiments, the dose is 50 μg orally linaclotide daily. In some embodiments, the dose is 100 μg linaclotide orally per day. In some embodiments, the dose is 145 μg linaclotide orally per day. In some embodiments, the dose is 200 μg linaclotide orally per day. In some embodiments, the dose is 290 μg linaclotide orally per day. In some embodiments, the dose is 300 μg linaclotide orally per day. In some embodiments, the dose is 500 μg orally linaclotide daily. In some embodiments, the dose is 600 μg linaclotide orally per day.

  In some embodiments, the effective pediatric dose range for linaclotide is 0.05 μg to 2 mg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.05 μg to 100 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.1 μg to 90 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.1 μg to 50 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.1 μg to 25 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.1 μg to 10 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.1 μg to 5 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.1 μg to 1 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.1 μg to 0.5 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.1 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.15 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.25 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 0.5 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 3.5 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 15 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 36 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 45 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 60 μg orally per day. In some embodiments, the effective pediatric dose range for linaclotide is 90 μg orally per day. In some embodiments, the unit dosage form and daily dose are equivalent.

  In some embodiments, the unit dosage form is administered with food at any time of the day, without food at any time of the day, and with food (eg, with breakfast) after an overnight fast. In some embodiments, the unit dosage form is administered once daily, twice daily or three times daily. In some embodiments, the one, two or three unit dosage forms comprise a daily oral dose of linaclotide. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose used will depend on several factors, including the age and sex of the patient, the exact disorder being treated, and its severity.

  In some embodiments, the composition is administered as a monotherapy. In some embodiments, the composition consists essentially of an effective amount of linaclotide. In some embodiments, the composition comprises an effective amount of linaclotide.

  In some embodiments, the composition is administered directly to the patient, for example in the form of a delayed release tablet or capsule. In some embodiments, the composition is dissolved, disintegrated, and / or mixed onto or in a food or beverage prior to administration to a patient (eg, an elderly or pediatric patient). In some embodiments, the composition is provided with stabilizer (s), preservative (s), sweetener (s) prior to administration to a patient (eg, an elderly or pediatric patient). ) Or the like as needed, in a liquid, solution or fluid, dissolved or disintegrated. In some embodiments, the composition is a multi-dose composition, ie, 2, 3, 5, 7, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 or Is a composition comprising a higher daily dose of linaclotide.

  In other embodiments, the composition is administered as part of a combination therapy. For example, the composition may be used in combination with other drugs or therapies used in the treatment, prevention, inhibition and / or amelioration of the diseases or conditions for which the compounds of this invention are useful. Linaclotide may be co-administered or co-formulated with other drug therapies. In one embodiment, the linaclotide composition is for treating gastrointestinal disorders including, but not limited to, antacids, such as histamine-2 receptor agonists (H2A) and / or proton pump inhibitors (PPI). Can be co-administered with other drug therapies used in. In one embodiment, the linaclotide composition may be co-administered with other drug therapies used to treat gastrointestinal disorders, including 5-ASA, such as mesalamine.

  Such other drug (s) may be administered by commonly used routes and in amounts and, therefore, contemporaneously or sequentially with a compound of the invention. When the compound of the invention is used concurrently with one or more other drugs, a pharmaceutical unit dosage form containing the compound of the invention in addition to such other drug can be used. Accordingly, the pharmaceutical compositions of the present invention include pharmaceutical compositions which, in addition to the compound of the present invention, also contain one or more other active ingredients.

  Includes immunoassays (eg enzyme linked immunosorbent assay), radioimmunoassays, immunoradiometric assays, gel electrophoresis (eg SDS-PAGE), high performance liquid chromatography (HPLC) and / or high performance capillary electrophoresis (HPCE). Several methods, including but not limited to, can be used to assess the bioactivity of a linaclotide composition. In some embodiments, the bioactivity of the composition is determined by immobilizing linaclotide, incubating linaclotide with guanylyl cyclase C (GCC), incubating linaclotide bound to GCC with an antibody against GCC, GCC The linaclotide bound to the antibody is incubated with a fluorescently labeled antibody against the GCC antibody, and the linaclotide bound to the GCC antibody is detected by measuring the fluorescence intensity using a plate reader. It The drug concentration can then be calculated based on the fluorescence reading of the solution.

  For example, the bioactivity of a linaclotide composition can be assessed and quantified using the following methods, although other methods are available. The composition is added to a volumetric flask containing 60 ml of phosphate buffer having a pH of 4.5 and the flask is shaken for 60 minutes. 0.2 ml of supernatant is then removed and added to one or more wells of a 96-well plate coated with GC-C receptor. The plate is sealed and incubated at 37 ° C for 2 hours. At the end of incubation, samples are removed and plates are washed with phosphate buffered saline (PBS). The bound linaclotide is then incubated in blocking buffer with fluorescein isocyanate (FITC) -labeled GC-C (available, for example, from Sigma-Aldrich Inc.) at room temperature for 1 hour. . After incubation, the wells are washed with PBS. The fluorescence intensity of the final product is detected, for example, by using a plate reader. The linaclotide concentration is then calculated based on the fluorescence reading of the solution.

  B. Delayed release composition

  A delayed release oral dosage form of linaclotide (collectively “DR”) is provided herein. The delayed release pharmaceutical composition of the present invention relates to a stable solid oral dosage form of linaclotide that exhibits a delayed release of linaclotide into the lower gastrointestinal tract. To date, the only approved formulations of linaclotide are capsules that exhibit immediate release ("IR"). These IR dosage forms release in the upper GI most or all of the linaclotide contained therein. This in turn causes GC-C receptor activation and intestinal secretions in the upper GI and to a lesser extent in the lower GI. The difference in GI activation and intestinal secretion between the upper and lower IR dosage forms indicates that linaclotide undergoes proteolytic digestion (when released from the dosage form), especially in the lower GI (eg, ileum, Partly due to the fact that by the time it reaches the terminal ileum, ileocecal valve or colon) it loses some or all of its ability to activate the GC-C receptor.

  In some embodiments, linaclotide is present in the composition in an amount between 30 μg and 1,000 μg. For example, in some embodiments, linaclotide is present in an amount of about 30 μg, about 100 μg, about 300 μg, about 500 μg, about 600 μg or about 1,000 μg, or linaclotide is 100 μg, 300 μg, 500 μg, 600 μg or 1 Present in an amount of 1,000 μg.

  In some embodiments, the composition comprises between 0% and 2% by weight of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline. , Serine, threonine, tryptophan, tyrosine and valine, or any mixture thereof, further comprising an amino acid selected from the group consisting of: In some embodiments, the composition further comprises between 0% and 2% by weight or between 0.5% and 1.5% by weight histidine. In some embodiments, the composition comprises between 0% and 3% by weight of calcium, potassium, magnesium, zinc, aluminum, manganese, chromium, cobalt, nickel, barium, and sodium, or any thereof. It further comprises a cationic salt selected from the group consisting of combinations or mixtures. In some embodiments, the composition further comprises between 0% and 3% by weight calcium salt. In some embodiments, the composition further comprises between 0 wt% and 2 wt% or between 0.2 wt% and 0.8 wt% anhydrous calcium chloride. In some embodiments, the composition further comprises between 0 wt% and 5 wt%, between 1 wt% and 3 wt%, or between 1 wt% and 1.88 wt% polyvinyl alcohol (PVA). Including.

  In some embodiments, the pH sensitive polymer has a solubility pH of at least 6.0, at least 6.5 or at least 7.0. In some embodiments, the pH sensitive polymer comprises a methyl acrylate-methacrylic acid copolymer (eg, Eudragit®). In some embodiments, the pH sensitive polymer comprises Eudragit S100. In some embodiments, the pH sensitive polymer comprises Eudragit L100. In some embodiments, the pH sensitive polymer consists essentially of Eudragit S100. In some embodiments, the pH sensitive polymer comprises a mixture of Eudragit S100 and Eudragit L100. In some embodiments, the pH sensitive polymer has a weight ratio between 1: 1 and 6: 1 (S100: L100), between 4.5: 1 and 5.5: 1 (S100: L100). Or a mixture of Eudragit S100 and Eudragit L100 in a weight ratio of 4.75: 1 (S100: L100).

In some embodiments, the delayed release pharmaceutical tablet composition comprises enteric coated tablets. In some embodiments, the delayed release pharmaceutical tablet composition comprises
Ca ²⁺ ;
Histidine; and Polyvinyl alcohol (PVA)
including.

  In some embodiments, the composition further comprises a protective polymeric film or subcoating. In some embodiments, the subcoating comprises Opadry II®.

  The DR dosage forms described herein release most or all of the linaclotide contained therein in the lower GI, eg, proximal to the ileocecal valve, or in the colon (stomach, duodenum). And / or less or no in the jejunum). Thus, the dosage forms of the present invention improve or still maintain superior efficacy for treating disorders, such as GI disorders, such as IBS-c, or conditions associated with the disorder, such as abdominal pain. , Has the ability to achieve lower overall intestinal secretions in the upper GI than the IR dosage form. IBS patients report abdominal pain in the lower left quadrant as a symptom of their disability, and it is therefore believed that IBS pain originates in the colon. Furthermore, DR dosage forms are considered to be ideally suited to treat lower GI related diseases and disorders. Since the DR dosage form does not release any (or a small percentage) its linaclotide in the stomach and upper GI, which can cause rapid digestion of linaclotide in the intestine, some preferred implementations of the DR dosage form. The form takes up a low dose of linaclotide (compared to the amount in the approved IR form) but maintains the same level of efficacy as IR in treating GI symptoms. Disorders suitable for treatment with a delayed release composition include irritable bowel syndrome (IBS), constipation, constipated irritable bowel syndrome (IBS-c), diarrhea-induced irritable bowel syndrome ((BS) in patients in need thereof). IBS-d), mixed IBS (IBS-m), unclassifiable IBS (IBS-u), chronic idiopathic constipation (CIC), diverticulitis, ulcerative colitis, functional gastrointestinal disorder, gastroesophageal reflux disease , Functional heartburn, dyspepsia, visceral pain, abdominal pain, gastroparesis, chronic pseudointestinal obstruction, pseudocolonic obstruction, Crohn's disease, inflammatory bowel disease, overactive bladder syndrome, bladder hypersensitivity or colitis induction Bladder afferent hyperactivity is included. Suitable conditions for treatment with a delayed release composition include, for example, abdominal pain, discomfort or bloating, or visceral pain in non-constipated patients.

  Generally, the guanylyl cyclase C (GC-C) receptor is a transmembrane receptor located on the apical surface of epithelial cells in the stomach, intestine and lower GI. This receptor has an extracellular ligand binding domain, a single transmembrane region and a C-terminal guanylyl cyclase domain. When the ligand binds to the extracellular domain of GC-C, the intracellular catalytic domain catalyzes the production of cGMP from GTP. In vivo, this increase in intracellular cGMP is due to, among other things, increased secretion of chloride and bicarbonate into the intestinal lumen, increased luminal pH, decreased luminal sodium absorption, increased intestinal fluid secretion, and intestinal Initiate a cascade of events that results in accelerated passage. cGMP is secreted bidirectionally from the epithelium into the submucosa and the lumen. Normally, the pH of the GI tract gradually increases from the stomach (pH 1.5-3) to the end of the ileum (pH 7-8) and then drops to pH 5.5-7.0 in the colon. Furthermore, the potent analgesic effect of linaclotide in vivo is that extracellular cGMP secreted from the IEC (intestinal epithelial cells) into the submucosa after activation of the GC-C / cGMP pathway by linaclotide is secreted by colonic nociceptors. There is increasing evidence that it is mediated by pathways that lead to altered function and produce peripheral analgesia.

Linaclotide binds to the intestinal GC-C receptor, a regulator of intestinal fluid and electrolyte balance in the intestine. Linaclotide is a peptide comprising the amino acid sequence _{Cys 1 Cys 2 Glu 3 Tyr 4} Cys 5 Cys 6 Asn 7 Pro 8 Ala 9 Cys 10 Thr 11 Gly 12 Cys 13 Tyr 14. Any desired form of linaclotide can be composed, for example, in any pharmaceutically acceptable salt or hydrate of the peptide, any isolated and / or purified form thereof, or any disulfide form thereof. Can be used in Linaclotide has disulfide bonds between Cys ₁ and Cys ₆ , Cys ₂ and Cys ₁₀ , and Cys ₅ and Cys ₁₃ .

  In some embodiments, the DR composition comprises an enteric coated tablet comprising an immediate release tablet core and a unit dose of linaclotide which dissolves only under the pH conditions of the distal compartment of the intestine. In some embodiments, the enteric or functional coating comprises a pH sensitive polymer.

  The pH sensitive polymer is selected based on a threshold pH (or dissolution pH) that matches the pH of the portion of the GI tract where release is desired. Thus, in one embodiment, the enteric coating has a pH of at least 6.0, such as a pH of at least 6.2, a pH of at least 6.4, a pH of at least 6.5, a pH of at least 6.6, at least It comprises a pH sensitive polymer having a dissolution profile of a pH of 6.8, a pH of at least 7.0, a pH of at least 7.2, a pH of at least 7.4, a pH of at least 7.6 or higher.

  In another embodiment, the pH sensitive polymer is a methyl acrylate-methacrylic acid copolymer (eg, Eudragit®); cellulose acetate succinate (CAS); hydroxypropyl methylcellulose phthalate (HPMCP); PVA; PVP; PVP- LP, hydroxypropyl methylcellulose acetate succinate (HPMCAS); polyvinyl acetate phthalate (PVAP); methyl methacrylate-methacrylic acid copolymer; sodium alginate and stearic acid; guar gum; and carbomer. In a further embodiment, the enteric coating is Eudragit® FS30D, PlasAcryl®, Eudragit® S100, Eudragit® L100, Eudragit® L100-55, Eudragit®. ) L30D-55, Eudragit (R) S, Eudragit (R) RL30D, Eudragit (R) RS30D, Eudragit (R) RS, Eudragit (R) EC, or a mixture thereof. In one embodiment, the pH sensitive polymer comprises Eudragit S100. In another embodiment, the pH sensitive polymer comprises Eudragit L100. In yet another embodiment, the pH sensitive polymer consists essentially of Eudragit S100. In yet another embodiment, the pH sensitive polymer comprises a mixture of Eudragit S100 and Eudragit L100. In yet another embodiment, the pH sensitive polymer comprises a mixture of Eudragit S100 and Eudragit L100 in a weight ratio between 1: 1 and 6: 1 (S100: L100). In another embodiment, the pH sensitive polymer comprises a mixture of Eudragit S100 and Eudragit L100 in a weight ratio between 4.5: 1 and 5.5: 1 (S100: L100). In one particular embodiment, the pH sensitive polymer comprises a mixture of Eudragit S100 and Eudragit L100 in a weight ratio between 4.875: 1 (S100: L100).

  In yet another embodiment, the enteric coating has an average thickness of at least 40 microns, eg, an average thickness of at least 45 microns, an average thickness of at least 50 microns, an average thickness of at least 55 microns, an average thickness of at least 50 microns. At least 60 microns, average thickness at least 65 microns, average thickness at least 70 microns, average thickness at least 75 microns, average thickness at least 80 microns, average thickness at least 85 microns, average thickness at least 90 Micron, average thickness of at least 95 microns, average thickness of at least 100 microns, average thickness of at least 105 microns, average thickness of at least 110 microns, average thickness of at least 115 microns, or average thickness of at least 120 microns Is. In another embodiment, the enteric coating has an average thickness of between 55 and 100 microns. In yet another embodiment, the enteric coating has an average thickness of between 65 and 95 microns. In certain embodiments, the enteric coating has an average thickness of about 75 microns and 85 microns.

In some embodiments, the delayed release composition comprises at least 1.25% (w / w) PVA, eg, at least 1.49% (w / w) PVA. In some embodiments, the delayed release composition comprises at least 0.44% (w / w) CaCl ₂ , such as at least 0.71% (w / w) CaCl ₂ . In some embodiments, the delayed release composition comprises at least 0.93% (w / w) histidine, eg, at least 1.49% (w / w) histidine.

  The delayed release composition may include any effective amount of linaclotide. In some embodiments, for example, the composition comprises 0.05 μg to 6 mg linaclotide. In some embodiments, for example, the composition comprises 1 μg to 2 mg linaclotide. In some embodiments, the composition comprises 25 μg to 2 mg linaclotide, eg, 50 μg to 1 mg linaclotide. In some embodiments, for example, the composition comprises 0.1 μg to 90 μg linaclotide. In some embodiments, for example, the composition comprises 0.1 μg to 45 μg linaclotide. In some embodiments, for example, the composition comprises 0.1 μg to 25 μg linaclotide. In some embodiments, for example, the composition comprises 30 μg to 300 μg linaclotide. In some embodiments, the composition comprises 0.05 μg, 0.1 μg, 0.15 μg, 0.25 μg, 0.5 μg, 0.75 μg, 1 μg, 1.5 μg, 2 μg, 2.5 μg, 3 μg, 3 μg. 0.5 μg, 4 μg, 4.5 μg, 5 μg, 7.5 μg, 9 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 36 μg, 40 μg, 45 μg, 50 μg, 60 μg, 72 μg, 75 μg, 90 μg, 100 μg, 145 μg, 150 μg , 200 μg, 250 μg, 290 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 550 μg, 579 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg or 1 mg linaclotide. In some embodiments, the composition comprises 100 μg to 600 μg linaclotide. In some embodiments, the composition comprises 30 μg, 50 μg, 75 μg, 100 μg, 150 μg, 290 μg, 300 μg, 400 μg, 500 μg or 600 μg linaclotide. In some embodiments, the composition comprises 9 μg, 10 μg, 15 μg, 36 μg, 72 μg, 75 μg, 145 μg, 290 μg, 579 μg or 600 μg linaclotide.

  In some embodiments, the composition comprises 30 μg linaclotide. In some embodiments, the composition comprises 50 μg linaclotide. In some embodiments, the composition comprises 100 μg linaclotide. In some embodiments, the composition comprises 145 μg linaclotide. In some embodiments, the composition comprises 300 μg linaclotide.

In some embodiments, the stability of the delayed release composition of linaclotide is controlled by a suitable amount of a sterically hindered primary amine (eg, amino acid) component, cation (eg, metal cation) component and / or polymer. It has been found that inclusion of ingredients in the composition can increase or improve. These components prevent, reduce, and / or reduce, for example, the degradation of linaclotide within the composition (eg, due to moisture-driven degradation reactions such as hydrolysis, deamidation and / or multimerization reactions). By decreasing, it increases or enhances the stability of the delayed release composition of linaclotide. For example, in some embodiments, the addition or inclusion of an appropriate amount of cations (eg, Mg ²⁺ , Ca ²⁺ , Zn ²⁺ ) in the composition increases the stability of the composition against oxidative degradation of linaclotide. It was found. Further, in some embodiments, the inclusion of a suitable amount of a sterically hindered primary amine in the composition, eg, in the form of an amino acid (eg, histidine), can, for example, by acting as a scavenger It has been found that buffering the composition and / or increasing the stability of the composition against, for example, the nucleophilic addition of formaldehyde or formaldehyde equivalents to the N-terminus of linaclotide. Further, in some embodiments, including in the composition both sterically hindered primary amines (eg, histidine) and cations (eg, Ca ²⁺ ) in suitable amounts results in hydrolysis of linaclotide and It was found to increase the stability of the composition against the formation of formaldehyde (Cys ¹ -IMD) product. In some embodiments, the inclusion of a suitable amount of polymer (eg, polyvinylpyrrolidone or polyvinylalcohol) in the delayed release composition reduces, for example, the mobility and / or reactivity of linaclotide within the composition. Thereby forming a hydrogen bond formation between linaclotide and water molecules, eg, by forming a complex or matrix (eg, a glassy and / or rigid matrix) with linaclotide (eg, by vitrification reaction). It has also been found to increase the stability of the composition by preventing or reducing and / or by enhancing the integrity of the three-dimensional structure of linaclotide.

  In this regard, in some embodiments, the linaclotide in the delayed release pharmaceutical composition is combined with a particular concentration or molar ratio of the cation and the sterically hindered primary amine to, for example, cation and / or sterically hinder It has been found to cause a synergistic enhancement or improvement in the stability of linaclotide within the composition as compared to similar compositions that do not contain a primary amine undergoing treatment and / or the same concentration of these components. ing. In some embodiments, the composition can include any stabilizing amount of a sterically hindered primary amine component. In another embodiment, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 400: 1 and 1: 1. In a further embodiment, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 200: 1 and 50: 1. In other embodiments, the composition may comprise a molar ratio of sterically hindered primary amine (eg, amino acid) to linaclotide between 100: 1 and 1: 100. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 100: 1 and 1: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 90: 1 and 2: 1. In some embodiments, the composition comprises a sterically hindered primary amine to linaclotide molar ratio of between 80: 1 and 5: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 70: 1 and 10: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 60: 1 and 20: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 50: 1 and 30: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 40: 1 and 20: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 100: 1 and 20: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 100: 1 and 25: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 100: 1 and 30: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 100: 1 and 40: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 100: 1 and 50: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 100: 1 and 60: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of between 100: 1 and 70: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of at least 5: 1. In some embodiments, the composition comprises a sterically hindered primary amine to linaclotide molar ratio of at least 10: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of at least 20: 1. In some embodiments, the composition comprises a sterically hindered primary amine to linaclotide molar ratio of at least 25: 1. In some embodiments, the composition comprises a sterically hindered primary amine to linaclotide molar ratio of at least 30: 1. In some embodiments, the composition comprises a molar ratio of sterically hindered primary amine to linaclotide of at least 40: 1.

  Suitable sterically hindered primary amines for inclusion in a delayed release composition include, for example, naturally occurring amino acids (e.g., alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, Isoleucine, leucine, lysine, meglumine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine), synthetic amino acids (e.g. lanthionine, theanine or 1-aminocyclohexane), amino sugars (e.g. chitosan or glucosamine), Or a combination or mixture thereof. In some embodiments, the composition comprises alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, Alternatively, it comprises an amino acid selected from a mixture thereof. In some embodiments, the composition comprises an amino acid selected from leucine, isoleucine, asparagine, glutamine, glutamic acid, histidine, cysteine, alanine, serine, threonine, tyrosine, proline, tryptophan, or a combination or mixture thereof. . In some embodiments, the composition comprises an amino acid selected from leucine, isoleucine, methionine, alanine, or a combination or mixture thereof. In some embodiments, the composition comprises an amino acid selected from leucine, isoleucine, alanine, or a combination or mixture thereof. In some embodiments, the composition comprises an amino acid selected from leucine, isoleucine, methionine, or a combination or mixture thereof. In some embodiments, the composition comprises an amino acid selected from leucine, methionine, alanine, or a combination or mixture thereof. In some embodiments, the composition comprises leucine, methionine, or a mixture thereof. In some embodiments, the composition comprises leucine, isoleucine, or a mixture thereof. In some embodiments, the composition comprises leucine, alanine, or a mixture thereof. In some embodiments, the composition comprises leucine. In some embodiments, the composition comprises isoleucine. In some embodiments, the composition comprises methionine. In some embodiments, the composition comprises alanine. In some embodiments, the composition comprises histidine.

  The delayed release composition can include any stabilizing amount of cations (eg, metal cations). In some embodiments, the composition comprises a molar ratio of cation to linaclotide of between 300: 1 and 1: 1. In a further embodiment, the composition comprises a molar ratio of cation to linaclotide of between 250: 1 and 30: 1. In other embodiments, the composition may comprise a molar ratio of cation to linaclotide of between 100: 1 and 1: 100. In some embodiments, the composition comprises a molar ratio of cation to linaclotide between 100: 1 and 1: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide between 90: 1 and 2: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide between 80: 1 and 5: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide of between 70: 1 and 10: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide of between 60: 1 and 20: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide of between 50: 1 and 30: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide of between 40: 1 and 20: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide between 100: 1 and 20: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide between 100: 1 and 25: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide between 100: 1 and 30: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide between 100: 1 and 40: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide between 100: 1 and 50: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide between 100: 1 and 60: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide between 100: 1 and 70: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide of at least 5: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide of at least 10: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide of at least 20: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide of at least 25: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide of at least 30: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide of at least 40: 1. In some embodiments, the composition comprises a molar ratio of cation to linaclotide of at least 60: 1.

Any suitable cation (s) may be included in the composition, eg, any suitable metal cation or organic cation. In some embodiments, the composition comprises a metal cation selected from calcium, potassium, magnesium, zinc, aluminum, iron, tin, manganese, chromium, cobalt, nickel, barium, sodium, or a combination or mixture thereof. Including. In some embodiments, the composition comprises a metal cation selected from calcium, potassium, magnesium, zinc, aluminum, manganese, chromium, cobalt, nickel, barium, sodium, or a combination or mixture thereof. In some embodiments, the composition comprises a metal cation selected from aluminum, calcium, potassium, sodium, magnesium, manganese, zinc, or a combination or mixture thereof. In some embodiments, the composition comprises a metal cation selected from calcium, magnesium, manganese, zinc, or a combination or mixture thereof. In some embodiments, the composition comprises a divalent metal cation. In some embodiments, the composition comprises a divalent metal cation selected from Al ^3+, Ca ²⁺ , Mg ²⁺ , Zn ²⁺ , Mn ²⁺ , or combinations or mixtures thereof. In some embodiments, the composition comprises Mg ²⁺ . In some embodiments, the composition comprises Ca ²⁺ . In some embodiments, the composition comprises Zn ²⁺ . In some embodiments, the composition comprises aluminum.

  Further, the metal cation can be added to the composition in any suitable form, eg, any pharmaceutically acceptable salt with any suitable counterion. Suitable metal salts include, for example, calcium chloride, calcium carbonate, calcium acetate, magnesium chloride, magnesium acetate, zinc acetate, zinc chloride, or mixtures thereof. In some embodiments, the composition comprises calcium chloride, magnesium chloride, zinc acetate, or any combination or mixture thereof. In some embodiments, the composition comprises calcium chloride. In some embodiments, the composition comprises magnesium chloride. In some embodiments, the composition comprises zinc acetate. Suitable organic cations include, for example, ammonium hydroxide, D-arginine, L-arginine, t-butylamine, calcium acetate hydrate, calcium carbonate, DL-calcium malate, calcium hydroxide, choline, ethanolamine, ethylenediamine. , Glycine, L-histidine, L-lysine, magnesium hydroxide, N-methyl-D-glucamine, L-ornithine hydrochloride, potassium hydroxide, procaine hydrochloride, L-proline, pyridoxine, L-serine, sodium hydroxide , DL-tryptophan, tromethamine, L-tyrosine, L-valine, carnitine, taurine, creatine malate, arginine alpha ketoglutarate, ornithine alpha ketoglutarate, spermine acetate, spermidine chloride, or a combination or mixture thereof. It is included. In some embodiments, the organic cation is N-methyl D-glucamine, choline, arginine, lysine, procaine, tromethamine (TRIS), spermine, N-methyl-morpholine, glucosamine, N, N-bis (2-hydroxy). Ethyl) glycine, diazabicycloundecene, creatine, arginine ethyl ester, amantadine, rimantadine, ornithine, taurine and citrulline, or any combination or mixture thereof.

  The composition may include any stabilizing amount of polymer. In some embodiments, the composition comprises between 1% and 25% by weight of polymer, based on the total weight of the composition. In some embodiments, the composition comprises between 1% and 10% by weight of polymer, based on the total weight of the composition.

  In some embodiments, the composition comprises between 2% and 4% by weight of polymer, based on the total weight of the composition. In some embodiments, the composition comprises 0.1 wt. % And 75 wt. % Polymer. In some embodiments, the composition comprises 0.1 wt. % And 55 wt. % Polymer. In some embodiments, the composition comprises 0.1 wt. % And 35 wt. % Polymer. In some embodiments, the composition comprises 0.1 wt. % And 30 wt. % Polymer. In some embodiments, the composition comprises 0.1 wt. % And 25 wt. % Polymer. In some embodiments, the composition comprises 1 wt. % And 25 wt. % Polymer. In some embodiments, the composition comprises 5 wt. % And 25 wt. % Polymer. In some embodiments, the composition comprises 10 wt. % And 25 wt. % Polymer. In some embodiments, the composition comprises 15 wt. % And 25 wt. % Polymer. In some embodiments, the composition comprises 0.1 wt. % And 22 wt. % Polymer. In some embodiments, the composition comprises 1 wt. % And 22 wt. % Polymer. In some embodiments, the composition comprises 5 wt. % And 22 wt. % Polymer. In some embodiments, the composition comprises 10 wt. % And 22 wt. % Polymer. In some embodiments, the composition comprises 0.1 wt. % And 20 wt. % Polymer. In some embodiments, the composition comprises 1 wt. % And 20 wt. % Polymer. In some embodiments, the composition comprises 5 wt. % And 20 wt. % Polymer. In some embodiments, the composition comprises 10 wt. % And 20 wt. % Polymer. In some embodiments, the composition comprises 0.01 wt. % And 15 wt. % Polymer. In some embodiments, the composition comprises 0.01 wt. % And 10 wt. % Polymer. In some embodiments, the composition comprises 0.01 wt. % And 5 wt. % Polymer. In some embodiments, the composition comprises 0.1 wt. % And 95 wt. %, For example, 5 wt. % And 95 wt. %, 15 wt. % And 95 wt. % Between 25 wt. % And 95 wt. %, 35 wt. % And 95 wt. %, 45 wt. % And 95 wt. %, 0.1 wt. % And 85 wt. % Between 1 wt. % And 85 wt. %, 5 wt. % And 85 wt. %, 15 wt. % And 85 wt. % Between 25 wt. % And 85 wt. %, 35 wt. % And 85 wt. %, 0.1 wt. % And 80 wt. % Between 1 wt. % And 80 wt. %, 5 wt. % And 80 wt. %, 15 wt. % And 80 wt. % Between 25 wt. % And 80 wt. %, 35 wt. % And 80 wt. %, 0.1 wt. % And 75 wt. % Between 1 wt. % And 75 wt. %, 5 wt. % And 75 wt. %, 15 wt. % And 75 wt. % Between 25 wt. % And 75 wt. %, 35 wt. % And 75 wt. %, 0.1 wt. % And 65 wt. % Between 1 wt. % And 65 wt. %, 5 wt. % And 65 wt. %, 15 wt. % And 65 wt. % Between 25 wt. % And 65 wt. %, 35 wt. % And 65 wt. %, 0.1 wt. % And 60 wt. % Between 1 wt. % And 60 wt. %, 5 wt. % And 60 wt. %, 15 wt. % And 60 wt. % Between 25 wt. % And 60 wt. % Or 35 wt. % And 60 wt. % Polymer.

  In some embodiments, the polymer acts within the delayed release composition as both a stabilizer, a protective coating, or as a film former. In some embodiments, the delayed release composition is between 80: 1 and 300: 1, such as between 100: 1 and 200: 1, 110: 1 and 190: 1, or even Comprises a molar ratio of polymer (eg PVP or PVA) to linaclotide between 120: 1 and 180: 1. In some embodiments, the delayed release composition is a polymer (eg, PVP or PVA) greater than about 80: 1, eg, greater than about 100: 1, or even greater than about 120: 1. Of linaclotide to linaclotide. In some embodiments, the delayed release composition is between 10: 1 and 300: 1, such as between 80: 1 and 200: 1, between 100: 1 and 180: 1, or even Comprises a weight ratio of polymer (eg PVP or PVA) to linaclotide between 110: 1 and 150: 1. In some embodiments, the delayed release composition is between 100: 1 and 500: 1, such as between 200: 1 and 400: 1, between 250: 1 and 350: 1, or even Comprises a weight ratio of polymer (eg PVP or PVA) to linaclotide between 300: 1 and 350: 1.

  Suitable polymers for inclusion in the delayed release composition include, for example, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl alcohol low peroxide (PVA-LP), hydroxypropylmethyl cellulose (HPMC). ), Hydroxypropyl cellulose (HPC), methyl cellulose, methacrylate polymer, cyclodextrin, dextrin, dextran, polyacrylic acid, chitosan, guar gum, xanthan gum, polyethylene oxide (eg, polyethylene polypropylene oxide), poly (vinyl sulfone) Acid sodium salt), polyethylene glycol, poly (arginine), polycarbophil, polyvinylpyrrolidone-co-vinyl acetate, poloxamer (eg, Pluronic® product available from BASF), alginate, trehalose, sucrose, inulin, or combinations or mixtures thereof. In some embodiments, the composition is PVP, PVA, methacrylate polymer, cyclodextrin, dextran, polyacrylic acid, chitosan, guar gum, xanthan gum, polyethylene oxide, polyethylene glycol, poly (arginine), polycarbophil, polyvinyl. Includes polymers selected from pyrrolidone-co-vinyl acetate, poloxamers, or combinations or mixtures thereof. In some embodiments, the composition comprises PVP, PVA, polyethylene oxide, or mixtures thereof. In some embodiments, the composition comprises PVP, PVA, or a mixture thereof. In some embodiments, the composition comprises PVP. In some embodiments, the composition comprises PVA.

  In some embodiments, the delayed release composition comprises two or more stabilizers. For example, the composition can include a stabilizing amount of polymer and a stabilizing amount of a sterically hindered primary amine. In addition, the composition can include a stabilizing amount of polymer and a stabilizing amount of a cation (eg, a metal cation). In addition, the composition can include a stabilizing amount of a sterically hindered primary amine and a stabilizing amount of a cation (eg, a metal cation). In some embodiments, the composition comprises a stabilizing amount of polymer, a stabilizing amount of a sterically hindered primary amine, and a stabilizing amount of a cation (eg, a metal cation). Including.

  In some embodiments, the delayed release composition comprises a stabilizing amount of PVP and a stabilizing amount of histidine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, It comprises an amino acid selected from isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or mixtures thereof. In some embodiments, the composition comprises a stabilizing amount of PVP, and a stabilizing amount of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, It comprises an amino acid selected from methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or mixtures thereof. In some embodiments, the composition comprises a stabilizing amount of PVP, and a stabilizing amount of leucine, isoleucine, methionine, alanine, or a combination or mixture thereof. In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of histidine.

  In some embodiments, the delayed release composition comprises a stabilizing amount of PVA and a stabilizing amount of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, It comprises an amino acid selected from leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or mixtures thereof. In some embodiments, the composition comprises a stabilizing amount of PVA, and a stabilizing amount of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, It comprises an amino acid selected from methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or mixtures thereof. In some embodiments, the composition comprises a stabilizing amount of PVA and a stabilizing amount of leucine, isoleucine, methionine, alanine, or a combination or mixture thereof. In some embodiments, the composition comprises a stabilizing amount of PVA and a stabilizing amount of leucine.

In some embodiments, the delayed release composition comprises a stabilizing amount of PVP and a stabilizing amount of a cation (eg, a metal cation). In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of a divalent metal cation. In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of Mg ²⁺ , Ca ²⁺ , Zn ²⁺ or salts thereof or combinations or mixtures thereof. In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of Ca ²⁺ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of Mg ²⁺ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of Zn ²⁺ or a salt thereof.

In some embodiments, the delayed release composition comprises a stabilizing amount of PVA and a stabilizing amount of a cation (eg, a metal cation). In some embodiments, the composition comprises a stabilizing amount of PVA and a stabilizing amount of a divalent metal cation. In some embodiments, the composition comprises a stabilizing amount of PVA and a stabilizing amount of Mg ²⁺ , Ca ²⁺ , Zn ²⁺ or salts thereof or combinations or mixtures thereof. In some embodiments, the composition comprises a stabilizing amount of PVA and a stabilizing amount of Ca ²⁺ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of PVA and a stabilizing amount of Mg ²⁺ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of PVA and a stabilizing amount of Zn ²⁺ or a salt thereof.

In some embodiments, the delayed release composition comprises a stabilizing amount of an amino acid selected from leucine, isoleucine, methionine, alanine; and a stabilizing amount of Mg ²⁺ , Ca ²⁺ , Zn ²⁺ or It includes divalent metal cations selected from their salts or combinations or mixtures thereof. In some embodiments, the composition comprises a stabilizing amount of an amino acid selected from leucine and isoleucine; and a stabilizing amount of Mg ²⁺ , Ca ²⁺ or salts thereof or combinations or mixtures thereof. A divalent metal cation selected from In some embodiments, the composition comprises a stabilizing amount of an amino acid selected from leucine or methionine; and a stabilizing amount of Ca ²⁺ , Zn ²⁺ or salts thereof or combinations or mixtures thereof. A divalent metal cation selected from In some embodiments, the composition comprises a stabilizing amount of leucine and a stabilizing amount of Ca ²⁺ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of a cation and a stabilizing amount of a sterically hindered primary amine. In some embodiments, the composition comprises at least 1.5: 1, such as at least 2: 1, at least 2.5: 1, at least 3: 1, at least 4: 1, or even at least 5: 1. , A cation: a sterically hindered primary amine (eg Ca ²⁺ : leucine) molar ratio (eg between 1.5: 1 and 5: 1, eg between 2: 1 and 4: 1). In a molar ratio) of cation and sterically hindered primary amine.

In some embodiments, the delayed release composition comprises (i) a stabilizing amount of PVP or PVA, (ii) a stabilizing amount of leucine, isoleucine, methionine, alanine, and (iii) stabilization. It contains an amount of Mg ²⁺ , Ca ²⁺ , Zn ²⁺ or salts thereof or combinations or mixtures thereof. In some embodiments, the composition comprises a stabilizing amount of PVP, a stabilizing amount of leucine, and a stabilizing amount of a metal cation. In some embodiments, the composition comprises a stabilizing amount of PVA, a stabilizing amount of histidine, and a stabilizing amount of Ca ²⁺ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of PVP, a stabilizing amount of leucine, and a stabilizing amount of Mg ²⁺ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of PVP, a stabilizing amount of leucine, and a stabilizing amount of Zn ²⁺ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of PVA, a stabilizing amount of leucine, and a stabilizing amount of Ca ²⁺ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of PVA, a stabilizing amount of leucine, and a stabilizing amount of Mg ²⁺ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of PVA, a stabilizing amount of leucine, and a stabilizing amount of Zn ²⁺ or a salt thereof.

In some embodiments, the composition comprises (i) 0.1 wt. % And 30 wt. % Of polymer, (ii) 100: 1 to 10: 1 molar ratio of primary amine to linaclotide, a sterically hindered primary amine (eg, amino acid), and (iii) 100. Cations (eg, metal cations) in a molar ratio of cations to linaclotide between: 1 and 40: 1. In some embodiments, the composition comprises (i) 5 wt. % And 25 wt. % Polymer, (ii) primary between 100: 1 and 30: 1 (eg between 60: 1 and 30: 1 or even between 50: 1 and 30: 1). A sterically hindered primary amine (eg, an amino acid) in a molar ratio of amine to linaclotide, and (iii) a cation (eg, such as a molar ratio of cation to linaclotide between 100: 1 and 60: 1). Metal cations). In some embodiments, the composition comprises (i) 0.1 wt. % And 30 wt. A polymer selected from PVP and PVA, (ii) an amino acid selected from leucine, isoleucine, alanine and methionine in a molar ratio of amino acid to linaclotide between 100: 1 and 10: 1. And (iii) a molar ratio of cation to linaclotide between 100: 1 and 40: 1, of a metal cation selected from Ca ²⁺ , Mg ²⁺ and Zn ²⁺ . In some embodiments, the composition comprises (i) 5 wt. % And 25 wt. A polymer selected from PVP and PVA, (ii) a molar ratio of amino acids to linaclotide of between 100: 1 and 30: 1 (eg between 60: 1 and 30: 1). An amino acid selected from leucine, isoleucine, alanine and methionine, and (iii) a molar ratio of cation to linaclotide between 100: 1 and 60: 1 selected from Ca ²⁺ , Mg ²⁺ and Zn ^2+. Containing metal cations. In some embodiments, the composition comprises (i) 0.1 wt. % And 30 wt. % (Eg 5 wt.% To 25 wt.%) PVP or PVA, (ii) 100: 1 to 30: 1 (eg 60: 1 to 30: 1 or Furthermore, a molar ratio of leucine to linaclotide of leucine of between 50: 1 and 30: 1) and (iii) a molar ratio of Ca ^{2+ to} linaclotide of Ca ²⁺ of between 100: 1 and 60: 1. including.

In some embodiments, the composition comprises (i) 45 wt. % And 99 wt. % Of polymer, (ii) 100: 1 to 10: 1 molar ratio of primary amine to linaclotide, a sterically hindered primary amine (eg, amino acid), and (iii) 100. Cations (eg, metal cations) in a molar ratio of cations to linaclotide between: 1 and 40: 1. In some embodiments, the composition comprises (i) 45 wt. % And 70 wt. % Polymer, (ii) primary between 100: 1 and 30: 1 (eg between 60: 1 and 30: 1 or even between 50: 1 and 30: 1). A sterically hindered primary amine (eg, an amino acid) in a molar ratio of amine to linaclotide, and (iii) a cation (eg, such as a molar ratio of cation to linaclotide between 100: 1 and 60: 1). Metal cations). In some embodiments, the composition comprises (i) 45 wt. % And 99 wt. A polymer selected from PVP and PVA, (ii) an amino acid selected from leucine, isoleucine, alanine and methionine in a molar ratio of amino acid to linaclotide between 100: 1 and 10: 1. And (iii) a molar ratio of cation to linaclotide between 100: 1 and 40: 1, of a metal cation selected from Ca ²⁺ , Mg ²⁺ and Zn ²⁺ . In some embodiments, the composition comprises (i) 45 wt. % And 70 wt. A polymer selected from PVP and PVA, (ii) a molar ratio of amino acids to linaclotide of between 100: 1 and 30: 1 (eg between 60: 1 and 30: 1). An amino acid selected from leucine, isoleucine, alanine and methionine, and (iii) a molar ratio of cation to linaclotide between 100: 1 and 60: 1 selected from Ca ²⁺ , Mg ²⁺ and Zn ^2+. Containing metal cations. In some embodiments, the composition comprises (i) 45 wt. % And 99 wt. % (Eg, 45 wt.% To 70 wt.%) PVP or PVA, (ii) 100: 1 to 30: 1 (eg, 60: 1 to 30: 1 or Furthermore, a molar ratio of leucine to linaclotide of leucine of between 50: 1 and 30: 1) and (iii) a molar ratio of Ca ^{2+ to} linaclotide of Ca ²⁺ of between 100: 1 and 60: 1. including.

  Delayed release compositions (eg, delayed release tablets) may also include any one or more fillers. Suitable fillers include starch, calcium carbonate, calcium sulfate, hydroxypropylmethylcellulose, fructose, methylcellulose, dextrate, dextrose, dextran, lactitol, maltose, sucrose, sorbitol, isomalt, pregelatinized starch, diphosphate diphosphate. Includes, but is not limited to, calcium, microcrystalline cellulose, mannitol, gelatin, trehalose, erythritol, maltitol, lactose, glucose, or combinations thereof, or mixtures thereof. In some embodiments, the filler is isomalt. In some embodiments, the filler is gelatin. In some embodiments, the filler is mannitol. In some embodiments, the filler is pregelatinized starch. In some embodiments, the filler is microcrystalline cellulose.

  Delayed release compositions, such as delayed release tablets, can include any suitable concentration of filler. In some embodiments, for example, the composition comprises one or more fillers at a concentration of 0.1-99% by weight, based on the total weight of the composition. In some embodiments, for example, the composition comprises 1 to 95 wt. Containing one or more fillers at a concentration of% filler (s). In some embodiments, for example, the composition comprises 10 to 90 wt. Containing one or more fillers at a concentration of% filler (s). In some embodiments, for example, the composition comprises 20 to 90 wt. Containing one or more fillers at a concentration of% filler (s). In some embodiments, for example, the composition comprises 25-85 wt. Containing one or more fillers at a concentration of% filler (s). In some embodiments, for example, the composition is 30-80 wt. Containing one or more fillers at a concentration of% filler (s). In some embodiments, for example, the composition comprises 40-70 wt. Containing one or more fillers at a concentration of% filler (s). In some embodiments, for example, the composition comprises 10-60 wt. Containing one or more fillers at a concentration of% filler (s). In some embodiments, for example, the composition comprises 20 to 50 wt. Containing one or more fillers at a concentration of% filler (s). In some embodiments, the composition has at least 20 wt. %, For example at least 40 wt. %, At least 60 wt. %, At least 70 wt. %, At least 80 wt. % Or at least 90 wt. %, With one or more fillers.

  In some embodiments, the delayed release composition (eg, delayed release film) comprises one or more plasticizers. Suitable plasticizers include polyethylene glycol, propylene glycol, glycerin, glycerol, monoacetin, diacetin, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl titrate, tributyl citrate. , Triethyl citrate, acetyl triethyl citrate, castor oil, acetylated monoglycerides, sorbitol or combinations thereof, but are not limited thereto. In an exemplary embodiment, the concentration of plasticizer in the formulation is from about 0 to about 30 wt. %, For example, about 1 to about 20 wt. %, About 0 to about 10 wt. %, About 1 to about 5 wt. %, Or even 0 to about 4 wt. Can be%.

  In some embodiments, the delayed release composition comprises a film forming agent, a water soluble polymer, a pH sensitive polymer, a biodegradable polymer, or a combination thereof. Water soluble, pH sensitive or biodegradable polymers that can be used in the orally soluble formulations of the present invention include, but are not limited to, cellulose derivatives, synthetic polymeric polyacrylates and natural gums. For example, the water-soluble polymer used in the orally-soluble formulation of the present invention, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, Amylose, dextran, casein, pullulan, gelatin, pectin, agar, carrageenan, xanthan gum, tragacanth, guar gum, acacia gum, acacia gum, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, cyclodextrin, carboxyvinyl polymer, sodium alginate , Polyacrylic acid, methyl methacrylate Mixtures thereof may be included without limitation. In an exemplary embodiment, the concentration of water-soluble polymer in the formulation can be between about 20% and about 90% (weight), preferably between about 40% and about 80% (weight).

  In some embodiments, the pH sensitive polymer is Eudagrit® L100 having a threshold pH of 6.0 (also referred to as the dissolution pH). In some embodiments, the pH sensitive polymer is Eudegrit® S100, which has a threshold pH of 7.0. In some embodiments, the pH sensitive polymer is Eudagrit® L-30D, which has a threshold pH of 5.6. In some embodiments, the pH sensitive polymer is Eudagrit® FS 30D, which has a threshold pH of 6.8. In some embodiments, the pH sensitive polymer is Eudagrit® L100-55, which has a threshold pH of 5.5. In some embodiments, the pH sensitive polymer is polyvinyl acetate phthalate having a threshold pH of 5.0. In some embodiments, the pH sensitive polymer is hydroxypropyl methylcellulose phthalate having a threshold pH of 4.5-4.8. In some embodiments, the pH sensitive polymer is hydroxypropyl methylcellulose phthalate 50 having a threshold pH of 5.2. In some embodiments, the pH sensitive polymer is hydroxypropyl methylcellulose phthalate 55 having a threshold pH of 5.4. In some embodiments, the pH sensitive polymer is Cellulose acetate trimelliate with a threshold pH of 4.8. In some embodiments, the pH sensitive polymer is cellulose acetate phthalate having a threshold pH of 5.0. In some embodiments, the delayed release composition comprises a combination of the pH sensitive polymers described above.

  Those of skill in the art will appreciate, using the present disclosure, that other ingredients may be included to enhance one or more properties of the delayed release composition. In some embodiments, for example, the delayed release composition comprises one or more disintegrants, lubricants, anti-caking additives, antibacterial agents, defoamers, emulsifiers, surfactants, buffers and And / or may include colorants.

  Suitable disintegrants include, for example, agar-agar, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, povidone, polacrylin potassium, sodium starch glycolate, potato or tapioca starch, other starches, alpha. Included are modified starches, clays, other algins, other celluloses, gums, and mixtures thereof. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is croscarmellose sodium.

  Suitable lubricants include, for example, calcium stearate, magnesium stearate, mineral oil, gas oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulphate, talc, hydrogenated vegetable oils (e.g. Peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, syloid silica gel (AEROSIL® 200, W) R. Grace Co., Baltimore, MD USA), coagulation aerosols of synthetic silica (Evonik Degussa Co., Plano, TX USA), pyrogenic silicon dioxide (CAB-O-SIL, Cabot Co., Bo. Ston, MA USA), and mixtures thereof.

  Suitable anti-caking additives include, for example, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, glyceryl, and mixtures thereof.

  For example, suitable antimicrobial additives that can be used as preservatives for linaclotide compositions include, for example, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridinium chloride, cresol, chlorobutanol, Dehydroacetic acid, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenoxyethanol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosol (thimersol) , Thymol, and mixtures thereof.

  The composition may also include any suitable pharmaceutically acceptable carrier or vehicle. Suitable pharmaceutically acceptable carriers include, for example, any solvent, dispersant, pH buffering agent, coating, absorption enhancer, controlled release agent, and one or more inert excipients (eg, Fillers, starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents) and the like are included. Furthermore, the composition may comprise any desired further ingredients, additives and / or species, such as surface-active additives, dispersing additives, water retention agents, suspension agents, solubilizers, buffering agents, disintegrants, Preservatives, colorants, flavorants and the like may be included. In some embodiments, the composition comprises one or more ionic species that interacts with linaclotide.

  The composition may also include any suitable pH buffering agent. In some embodiments, the pH buffering agent is present in the composition in an amount sufficient to achieve the isoelectric point of linaclotide. In this regard, the composition may have any desired pH. In some embodiments, the composition has a pH of 2-5 (eg, a pH of 2-4.5, a pH of 2-4, a pH of 2.5-4, a pH of 2.5-3.5. , A pH of 2.5 to 3, or even a pH of 3),

In some embodiments, the composition comprises linaclotide and a hydrolyzate, eg,
A hydrolyzate containing or having the structure: The composition may include any desired concentration of hydrolyzate. In some embodiments, the composition comprises 10 wt. Contains less than% hydrolyzate. In some embodiments, the composition comprises 7 wt. Contains less than% hydrolyzate. In some embodiments, the composition comprises 6 wt. Contains less than% hydrolyzate. In some embodiments, the composition comprises 5 wt. Contains less than% hydrolyzate. In some embodiments, the composition comprises 4 wt. Contains less than% hydrolyzate. In some embodiments, the composition comprises 3 wt. Contains less than% hydrolyzate. In some embodiments, the composition comprises 2 wt. Contains less than% hydrolyzate. In some embodiments, the composition comprises 1 wt. Contains less than% hydrolyzate. In some embodiments, the composition comprises 0.01 wt. % And 10 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.1 wt. % And 7 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.1 wt. % And 5 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.5 wt. % And 5 wt. % Of hydrolysates. In some embodiments, the composition comprises 1 wt. % And 5 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.1 wt. % And 4 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.5 wt. % And 4 wt. % Of hydrolysates. In some embodiments, the composition comprises 1 wt. % And 4 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.1 wt. % And 3 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.5 wt. % And 3 wt. % Of hydrolysates. In some embodiments, the composition comprises 1 wt. % And 3 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.1 wt. % And 2.5 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.5 wt. % And 2.5 wt. % Of hydrolysates. In some embodiments, the composition comprises 1 wt. % And 2.5 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.1 wt. % And 2 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.5 wt. % And 2 wt. % Of hydrolysates. In some embodiments, the composition comprises 1 wt. % And 2 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.1 wt. % And 1.5 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.5 wt. % And 1.5 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.1 wt. % And 1 wt. % Of hydrolysates. In some embodiments, the composition comprises 0.5 wt. % And 1 wt. % Of hydrolysates.

In some embodiments, the composition comprises linaclotide and an oxidation product, such as:
Including the oxidation product having or having the structure Alternatively, or additionally, the composition comprises linaclotide and an oxidation product having the indicated structure, but the oxidation occurs at any one or more of the six indicated cysteinyl sulfurs. The composition can include any desired concentration of oxidation product. In some embodiments, the composition comprises 10 wt. Contains less than% oxidation products. In some embodiments, the composition comprises 7 wt. Contains less than% oxidation products. In some embodiments, the composition comprises 6 wt. Contains less than% oxidation products. In some embodiments, the composition comprises 5 wt. Contains less than% oxidation products. In some embodiments, the composition comprises 4 wt. Contains less than% oxidation products. In some embodiments, the composition comprises 3 wt. Contains less than% oxidation products. In some embodiments, the composition comprises 2 wt. Contains less than% oxidation products. In some embodiments, the composition comprises 1 wt. Contains less than% oxidation products. In some embodiments, the composition comprises 0.01 wt. % And 10 wt. % Oxidation products. In some embodiments, the composition comprises 0.1 wt. % And 7 wt. % Oxidation products. In some embodiments, the composition comprises 0.1 wt. % And 5 wt. % Oxidation products. In some embodiments, the composition comprises 0.5 wt. % And 5 wt. % Oxidation products. In some embodiments, the composition comprises 1 wt. % And 5 wt. % Oxidation products. In some embodiments, the composition comprises 0.1 wt. % And 4 wt. % Oxidation products. In some embodiments, the composition comprises 0.5 wt. % And 4 wt. % Oxidation products. In some embodiments, the composition comprises 1 wt. % And 4 wt. % Oxidation products. In some embodiments, the composition comprises 0.1 wt. % And 3 wt. % Oxidation products. In some embodiments, the composition comprises 0.5 wt. % And 3 wt. % Oxidation products. In some embodiments, the composition comprises 1 wt. % And 3 wt. % Oxidation products. In some embodiments, the composition comprises 0.1 wt. % And 2.5 wt. % Oxidation products. In some embodiments, the composition comprises 0.5 wt. % And 2.5 wt. % Oxidation products. In some embodiments, the composition comprises 1 wt. % And 2.5 wt. % Oxidation products. In some embodiments, the composition comprises 0.1 wt. % And 2 wt. % Oxidation products. In some embodiments, the composition comprises 0.5 wt. % And 2 wt. % Oxidation products. In some embodiments, the composition comprises 1 wt. % And 2 wt. % Oxidation products. In some embodiments, the composition comprises 0.1 wt. % And 1.5 wt. % Oxidation products. In some embodiments, the composition comprises 0.5 wt. % And 1.5 wt. % Oxidation products. In some embodiments, the composition comprises 0.1 wt. % And 1 wt. % Oxidation products. In some embodiments, the composition comprises 0.5 wt. % And 1 wt. % Oxidation products.

In some embodiments, the composition comprises linaclotide and an acetylation product, such as
Includes or has an acetylated product. The composition may include any desired concentration of acetylated product. In some embodiments, the composition comprises 10 wt. Contains less than% acetylated products. In some embodiments, the composition comprises 7 wt. Contains less than% acetylated products. In some embodiments, the composition comprises 6 wt. Contains less than% acetylated products. In some embodiments, the composition comprises 5 wt. Contains less than% acetylated products. In some embodiments, the composition comprises 4 wt. Contains less than% acetylated products. In some embodiments, the composition comprises 3 wt. Contains less than% acetylated products. In some embodiments, the composition comprises 2 wt. Contains less than% acetylated products. In some embodiments, the composition comprises 1 wt. Contains less than% acetylated products. In some embodiments, the composition comprises 0.01 wt. % And 10 wt. % Of acetylated products. In some embodiments, the composition comprises 0.1 wt. % And 7 wt. % Of acetylated products. In some embodiments, the composition comprises 0.1 wt. % And 5 wt. % Of acetylated products. In some embodiments, the composition comprises 0.5 wt. % And 5 wt. % Of acetylated products. In some embodiments, the composition comprises 1 wt. % And 5 wt. % Of acetylated products. In some embodiments, the composition comprises 0.1 wt. % And 4 wt. % Of acetylated products. In some embodiments, the composition comprises 0.5 wt. % And 4 wt. % Of acetylated products. In some embodiments, the composition comprises 1 wt. % And 4 wt. % Of acetylated products. In some embodiments, the composition comprises 0.1 wt. % And 3 wt. % Of acetylated products. In some embodiments, the composition comprises 0.5 wt. % And 3 wt. % Of acetylated products. In some embodiments, the composition comprises 1 wt. % And 3 wt. % Of acetylated products. In some embodiments, the composition comprises 0.1 wt. % And 2.5 wt. % Of acetylated products. In some embodiments, the composition comprises 0.5 wt. % And 2.5 wt. % Of acetylated products. In some embodiments, the composition comprises 1 wt. % And 2.5 wt. % Of acetylated products. In some embodiments, the composition comprises 0.1 wt. % And 2 wt. % Of acetylated products. In some embodiments, the composition comprises 0.5 wt. % And 2 wt. % Of acetylated products. In some embodiments, the composition comprises 1 wt. % And 2 wt. % Of acetylated products. In some embodiments, the composition comprises 0.1 wt. % And 1.5 wt. % Of acetylated products. In some embodiments, the composition comprises 0.5 wt. % And 1.5 wt. % Of acetylated products. In some embodiments, the composition comprises 0.1 wt. % And 1 wt. % Of acetylated products. In some embodiments, the composition comprises 0.5 wt. % And 1 wt. % Of acetylated products.

In some embodiments, there is provided a pharmaceutical composition comprising linaclotide and one or more peptides selected from:
i. A peptide (“Cys ¹ -IMD”) or a pharmaceutically acceptable salt thereof, which peptide comprises:
Including the amino acid structure of
ii. A hydrolyzed peptide (“Asp ⁷ ”) or a pharmaceutically acceptable salt thereof, which peptide comprises:
Including the amino acid structure of
iii. An acetylated peptide (“Cys ¹ -N-acetyl”) or a pharmaceutically acceptable salt thereof, which peptide comprises:
Including the amino acid structure of
iv. A linaclotide trisulfide peptide or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence of Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr, wherein the additional sulfur atom is 6 cysteinyl. May be bound to any one of the sulfur;
v. A peptide (“Des-Tyr ¹⁴ ”) or a pharmaceutically acceptable salt thereof, which peptide comprises:
Or vi. A peptide (Cys ¹ -α-ketone) or a pharmaceutically acceptable salt thereof, which comprises:
Including the amino acid structure of

In some embodiments, the Cys ¹ -α-ketone peptide can be present in its hydrated form or its pharmaceutically acceptable salt, wherein the peptide is
Including the amino acid structure of Those skilled in the art will recognize that Cys ¹ -α-ketone peptides readily convert between their hydrate and ketone forms.

In some embodiments, the Cys ¹ -α-ketone peptide is less than about 15% by weight of the composition, less than about 10% by weight of the composition, less than about 7% by weight of the composition, about 5% by weight of the composition. Less than about 4% by weight of the composition, less than about 3% by weight of the composition, less than about 2% by weight of the composition, less than about 1.5% by weight of the composition, or less than about 1% by weight of the composition. Constitute. In another exemplary embodiment, the Cys ¹ -α-ketone peptide is about 0.01% to about 15% by weight of the composition, about 0.05% to about 10% by weight of the composition, About 0.05% to about 7% by weight of the composition or about 0.05% to about 5% by weight of the composition.

In some embodiments, the Cys ¹ -IMD peptide is less than about 15% by weight of the composition, less than about 10% by weight of the composition, less than about 7% by weight of the composition, less than about 5% by weight of the composition, Less than about 4% by weight of the composition, less than about 3.5% by weight of the composition, less than about 3% by weight of the composition, less than about 2% by weight of the composition, or less than about 1% by weight of the composition. . In another exemplary embodiment, the Cys ¹ -IMD peptide is about 0.01% to about 15% by weight of the composition, about 0.05% to about 10% by weight of the composition, about It comprises from 0.05% to about 7% or from about 0.05% to about 5% by weight of the composition.

In some embodiments, the hydrolyzed peptide (“Asp ⁷ ”) is less than about 15% by weight of the composition, less than about 10% by weight of the composition, less than about 7% by weight of the composition, about 5% of the composition. Less than about 4% by weight of the composition, less than about 3.5% by weight of the composition, less than about 3% by weight of the composition, less than about 2% by weight of the composition, or about 1% by weight of the composition. Make up less than. In another exemplary embodiment, the hydrolyzed peptide (“Asp ⁷ ”) is from about 0.01% to about 15% by weight of the composition, from about 0.05% to about 10% by weight of the composition, About 0.05% to about 7% by weight of the composition or about 0.05% to about 5% by weight of the composition.

In some embodiments, the acetylated peptide (“Cys ¹ -N-acetyl”) is less than about 15% by weight of the composition, less than about 10% by weight of the composition, less than about 7% by weight of the composition, Less than about 5% by weight of the composition, less than about 4% by weight of the composition, less than about 3.5% by weight of the composition, less than about 3% by weight of the composition, less than about 2% by weight of the composition, or of the composition. Make up less than about 1% by weight. In another exemplary embodiment, the acetylated peptide (“Cys ¹ -N-acetyl”) is about 0.01% to about 15% by weight of the composition, about 0.05% to about 15% by weight of the composition. It comprises 10% by weight, about 0.05% to about 7% by weight of the composition or about 0.05% to about 5% by weight of the composition.

  In some embodiments, the linaclotide trisulfide peptide is less than about 15% by weight of the composition, less than about 10% by weight of the composition, less than about 7% by weight of the composition, less than about 5% by weight of the composition, Less than about 4% by weight of the composition, less than about 3.5% by weight of the composition, less than about 3% by weight of the composition, less than about 2% by weight of the composition, or less than about 1% by weight of the composition. .. In another exemplary embodiment, the linaclotide trisulfide peptide is about 0.01% to about 15% by weight of the composition, about 0.05% to about 10% by weight of the composition, about 10% by weight of the composition. It comprises from 0.05% to about 7% or from about 0.05% to about 5% by weight of the composition.

In some embodiments, the Des-Tyr ¹⁴ peptide is less than about 15% by weight of the composition, less than about 10% by weight of the composition, less than about 7% by weight of the composition, less than about 5% by weight of the composition, Less than about 4% by weight of the composition, less than about 3.5% by weight of the composition, less than about 3% by weight of the composition, less than about 2% by weight of the composition, or less than about 1% by weight of the composition. . In another exemplary embodiment, the Des-Tyr ¹⁴ peptide is about 0.01% to about 15% by weight of the composition, about 0.05% to about 10% by weight of the composition, about It comprises from 0.05% to about 7% or from about 0.05% to about 5% by weight of the composition.

  In some embodiments, the composition comprises linaclotide and any desired concentration of multimers. In some embodiments, the composition comprises 10 wt. Contain less than% multimer (s). In some embodiments, the composition comprises 0.5 wt. % And 1 wt. % With multimer (s).

  In some embodiments, the composition comprises an effective amount of linaclotide and any desired amount of the reduced form of linaclotide. As used herein, the term "reduced form of linaclotide" refers to linaclotide having no disulfide bonds between cysteine amino acids. In some embodiments, the composition comprises 10 wt. Contain less than% reduced form of linaclotide. In some embodiments, the composition comprises 0.5 wt. % And 1 wt. % Of linaclotide in the reduced form.

In some embodiments, the composition comprises an effective amount of linaclotide and any desired amount of scrambled form of linaclotide. As used herein, the term “scrambled form of linaclotide” means between Cys ₁ and Cys ₁₀ , between Cys ₁ and Cys ₁₃ , between Cys ₁ and Cys ₅ , between Cys ₁ and Cys. _{Between 2} , between Cys ₂ and Cys ₆ , between Cys ₂ and Cys ₁₃ , between Cys ₂ and Cys ₅ , between Cys ₅ and Cys ₆ and / or between Cys ₅ and Cys ₁₀ . Refers to linaclotide with a disulfide bond in between. In some embodiments, the composition comprises 0.5 wt. % And 1 wt. % Of linaclotide in scrambled form. In some embodiments, the composition comprises 10 wt. Contain less than% scrambled form of linaclotide

  In some embodiments, the composition comprises about 10 wt. Includes a total degradant concentration of less than%. In some embodiments, the composition comprises about 8 wt. Includes a total degradant concentration of less than%. In some embodiments, the composition comprises about 7 wt. Includes a total degradant concentration of less than%. In some embodiments, the composition comprises about 6.5 wt. Includes a total degradant concentration of less than%. In some embodiments, the composition comprises about 6 wt. Includes a total degradant concentration of less than%. In some embodiments, the composition comprises about 5.5 wt. Includes a total degradant concentration of less than%. In some embodiments, the composition comprises about 5 wt. Includes a total degradant concentration of less than%. In some embodiments, the composition comprises about 4 wt. Includes a total degradant concentration of less than%. In some embodiments, the composition comprises about 3 wt. Includes a total degradant concentration of less than%. In some embodiments, the composition comprises about 2.5 wt. Includes a total degradant concentration of less than%. In some embodiments, the composition comprises about 2 wt. Includes a total degradant concentration of less than%. In some embodiments, the composition comprises about 1 wt. Includes a total degradant concentration of less than%.

  In some embodiments, the composition may be prepared by spray drying, a technique used to prepare microparticles of a drug, such as microcapsules or microspheres. Spray dried peptides generally retain their bioactivity upon dissolution and may have useful physical characteristics including uniform particle size and spherical shape. In addition, microparticles prepared by spray drying are often free flowing, which is beneficial for pharmaceutical manufacturing processes such as tablet formation and capsule filling. The spray drying process is also useful because it can be easily scaled up for clinical and commercial manufacturing. In one embodiment, the spray buffer comprises HCl, histidine, 1.5% PVA and 0.6% talc. This formulation can be used to produce a lower dosage range between 36 and 290 μg.

  When administered, the composition dissolves in the targeted area of the gastrointestinal tract, releasing linaclotide. The formulation may release linaclotide over a period of time determined by several different factors. These factors include the size of the formulation, the concentration of linaclotide, and how the linaclotide is dispersed in the formulation. For example, the rate of dissolution can be adjusted by varying the thickness and surface area of the formulation. Thick formulations dissolve more slowly than otherwise similar thin formulations and may be desirable for administering higher doses of linaclotide.

  In some embodiments, the delayed release composition has a disintegration rate at targeted pH conditions of less than about 60 minutes. In some embodiments, the delayed release composition has a disintegration rate at targeted pH conditions of less than about 30 minutes. In some embodiments, the delayed release composition has a disintegration rate of less than about 25 minutes. In some embodiments, the delayed release composition has a disintegration rate of less than about 20 minutes. In some embodiments, the delayed release composition has a disintegration rate of less than about 15 minutes. In some embodiments, the delayed release composition has a disintegration rate of less than about 10 minutes. In some embodiments, the delayed release composition disintegrates in less than about 30 minutes after entering the targeted environment. In some embodiments, the delayed release composition disintegrates in less than about 25 minutes after entering the targeted environment. In some embodiments, the delayed release composition disintegrates in less than about 20 minutes after entering the targeted environment. In some embodiments, the delayed release composition disintegrates in less than about 15 minutes after entering the targeted environment.

  In some embodiments, the delayed release composition releases at least about 75% of the linaclotide contained therein within 60 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 75% of the linaclotide contained therein within 30 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 80% of the linaclotide contained therein within 30 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 85% of the linaclotide contained therein within 30 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 90% of the linaclotide contained therein within 30 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 95% of the linaclotide contained therein within 30 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 99% of the linaclotide contained therein within 30 minutes of entering the targeted environment.

  In some embodiments, the delayed release composition releases at least about 40% of the linaclotide contained therein within 15 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 50% of the linaclotide contained therein within 15 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 60% of the linaclotide contained therein within 15 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 70% of the linaclotide contained therein within 15 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 80% of the linaclotide contained therein within 15 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 85% of the linaclotide contained therein within 15 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 90% of the linaclotide contained therein within 15 minutes of entering the targeted environment. In some embodiments, the delayed release composition releases at least about 95% of the linaclotide contained therein within 15 minutes of entering the targeted environment.

  In some embodiments, the delayed release composition releases at least about 80% of the linaclotide contained therein within about 2 to about 2 hours of entering the targeted environment.

  In some embodiments, the delayed release composition releases at least about 75% of the linaclotide contained therein within 30 minutes of contact with a pH greater than 5. In some embodiments, the delayed release composition releases at least about 80% of the linaclotide contained therein within 30 minutes of contacting with a pH greater than 5. In some embodiments, the delayed release composition releases at least about 85% of the linaclotide contained therein within 30 minutes of contact with a pH greater than 5. In some embodiments, the delayed release composition releases at least about 90% of the linaclotide contained therein within 30 minutes of contact with a pH greater than 5. In some embodiments, the delayed release composition releases at least about 95% of the linaclotide contained therein within 30 minutes of contact with a pH greater than 5. In some embodiments, the delayed release composition releases at least about 99% of the linaclotide contained therein within 30 minutes of contact with a pH greater than 5.

  In some embodiments, the delayed release composition releases at least about 75% of the linaclotide contained therein within 30 minutes of contacting the pH above 7. In some embodiments, the delayed release composition releases at least about 80% of the linaclotide contained therein within 30 minutes of contacting the pH above 7. In some embodiments, the delayed release composition releases at least about 85% of the linaclotide contained therein within 30 minutes of contact with a pH greater than 7. In some embodiments, the delayed release composition releases at least about 90% of the linaclotide contained therein within 30 minutes of contacting the pH above 7. In some embodiments, the delayed release composition releases at least about 95% of the linaclotide contained therein within 30 minutes of contacting the pH above 7. In some embodiments, the delayed release composition releases at least about 99% of the linaclotide contained therein within 30 minutes of contacting the pH above 7.

  In some embodiments, the linaclotide DR composition is formulated for delivery of linaclotide to the ileum, late ileum, or colon. In some embodiments, the linaclotide DR composition is formulated for delivery of linaclotide to the ileum or ileal region. In some embodiments, the linaclotide DR composition is formulated for delivery of linaclotide from within the lower ileum to the ascending colon (eg, at or near the ileocecal junction).

  In some embodiments, the composition or oral dosage form is administered as a tablet, capsule or sachet to a pediatric patient in need thereof. In some embodiments, a sachet containing the composition is opened and the contents are sprinkled onto or agitated onto a food product such as apple sauce, or a beverage such as water. In some embodiments, the capsule is swallowed or opened whole with a fluid such as water and sprinkled onto or agitated onto a food or beverage. The tablet may be swallowed whole, ground, agitated in a food or beverage, or formulated as a chewable tablet.

  The subject or patient for whom administration of the pharmaceutical composition is an effective therapeutic regimen for a disease or disorder is preferably a human, but can be any animal, including laboratory animals for clinical trials or screening or activity studies. Thus, as will be readily appreciated by those of skill in the art, the methods, compounds and compositions described herein are, for example, for veterinary use, particularly mammalian, but human, rodent and Non-rodents, such as cats or dogs, including but not limited to cattle, horses, goats, sheep and pigs, livestock, wildlife (whether in the wild or in the zoo), research animals , Particularly suitable for administration to any animal, including, but not limited to, mouse, rat, rabbit, goat, sheep, pig, dog, cat, etc., bird species such as chicken, turkey, songbird, etc. There is.

  In some embodiments, the linaclotide composition may be formulated as a rectal dosage form for rectal administration. Rectal dosage forms include, but are not limited to, rectal suppositories, rectal foams or aerosols, enemas, rectal gels and ointments. In some embodiments, the rectal dosage form may be administered to a patient in need thereof. In some embodiments, the rectal dosage form may be administered to a pediatric or geriatric patient.

  Another aspect of the invention is a method of making a delayed release composition, the steps of preparing a linaclotide base, a pre-granulated filler and a placebo base; and a linaclotide base, a pre-granulated Blending the filled filler and placebo base and compressing it into tablets. In some embodiments, the pre-granulated filler is prepared via wet granulation, dried, then blended and compressed into tablets. In some embodiments, the method further comprises applying a subcoat to the tablet. In some embodiments, the method further comprises applying an enteric or functional coating to the tablet.

Another aspect of the invention is a method of making a delayed release composition, the method comprising preparing an aqueous solution comprising linaclotide or a pharmaceutically acceptable salt thereof; and the aqueous solution in a pharmaceutically acceptable carrier. A method including applying steps.
Definition

  As used herein, unless otherwise indicated, the term "delayed release" refers to the composition having a gastrointestinal tract such that substantially no linaclotide remains in the formulation, composition or dosage form. In the targeted regions of the, it means to dissolve, melt, disintegrate, liquefy, etc. Delayed release compositions include sustained release compositions, gastric retentive compositions, targeted release compositions (such as colon release compositions, or compositions that target the ileocecal valve), extended release compositions and And / or combinations thereof.

  As used herein, unless otherwise indicated, the term "delayed release composition" ("DR") refers to a dosage form in which the composition releases linaclotide at a time other than immediately after oral administration. Means

  As used herein, unless otherwise indicated, the term "prolonged release composition" means that the composition is a dosage form that releases linaclotide over an extended period of time after administration. This allows for a reduction in dosing frequency as compared to immediate release compositions.

  As used herein, unless otherwise indicated, "disintegration" and "release" refer to substantially all of the linaclotide at, for example, a pH of greater than 5 or 7, or 37 ± ± in phosphate buffer. Means that a capsule, film, bead or tablet containing linaclotide dissolves, melts, disintegrates, liquefies, etc. in the oral environment so that it does not remain in the dosage form further when maintained at 1 ° C. As used herein.

  The term "released from" with respect to the release of linaclotide from a composition is used herein to mean that no further linaclotide remains in the composition form unless otherwise stated.

  As used herein, unless otherwise indicated, the term "entry into a targeted environment" is intended for release of linaclotide in a targeted organ or compartment thereof, for example 5 or By contacting the composition within the patient within the compartment of the GI having a pH greater than 7.

  As used herein, unless otherwise indicated, the term "lower gastrointestinal (GI)" means the distal compartment of the gastrointestinal tract, such as the ileum, terminal ileum, ileocecal valve or colon.

  As used herein, unless otherwise indicated, the term “upper gastrointestinal (GI)” means the proximal compartment of the gastrointestinal tract, eg, stomach, duodenum and / or jejunum.

  As used herein, unless otherwise noted, "stabilizer" refers to a polymer of the composition, a sterically hindered primary amine (e.g., Amino acid) or cation (eg, metal cation) component. For example, the polymeric stabilizer is a polymer included in the composition in an amount that provides stabilization. Similarly, a sterically hindered primary amine stabilizer is a sterically hindered primary amine contained in the composition in a stabilizing amount. In addition, cationic stabilizers are cations that are included in the composition in stabilizing amounts.

  As used herein, unless otherwise specified, "stabilizing amount" refers to the amount of linaclotide in a composition as compared to a similar composition that does not have the same amount of stabilizing component. Refers to the concentration of polymer, sterically hindered primary amine (eg, amino acid) or metal cation component in the composition that increases the stability of the component.

  As used herein, unless otherwise indicated, the term "substantially all" means at least about 90%, such as at least about 95% or even at least about 99%.

  As used herein, unless otherwise stated, the term "isolated and purified" means, for example, at least 95 percent pure (eg, at least 96 percent pure) as measured by chromatographic purity using, for example, HPLC. % Pure, at least 97% pure, at least 98% pure, or even at least 99% pure).

  As used herein, unless otherwise indicated, "therapeutically effective amount" means that treatment (as defined below) when administered to a mammal to treat a condition, disorder or condition. Sufficient amount of linaclotide or a pharmaceutically acceptable salt thereof. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, sex, weight, health and responsiveness of the mammal being treated. For example, a therapeutically effective amount of linaclotide or a pharmaceutically acceptable salt or hydrate thereof can be an amount effective to treat gastrointestinal disorders including irritable bowel syndrome constipation.

  As used herein, unless otherwise indicated, "pharmaceutically acceptable" means biologically or pharmacologically compatible for in vivo use in animals or humans. , Preferably approved by a federal or state regulatory agency, or listed on the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. means.

  As used herein, unless otherwise indicated, the term "treat" in its all verb form, refers to a disorder in a subject, such as at least one disorder including gastrointestinal disorders, such as constipated irritable bowel syndrome. As used herein to mean reducing, alleviating, preventing and / or managing symptoms. Within the meaning of the present invention, the term “treating” also refers to stopping the disease, delaying its onset (ie the period before the clinical manifestation of the disease) and / or developing or exacerbating the disease. It indicates that the risk of The term "treatment" means the act of "treating" as defined above.

  As used herein, unless otherwise indicated, the term “preventing” refers to a subject at risk of developing a condition (eg, stress-related disorder) that results in a decrease in the probability that the subject will develop the condition. Refers to the preventive treatment of.

  As used herein, unless otherwise indicated, the term "adverse event" refers to any undesired medical event in a patient to whom a pharmaceutical product has been administered or in a clinical investigation subject that does not necessarily have a causal relationship to treatment. Refers to an event. For example, one adverse event is diarrhea.

  As used herein, unless otherwise specified, the term "additive" refers to a pharmaceutically acceptable additive. Pharmaceutically acceptable additives include binders, disintegrants, dispersion additives, lubricants, glidants, antioxidants, coating additives, diluents, surfactants, flavoring additives, water retention. Agents, absorption-promoting additives, controlled-release additives, anti-caking additives, antibacterial agents (eg preservatives), colorants, desiccants, plasticizers and pigments, but are not limited thereto.

  As used herein, unless otherwise specified, an "excipient" is any pharmaceutically acceptable additive, filler, binder or drug.

  As used herein, unless otherwise stated, “stress conditions” refers to 40 ° C. and 75% relative humidity (RH).

  As used herein, unless otherwise stated, the terms "about" and "approximately" refer to those skilled in the art that depend in part on how the value was measured or determined, ie, the limits of the measurement system. It is within the allowable error range for the specific value determined by. For example, "about" can mean within 1 standard deviation or within 1 standard deviation, according to practice in the art. Alternatively, "about" can mean plus or minus a maximum of 20%, preferably a maximum of 10%, with respect to the composition. Alternatively, and especially with respect to biological systems or processes, the term means within a certain order of magnitude, preferably within a factor of 5 and more preferably within a factor of 2. Where a particular value is set forth in the present application and claims, unless otherwise stated, the term "about" means within an acceptable error range for the particular value.

  All weight percentages (ie, "wt%" and "wt.%" And w / w) referred to herein are measured relative to the total weight of the pharmaceutical composition, unless otherwise specified.

  The term "consisting essentially of" and variants thereof, when used in reference to a composition, indicates that the composition is linaclotide and other desired pharmaceutically inactive additives, excipients and / or Or components (eg polymers, sterically hindered primary amines, cations, fillers, binders, carriers, excipients, diluents, disintegrating additives, lubricants, solvents, dispersants, coating additives, Absorption-promoting additives, hydrolysis products, formaldehyde imine products, oxidation products, acetylation products, deamidation products, multimers, controlled release additives, anti-caking additives, antibacterial additives, preservatives, sweetening additives, colorants , Flavoring agents, desiccants, plasticizers, dyes, etc.) and is free of other active pharmaceutical ingredient (s).

  The following examples merely illustrate the present invention, and upon reading the present disclosure, many variations and equivalents encompassed by the present invention will become apparent to those skilled in the art, and therefore the scope of the present invention is never exceeded. Is not meant to be limited.

  Enteric coated tablets, including core immediate release tablets containing a unit dose of linaclotide, are coated with a coating that dissolves only under pH conditions in the distal compartment of the intestine, such that linaclotide is released into the lower GI tract. Can be done.

  Linaclotide or a pharmaceutically acceptable salt thereof may be produced and purified using standard techniques known in the art, such as chemical synthesis or recombinant expression using standard techniques followed by purification. it can.

  Preparation of linaclotide coating solution for beads: About 32 g to 42 g of purified water is mixed with hydrochloric acid to make a solution with a pH between 1.5 and 2.0. The cation, if used, is added to this solution in an amount to provide the desired concentration and the solution is mixed for a time sufficient to produce a clear solution. The sterically hindered primary amine, if used, is added to this solution in an amount to provide the desired concentration and the solution is mixed for a time sufficient to produce a clear solution. If desired, then other additives such as antioxidants are added. The pH of the solution is tested and hydrochloric acid is added if necessary to produce a solution with a pH between 1.5 and 2.0. The binder is then added to the solution and the mixture is then stirred for a time sufficient to achieve a clear solution. The desired amount of linaclotide is added to the solution and mixed for 30-100 minutes to provide the coating solution.

  In one embodiment, the coating solution comprises linaclotide, histidine, 1.5% PVA and 0.6% talc. This formulation can be used to produce a dosage range in the range of 30-300 μg.

Preparation of Active Beads: About 30-36 g of dry microcrystalline cellulose beads are added to a minicolumn fluid bed coater. The microcrystalline cellulose beads are fluidized, heated and then laminated. The coating solution is then laminated to the beads. The atomization temperature is controlled between 24 ° C and 55 ° C by controlling the inlet temperature, atomization rate, atomization pressure and air volume. After the entire coating solution has been layered on the beads, the beads are dried. The products of this process are called activated beads.
(Example 1)
Delayed release linaclotide tablets

  Linaclotide may be formulated in tablets for delayed drug release. Tablets have a much smaller specific surface area compared to equal volumes of beads, which may reduce their tendency to undergo degradation induced by environmental factors such as humidity, oxidation, and amidolysis. . In addition, the smaller surface area of tablets may be advantageous as enteric coatings are required, as much less coating material is needed to cover the surface of the dosage form.

The enteric coating may be applied in a tablet coating pan and the coating used on the delayed release beads may be used on the tablets to form a delayed release tablet. The amount of coating polymer on the tablet can vary from 5 to 60% (weight gain) depending on the size, shape and surface characteristics of the tablet. The subcoat may be applied to the tablet to separate the linaclotide from the enteric or functional coat.
(Example 2)
Enteric coated tablets
Manufacturing process:
A. tablet

The granulation solution can be prepared by dissolving PVP, histidine and calcium chloride in water, adjusting the pH of the solution to 2 and dissolving linaclotide. Granulation is carried out by spraying the granulation solution in a fluidized bed onto the filler isomalt. At the end of granulation, the granules are dried for 30 minutes. The granules are then blended until homogeneous with tablet ingredients including isomalt, crospovidone, Mg stearate and talc and compressed into tablets.
B. Enteric coating

For tablet coating, place the linaclotide core tablets in a pan coater and warm to 35 ° C. Tablet coating is started with the Eudragit® FS 30 D suspension, maintaining the product temperature at 28 ° C. to 32 ° C. and atomizing air pressure at 3 bar. At the end of coating, the tablets are discharged, they are placed in a circulating air oven and dried at 40 ° C. for 2 hours. Similarly, other enteric coatings such as Eudragit® L, S, ethyl cellulose, HPMCAS, PVAP, CAP, CAS can also be applied to form delayed release tablets with various weight gains.
(Example 3)
Delayed release composition comprising linaclotide

  Delayed release capsules containing linaclotide can be formulated to target the ileum or colon (eg, ileum, lower ileum, and / or ascending colon). The composition may be formulated to include pH-triggered release based on the enteric coating of linaclotide coated beads contained in linaclotide tablets, capsules or hard gelatin capsules. The composition can be formulated to further include stabilizing additives such as divalent cations and amino acids. PVA can be used as a binder as well as a protective layer between linaclotide and the enteric coating. Linaclotide or linaclotide with a PVA overcoat (as beads, capsules, or tablets) is added to an additional enteric coating (eg, Eudragit (Eudragit ( (Registered trademark) FS30D, Eudragit (registered trademark) S100, Eudragit (registered trademark) L100, Eudragit (registered trademark) L100-55, Eudragit (registered trademark) L30D-55). The enteric coating is a blend that combines different types of Eudragit®-different ratios (eg, 50/50 ratio) of Eudragit® S100 / Eudragit® L100; various ratios of Eudragit®. ) S100 / Eudragit® L100-55; various ratios of Eudragit® FS30D / Eudragit® L30D-55, Eudragit® FS30D Eudragit® S / Eudragit®. It can consist of RS or EC. The composition may further comprise other excipients including plasticizers such as triethyl citrate. The coating may further include disintegrants as suspended solids to facilitate suitable pH-triggered release, resulting in a mixed system such as croscarmellose sodium / Eudragit® S. To facilitate processing, anti-sticking agents such as talc, Aerosil® 200 or PlasAcryl ™ can be used to prevent sticking of the beads.

In addition, two Eudragit® coatings, including partially neutralized coating systems, can be applied to ensure rapid release once the desired pH range of the GI tract is reached. A buffering agent such as potassium hydrogen phosphate may be included in one of the two Eudragit® films. Alternative non-Eudragit® pH dependent film coatings include hydroxypropylmethyl cellulose acetate succinate (HPMCAS, eg, Aquat® AS-HF), cellulose acetate phthalate (CAP, eg, Aquateric®). )) Or shellac.
(Example 4)
Determination of content and purity of exemplary peptides

Linaclotide, imidazolidinone degradation products (“Cys ¹ -IMD”) and α-ketone degradation products (“Cys ¹ -α-ketone”) are described in US 2010/0048489, US 2013/0190238. And can be measured and purified as described in US 2015/0094272. Overall, the content and purity of linaclotide was determined by Chemstation Rev A. et al. It can be determined by reverse phase gradient liquid chromatography using an Agilent Series 1100 LC System with 09.03 software or equivalent. A YMC Pro ™ C18 column (dimensions: 3.0 × 150 mm, 3.5 um, 120Å; Waters Corp., Milford, MA) or equivalent is used and maintained at 40 ° C. Mobile phase A (MPA) consisted of water with 0.1% trifluoroacetic acid, while mobile phase B (MPB) consisted of 95% acetonitrile: 5% water with 0.1% trifluoroacetic acid. Elution of linaclotide is achieved by washing the column with a gradient of 0% to 47% MPB for 28 minutes, then a 4 minute ramp to 100% MPB, holding 5 minutes at 100% MPB. Re-equilibration of the column is performed by returning to MPB 0% for 1 minute and then holding MPA 100% for 10 minutes. The flow rate is 0.6 mL / min and detection is achieved by UV at 220 nm.
(Example 5)
in vitro drug release test

Release of linaclotide from coated tablets can be assessed by dissolution testing using a USP XXIV Type II Paddle Dissolver (Model PTWS, Pharma Test, Hainburg, Germany). The test is carried out in triplicate in 900 ml of dissolution medium maintained at 37.0 ± 0.5 ° C. with a paddle speed of 100 rpm. Tablets were first prepared in 0.1 N hydrochloric acid (pH 1.2) for 30 minutes or 2 hours to mimic the gastric space, and then in buffered media of various pH and ionic composition similar to those of the small intestine. Time will be tested. The linaclotide release was carried out at pH 6.8-7.4 in two official buffer media: 0.067M mixed sodium and potassium phosphate (salensen) buffer and 0.05M potassium phosphate buffer, and ionic. It can be evaluated in a polyelectrolyte salt solution (Hanks) buffer at pH 7.4, which is similar in composition to intestinal fluid. All buffers are freshly prepared with deionized water and degassed by sparging with helium before use. The amount of linaclotide released from the dosage form can be determined by reverse phase gradient liquid chromatography as described in Example 4.
(Example 6)
Linaclotide tablet release profile

The linaclotide tablet release profile was tested for three delayed release formulations at various pHs. Samples 181-64B contain a 100 μg dose of linaclotide, a subcoat of Opadry® II, and a functional coat of Eudragit® FS 30D and talc. Samples 181-64C contain a 100 μg dose of linaclotide, a subcoat of Opadry II, and a functional coat of Eudragit® FS30D and Eudragit® PlasAcryl®. Release profiles for lots 181-64B and lots 181-64C are provided at the top of FIG. In addition, various formulations were tested using various ratios of Eudagrit L100 and Eudagrit S100 and Physilution® dissolution devices (Physilution GmbH, Greifswald, Germany). Briefly, various tablets were tested for drug dissolution in physiological buffer under various pH conditions that mimic the gastrointestinal pathway to determine the location of dissolution. As shown in Figure 20B, the rate of drug release is plotted against the time during which the device changes pH according to Table 40.
In FIG. 20B, the same core tablets of linaclotide prepared as described herein, at different ratios of Eudagrit L100 (degrades above pH 6.0) and Eudragit S100 (degrades above pH 7.0). Coated. By changing the ratio from 40:60 (S100: L100) to 95: 5 (S100: L100), the drug was released in the duodenum / jejunum (40:60, 50:50), ileum (60:40, 80). : 20 and 85:15) and can vary dramatically from the lower release to the lower ileum / colon (90:10 and 95: 5). Based on these studies, the ratios leading to the release of the upper (83:17 S100: L100) and lower (100% S100) of the lower GI were selected for the delayed release formulation.
(Example 7)
Preparation of linaclotide tablets

Delayed release tablets may be prepared by first preparing the following core tablet components: placebo base, linaclotide 750 μg / 225 mg base and pre-granulated filler.
Granule manufacturing process:

The tablet ingredients may be prepared in separate granules for blending prior to tablet compression. The use of separate tablet ingredients such as a placebo base and a pre-granulated filler base has led, among other things, to advantageous properties in tablet stability and release profile. For example, all tablet ingredients listed in Table 2 can be prepared separately by wet granulation and blended prior to compression, or blended together and processed as a mixture for wet granulation. In another process, the tablet ingredients listed in Table 2 can be prepared separately by dry granulation and blended prior to compression, or blended together and processed as a mixture for dry granulation. In another process, tablet ingredients are blended directly for compression. In a preferred process, the pre-granulated filler base and / or the placebo base are prepared by wet granulation, dried and then mixed with 750 μg / 225 mg linaclotide base. The linaclotide base can be prepared by a wet granulation process or by a Wurster coating process. This preferred process showed a further increase in tablet stability by reducing moisture exposure of linaclotide during processing and minimizing residual moisture in the tablet core.

The above blend is then compressed on a suitable tablet press to a target core tablet weight of 225mg. In a perforated pan coater, add the subcoat (OPADRY® II) at a 4% w / w weight gain. The coating conditions should be set and monitored to keep moisture uptake in the coating to a minimum. The subcoated tablets should have a LOD of 1.5% or less, as measured by the weight loss on drying (LOD) method. In a perforated pan coater, add the functional coat on the subcoated tablets. The functional coat is either Eudragit® FS30D, Eudragit® S100 or Eudragit® L100. The functional coat is applied on the tablet surface with 5 mg polymer weight / cm ² . This results in a weight gain of about 4.5% total polymer in the functional coating. The coating conditions should be set and monitored to keep moisture uptake in the coating to a minimum. Functionally coated tablets should have a LOD of 2.0% or less as measured by the weight loss on drying method.
Preparation of placebo base:

Table 3 represents the formulation for placebo-based granulation:

A placebo-based preparation can be prepared by first dispensing the ingredients in Table 4.

  Weigh the mixing vessel and add 2682.1 ± 5.0 g of treated water into the vessel. Install mixer and start stirring water. Add EMPROVE® to this water with stirring and start the timer. While stirring, cover the solution and heat to 70 ° C., maintaining the temperature until the material visually dissolves.

The pH of the solution is adjusted to 1.5 with hydrochloric acid. Calcium chloride dihydrate is added to the solution with stirring. Mix until dissolved. Add L-histidine to the solution with stirring. Stir for about 15 minutes. Record the initial pH. Adjust the pH of the solution to 5.0 with hydrochloric acid. Record the final pH of the solution and the addition of hydrochloric acid. Mix until all ingredients are dissolved. While mixing, the pH of the solution is adjusted to 2.5 with hydrochloric acid. Record the final pH of the solution and the addition of hydrochloric acid. A high shear granulator equipped with a 25 L bowl, mixing vanes and chopper should be properly installed for granulation. The microcrystalline cellulose is passed through a 16 mesh screen into the granulator bowl. Calculate and add the net weight of the granulation solution. While mixing the granulation solution at the following parameters: impeller speed 1 (290 rpm, tip speed of 5.5 m / sec), chopper speed 1 (1760 rpm), pump into the granulator at a speed of about 300 g / min. Suck up. Stop the granulator and rub down the sides and bottom of the bowl. Mix for an additional 3 minutes according to the following parameters: impeller speed 1 (290 rpm, tip speed of 5.5 m / sec), chopper speed 1 (1760 rpm). The polybag is weighed and the finished wet granulation is discharged into it. Weigh the granulate. The wet granulation is transferred to a FLM-3 fluid bed for drying. Dry the granulate using the following approximate settings. Dry until the LOD of the granulation is 1.2% water or less. The dried granulate is discharged into a weighed plastic bag.
The settings are only recommended settings and may be adjusted for optimal drying.

The dried granulation is screened through a # 30 mesh sieve. The polybag is weighed and the dried granulation is discharged into it. Weigh the granulate. The dried granulation is packaged in a foil sealed bag with a desiccant.
Linaclotide-based preparation (ie 750 μg / 225 mg):

Table 5 represents the formulation of 750 μg / 225 mg of base granulation.

A 750 μg / 225 mg base granulate can be prepared by first dispensing the raw materials in Table 6.

Add linaclotide to the granulation solution while mixing. Mix until dissolved. A high shear granulator with a 25 L bowl, mixing blades, and chopper is ensured to be properly installed for granulation. Microcrystalline cellulose is passed through a 16 mesh screen into the granulator bowl. While mixing the granulation solution at the following parameters: impeller speed 1 (290 rpm, tip speed of 5.5 m / sec), chopper speed 1 (1760 rpm), pump into the granulator at a speed of about 300 g / min. Suck up. The polybag is weighed and the finished wet granulation is discharged into it. Weigh the granulate. Transfer the wet granulation to a fluidized bed for drying. Dry the granulate using the following approximate settings. Dry until the LOD of the granulation is 1.2% water or less. The dried granulate is discharged into a weighed plastic bag.

The dried granulation is screened through a # 30 mesh sieve. The polybag is weighed and the dried granulation is discharged into it. Weigh the granulate. The dried granulation is packaged in a foil sealed bag with a desiccant.
Pre-granulated filler preparation:

Table 7 represents the formulation for the pre-granulated filler.

Filler preparations may be prepared by first dispensing the raw materials in Table 8.

The tare weight of the stainless steel container is then recorded. Weigh the container and weigh the required amount of treated water in the container. Transfer the water into the double kettle. Install a mixer and start stirring water in the kettle. Add EMPROVE® (polyvinyl alcohol) to the water with stirring and start the timer. The solution is covered with stirring and heated to 70 ° C., maintaining the temperature until the material visually dissolves. Calculate the weight of water loss due to evaporation during heating. This amount of treated water is added to the solution. Microcrystalline cellulose, croscarmellose sodium, and mannitol each are added to the bowl of a high shear granulator. Mix for about 2 minutes according to the following parameters: impeller speed 1 (290 rpm, tip speed of 5.5 m / sec), chopper speed 1 (1760 rpm). 2217 ± 5 g of the granulation solution was mixed at the following parameters: impeller speed 1 (290 rpm, tip speed of 5.5 m / sec), chopper speed 1 (1760 rpm), while granulating at a speed of about 300 g / min. Pump up into the plane. Stop the granulator and rub down the sides and bottom of the bowl. Mix for an additional 30 seconds to 1 minute according to the following parameters: impeller speed 1 (290 rpm, tip speed of 5.5 m / sec), chopper speed 1 (1760 rpm). The polybag is weighed and the finished wet granulation is discharged into it. Weigh the granulate. The wet granulation is passed through a Comil equipped with a 2A375Q03763 screen with 5-10% force. The wet granulation is transferred to a FLM-3 fluid bed for drying. Dry the granulate using the following approximate settings. The granulated product is dried until the LOD becomes 1.0% or less of water. The dried granulate is discharged into a weighed plastic bag.

Mill the granulation using a Comil, circular impeller, 2A045R03137 screen. The polybag is weighed and the dried and milled granulate is discharged into it. Weigh the granulate. The dried granulation is packaged in a foil sealed bag with a desiccant.
(Example 8)
25 μg tablet blending and compression

Following the procedure of Example 7, a 25 μg dose tablet of linaclotide can be prepared using the formulation in Table 9.

First, the raw materials in Table 10 are distributed.

  Preblend: Install 8 qt blender and add 750 μg / 225 mg of base and placebo base. Close the lid and blend for 10 minutes. Weigh the polybag and drain the preblend into it.

  Subblend A: 650 g of preblend is added to a 16 qt v-blender. Add the pre-granulated filler for Subblend A to the 16qt v-blender. Close the lid and blend for 10 minutes. Magnesium stearate for Subblend A is passed through a 40 mesh screen. Add to 16qt v-blender. Close the lid and blend for 3 minutes. Weigh the polybag and drain the blend into it.

  Subblend B: 650 g of preblend are added to a 16 qt v-blender. Add the pre-granulated filler for subblend B to the 16qt v-blender. Close the lid and blend for 10 minutes. Magnesium stearate for Subblend B is passed through a 40 mesh screen. Add to 16qt v-blender. Close the lid and blend for 3 minutes. Weigh the polybag and drain the blend into it.

Compression: Korsch XL100 tablet press with 0.32 inch sc tool, 0.32 inch circular concave tool (10 stations preferred), securely installed with paddle feeder, and all other Correctly fix the parts. To ensure proper installation, manually turn the die table at least once a full revolution. Visually confirm the presence of all dies and punches and that the dies are flush with the die table. Verify that the tablet specifications meet the in-process tablet specifications in Table 11.

Charge the blend into the hopper. Set the turret speed to an appropriate speed. The die fill and compression parameters are adjusted to obtain tablets with a target weight of 225 mg and a target hardness of 8-12 kP. All waste must be collected in tableting waste polybags. Start the timer to compress the tablets.
(Example 9)
Blending and compression of 100 μg tablets

Following the procedure of Example 7, a 100 μg dose tablet of linaclotide can be prepared using the formulation in Table 12.

First, the raw materials in Table 13 are distributed.

  Preblend: Install 16 qt blender and add 750 μg / 225 mg of base and placebo base. Close the lid and blend for 10 minutes. Weigh the polybag and drain the preblend into it.

  Add 2500 g of the preblend to a 1 ft. V-blender. Pre-granulated filler is added to this one-dimensional foot v-blender. Close the lid and blend for 10 minutes. Magnesium stearate is passed through a 40 mesh screen. Add 1 ft. V-blender. Close the lid and blend for 3 minutes. Weigh the polybag and drain the blend into it.

Compression: Korsch XL100 tablet press with 0.32 inch sc tool, 0.32 inch circular concave tool (10 stations preferred), securely installed with paddle feeder, and all other Correctly fix the parts. To ensure proper installation, manually turn the die table at least once a full revolution. Visually confirm the presence of all dies and punches and that the dies are flush with the die table. Confirm that the tablet specifications meet the in-process tablet specifications in Table 14.

Charge the blend into the hopper. Set the turret speed to an appropriate speed. The die fill and compression parameters are adjusted to obtain tablets with a target weight of 225 mg and a target hardness of 8-12 kP. All waste must be collected in tableting waste polybags. Start the timer to compress the tablets.
(Example 10)
Blending and compression of 290 μg tablets

Following the procedure of Example 7, a 290 μg dose tablet of linaclotide can be prepared using the formulation in Table 15.

First, the raw materials in Table 16 are distributed.

  Sub-Blend A: Add pre-granulated filler for Sub-Blend A and linaclotide base to a 16qt v-blender. Close the lid and blend for 10 minutes. Magnesium stearate for Subblend A is passed through a 40 mesh screen. Add to 16qt v-blender. Close the lid and blend for 3 minutes. Weigh the polybag and discharge the blend into it.

  Sub-blend B: Add pre-granulated filler for sub-blend B and linaclotide base to 16qt v-blender. Close the lid and blend for 10 minutes. Magnesium stearate for Subblend B is passed through a 40 mesh screen. Add to 16qt v-blender. Close the lid and blend for 3 minutes. Weigh the polybag and discharge the blend into it.

Compression: Korsch XL100 tablet press with 0.32 inch sc tool, 0.32 inch circular concave tool (10 stations preferred), securely installed with paddle feeder, and all other Correctly fix the parts. To ensure proper installation, manually turn the die table at least once a full revolution. Visually confirm the presence of all dies and punches and that the dies are flush with the die table. Verify that the tablet specifications meet the in-process tablet specifications in Table 17.

Charge the blend into the hopper. Set the turret speed to an appropriate speed. The die fill and compression parameters are adjusted to obtain tablets with a target weight of 225 mg and a target hardness of 8-12 kP. All waste must be collected in tableting waste polybags. Start the timer to compress the tablets.
(Example 11)
Linaclotide 25μg tablet sub-coating

The 25 μg tablet of Example 8 may be subcoated with an Opadry® II subcoating. The formulations in Table 18 represent the amounts needed to prepare coating material that is over-prepared to address losses in the coating process.

  Dispense 1600 g of purified water into a suitably sized container. Dispense 400 g of Opadry® II into appropriately sized containers. Add Opadry® to the water. Calculate the theoretical amount of solution required to apply a 4.0% weight gain with a theoretical efficiency of 85%. Provide a plastic bag for waste tablets to be collected during the coating process. The Compu-Lab was securely set with a 19 inch pan and plenum assembly. Make sure the liquid supply line is a Tygon 17 tube. Make sure the gun assembly is attached to the pan. The spray gun assembly should consist of a 1 × 1/4 JAU spray gun equipped with a 40100AB liquid spray nozzle and matching air cap. The gun assembly should be mounted as far as possible from the tablet bed, with the spray angle perpendicular to the upper third of the bed. Confirm the initial tablet weight by weighing 100 uncoated tablets. Divide the tablet weight by 100 to calculate the average weight of a single tablet. The initial tablet moisture is checked by grinding approximately 1 gram of the tablet and performing LOD at 105 ° C. for 10 minutes. Adjust the pump so that the liquid flow rate is approximately 10 g / min. Prepare the line through the gun and make sure there are no leaks in the line or the gun. The tablets are placed in a coating pan and heating is started for 20 minutes with an inlet temperature of 50 ° C. and a stream of 350 CFM. Swing occasionally during preheat.

Once the target bed temperature is reached, spraying of the coating suspension is initiated according to the target process parameters outlined in Table 19 below. If desired, regularly check and report the water content of the tablets. Once the theoretical amount of solution has been applied, check the tablet weight gain. When a 4% weight gain is achieved, stop spraying and reduce pan speed to minimum or fine motion to dry the tablets for 30 minutes at an inlet temperature of 50 ° C. The tablets are discharged and the new weight of the coated tablets is determined.
(Example 12)
Subcoating of 100 μg linaclotide tablets

The 100 μg tablet of Example 9 may be subcoated with an Opadry® II coating. The formulations in Table 20 represent the amounts required to prepare coating material that is over-prepared to address losses in the coating process.

  Dispense 4000 g of purified water into an appropriately sized container. Dispense 1000 g of Opadry® II into appropriately sized containers. Add Opadry® to the water. Calculate the theoretical amount of solution required to apply a 4.0% weight gain with a theoretical efficiency of 85%. The Compu-Lab was securely set with a 24-inch pan and plenum assembly. Make sure the liquid supply line is a Tygon 17 tube. Make sure the gun assembly is attached to the pan. The spray gun assembly should consist of a 2x1 / 4 JAU spray gun equipped with a 40100 AB liquid spray nozzle and matching air cap. The gun assembly should be mounted as far as possible from the tablet bed, with the spray angle perpendicular to the upper third of the bed. Confirm the initial tablet weight by weighing 100 uncoated tablets. Divide the tablet weight by 100 to calculate the average weight of a single tablet. The initial tablet moisture is checked by grinding approximately 1 gram of the tablet and performing LOD at 105 ° C. for 10 minutes. Adjust the pump so that the liquid flow rate is about 20 g / min. Prepare the line through the gun and make sure there are no leaks in the line or the gun. The tablets are placed in a coating pan and heating is started for 20 minutes with an inlet temperature of 50 ° C. and a stream of 400 CFM. Swing occasionally during preheat.

Once the target bed temperature is reached, spraying of the coating suspension is initiated according to the target process parameters outlined in Table 21 below. If desired, regularly check and report the water content of the tablets. Once the theoretical amount of solution has been applied, check the tablet weight gain. When a 4% weight gain is achieved, stop spraying and reduce pan speed to minimum or fine motion to dry the tablets for 30 minutes at an inlet temperature of 50 ° C. The tablets are discharged and the new weight of the coated tablets is determined.
(Example 13)
Subcoating of 290 μg linaclotide tablets

The 290 μg tablet of Example 10 may be subcoated with an Opadry® II coating. The formulations in Table 22 represent the amounts needed to prepare coating material that is over-prepared to address losses in the coating process.

  Dispense 1600 g of purified water into a suitably sized container. Dispense 400 g of Opadry® II into appropriately sized containers. Add Opadry® to the water. Calculate the theoretical amount of solution required to apply a 4.0% weight gain with a theoretical efficiency of 85%. The Compu-Lab was securely set with a 19 inch pan and plenum assembly. Make sure the liquid supply line is a Tygon 17 tube. Make sure the gun assembly is attached to the pan. The spray gun assembly should consist of a 1 × 1/4 JAU spray gun equipped with a 40100 AB liquid spray nozzle and matching air cap. The gun assembly should be mounted at a vertical spray angle in the upper third of the bed as far as possible from the tablet bed. Confirm the initial tablet weight by weighing 100 uncoated tablets. Divide the tablet weight by 100 to calculate the average weight of a single tablet. The initial tablet moisture is checked by grinding approximately 1 gram of the tablet and performing LOD at 105 ° C. for 10 minutes. Adjust the pump so that the liquid flow rate is approximately 10 g / min. Prepare the line through the gun and make sure there are no leaks in the line or the gun. The tablets are placed in a coating pan and heating is started for 20 minutes with an inlet temperature of 50 ° C. and a stream of 350 CFM. Swing occasionally during preheat.

Once the target bed temperature is reached, spraying of the coating suspension is begun according to the target process parameters outlined in Table 23 below. If desired, regularly check and report the water content of the tablets. Once the theoretical amount of solution has been applied, check the tablet weight gain. When a 4% weight gain is achieved, stop spraying and reduce pan speed to minimum or fine motion to dry the tablets for 30 minutes at an inlet temperature of 50 ° C. The tablets are discharged and the new weight of the coated tablets is determined.
(Example 14)
Functional or enteric coating of linaclotide tablets (“DR1”)

The tablets of the previous example may be prepared with a functional coating. The formulations in Table 24 represent the amounts needed to prepare coating materials that are over-prepared to address losses in the coating process:

  To prepare the functional coating, the required amount of Eudragit® S100 and Eudragit® L100 are dispensed into appropriately sized containers. Dispense required amount of 2/3 purified water into appropriately sized containers. Start stirring water until vortex is achieved. Eudragit® S100 and Eudragit® L100 are slowly added to the water and mixed (about 5 minutes) until the powder is completely moist and the formation of lumps or bubbles has dissipated.

  Dispense the required amount of 1N NH3 into appropriately sized containers. Slowly add 1N NH3 to the Eudragit® suspension and mix for a minimum of 60 minutes. Dispense the required amount of triethyl citrate into appropriately sized containers. Add triethyl citrate to the Eudragit® suspension and mix for a minimum of 60 minutes. Dispense the required amount of talc in an appropriately sized container. Homogenize talc for 10 minutes (or until homogenous) in the remaining 1/3 of the purified water using a Silverson Homogenizer. The talc suspension is poured into the Eudragit® suspension with mixing. Mix for 5 minutes or less. The coating suspension is screened through a # 30 mesh screen.

  Calculate the theoretical amount of solution needed to apply a 9.0% weight gain with a theoretical efficiency of 90%. The Compu-Lab was securely set with a 19 inch pan and plenum assembly. Make sure the liquid supply line is a Tygon 17 tube. Make sure the gun assembly is attached to the pan. The spray gun assembly should consist of a 1 × 1/4 JAU spray gun equipped with a 40100 AB liquid spray nozzle and matching air cap. The gun assembly should be mounted at a vertical spray angle in the upper third of the bed as far as possible from the tablet bed. Place tablets in coating pan. Warm the tablets at an inlet temperature of 30 degrees. Make sure the bed temperature reaches about 30 degrees before proceeding to the next step. Adjust the pump so that the liquid flow rate is about 12 g / min. Prepare the line through the gun and make sure there are no leaks in the line or the gun. Check the starting tablet moisture by grinding approximately 2 grams of the tablet and performing LOD at 105 ° C. for 10 minutes.

Once the target bed temperature is reached, spraying of the coating suspension is begun according to the target process parameters outlined in Table 25 below. If desired, regularly check and report the water content of the tablets. Once the theoretical amount of solution has been applied, check the tablet weight gain. When a 9% weight gain is achieved, stop spraying and reduce pan speed to minimum or fine motion to dry the tablets for 5-10 minutes at an inlet temperature of 40 ° C.

Final tablet moisture is determined by crushing approximately 2 grams of tablets and performing LOD at 105 ° C. for 10 minutes. Moisture should be ≤ initial tablet moisture. The tablets are discharged and the new weight of the coated tablets is determined. Dry the tablets in a mechanical convection oven set at a temperature of 40 ° C. for at least 2 hours. Tablets are bulk packaged in foil bags with desiccant and stored at 5 ° C. The coating of this Example 14 is used as a coating for the DR1 delayed release composition described herein.
(Example 15)
Alternative functional or enteric coating of linaclotide tablets (“DR2”)

An alternative coating can be prepared according to the method of Example 14, but has the formulation in Table 26. The coating of this Example 15 is used as a coating for the DR2 delayed release composition described herein.
(Example 16)
Organic coating of linaclotide tablets

Organic coatings may be provided for the linaclotide tablets of the above example. The formulation in Table 27 was used for coating 100 μg tablets.

  Dispense the required amount of purified water into an appropriately sized container. Dispense the required amount of acetone into appropriately sized containers. Start mixing acetone and add water. Dispense the required amount of isopropanol into appropriately sized containers. Isopropanol is added to this water and acetone to make a dilute mixture. Pour about half of the diluted mixture into the second container and resume mixing of the first half of the diluted mixture. Dispense the required amount of Eudragit S100 into appropriately sized containers. Begin mixing the second half of the diluted mixture and add Eudragit S100. Dispense the required amount of Eudragit L100 into appropriately sized containers.

  Add Eudragit L100 to the diluted mixture containing Eudragit S100 and start the timer. Stir until the polymer is completely dissolved. Add triethyl citrate to the first half of the diluted mixture while mixing with a high shear mixer. Dispense the required amount of talc into appropriately sized containers. Talc is added to the first half of the diluted mixture while mixing with a high shear mixer to make an excipient suspension. Start timer and mix for at least 10 minutes. Record the mixing time of the Eudragit solution. The excipient suspension is slowly poured into the Eudragit solution while continuing to mix the Eudragit solution. Once the coating suspension is uniform, pass it through a 35 mesh screen. Resume mixing. Calculate the theoretical amount of solution needed to apply a weight gain of 8.5% with a theoretical efficiency of 88%.

Provide a plastic bag for waste tablets to be collected during the coating process. The Compu-Lab was securely set with a 15 inch pan and plenum assembly. Make sure the liquid supply line is solvent resistant 17 tubes. Make sure the gun assembly is attached to the pan. The spray gun assembly should consist of a 1 × 1/4 JAU spray gun equipped with a 40100 AB liquid spray nozzle and matching air cap. The gun assembly should be mounted at a vertical spray angle in the upper third of the bed as far as possible from the tablet bed. Adjust the pump so that the liquid flow rate is about 28 g / min. Prepare the line through the gun and make sure there are no leaks in the line or the gun. The tablets are placed in a coating pan and heating is started with an inlet temperature of 38 ° C. and a stream of 200 CFM. Swing occasionally during preheat. Once the product temperature reaches about 27 ° C, spraying of the coating suspension is begun according to the target process parameters outlined below. When a weight gain of 8.5% is achieved, stop spraying, reduce pan speed to minimum or fine and allow tablets to dry for 10 minutes at an inlet temperature of 40 ° C.

The tablets are placed in a tray and dried in a mechanical convection oven set at a temperature of 45 ° C for at least 24 hours.
(Example 17)
Preparation of alternative linaclotide tablets

Delayed release tablets were prepared by first preparing the following core tablet components: placebo base, linaclotide 1000 μg / 225 mg base and pre-granulated filler.
Granulation manufacturing process:

The tablet ingredients were prepared essentially as described above in Example 7, with some modifications as described below. A placebo base as described in Table 28 was used to provide core tablets having the ingredients listed in Table 28. A final pH of 2.25 was used for placebo and active base granulation.
Preparation of placebo base:

Table 29 represents the formulation for placebo-based granulation:

A placebo-based preparation was prepared by first dispensing the ingredients in Table 30.

Weigh the mixing vessel and add 2200 ± 5.0 g of treated water (not 2682.1 ± 5.0 g) into the vessel.
Linaclotide base preparation (1000 μg / 225 mg):

Table 31 represents the formulation for 1000 μg / 225 mg of base granulation.

1000 μg / 225 mg base granulate can be prepared by first dispensing the raw materials in Table 32.
Pre-granulated filler preparation:

Table 33 represents the formulation for the pre-granulated filler.

Filler preparations are prepared by first dispensing the ingredients in Table 34.
(Example 18)
Alternative 225 mg linaclotide tablet formulation

  Delayed release 225 mg tablets may be prepared with excipient proportions as shown in Table 34 and Table 35. The 225 mg tablet of this Example 18 can be prepared with an active ingredient content of 30 μg, 100 μg or 300 μg. Two exemplary embodiments of excipient proportions, A and B, are provided for each active ingredient content. Embodiment A in Table 34 (at each dosage) corresponds to the DR1 formulation in Example 20 and Embodiment A in Table 35 (at each dosage) corresponds to the DR2 formulation in Example 20. The tablet comprises a tablet core, a barrier coat, a functional coat and optionally an aesthetic coat.

(Example 19)
Alternative 450mg linaclotide tablet formulation

  Delayed release 450 mg tablets may be prepared with excipient proportions as shown in Table 36 and Table 37. The 450 mg tablet of this Example 19 can be prepared with an active ingredient content of 300 μg or 600 μg. Tablets include a tablet core, a barrier coat, a functional coat and an aesthetic coat.

(Example 20)
Administration of linaclotide for the treatment of constipation irritable bowel syndrome (IBS-c)

  Randomized, double-blind, double-dummy, placebo-controlled, concomitant group, late phase 2 of two delayed release formulations of linaclotide (“DR1” and “DR2”) administered orally to IBS-c patients for 12 weeks A delayed release linaclotide tablet was administered in the study ("Trial").

Method of clinical trial

  The trial was a multi-center, multi-dose study with three different periods: a screening period, a pretreatment period and a treatment period (see Figure 1). The study enrolled patients diagnosed with IBS-c using Rome III criteria. Equalized proportion of eligible patients for 8 treatments: 30 μg, 100 μg or 300 μg of linaclotide DR1 formulation; 30 μg, 100 μg or 300 μg of linaclotide DR2 formulation; 290 μg of immediate release (IR) formulation of linaclotide; or 1 of placebo. One day it was randomized. Linaclotide IR was included as a positive control to compare safety and efficacy. The DR1 delayed release composition was designed to release linaclotide core tablets to the ileal region. The DR2 delayed release composition was designed to release linaclotide core tablets from the lower ileum to the ascending colon (ie, at or near the ileocecal junction).

Pretreatment period:

After the screening period (to determine patient eligibility), the pretreatment period began. The pretreatment period was defined as 14 to 21 calendar days immediately before the start of the treatment period. During the pretreatment period, patients were given daily symptom severity for bowel movements, daily abdominal symptom severity, weekly constipation severity, weekly IBS symptom severity, sufficient weekly relief and perprocontrol. Information on the use of rescue medication or other laxatives, suppositories or enemas was provided, in principle, in the event of an event. Patients meeting all of the inclusion criteria were included in the treatment period. Patient information for the pretreatment period was used for the baseline characteristics data tabulated in Table 38. Pain, bloating and discomfort were an NRS of 11 (0 = none, 10 = very poor). The hungry belly had a score of 5 points (1 = none, 5 = extremely large).

Treatment period:

  The treatment period started with treatment allocation (randomization) and lasted 12 weeks. Patients were randomly assigned to 8 treatments with linaclotide: 30 μg, 100 μg or 300 μg of linaclotide DR1 formulation; 30 μg, 100 μg or 300 μg of linaclotide DR2 formulation; 290 μg of IR formulation; or one of the placebos. Patients were instructed to take study medication once daily in the morning, at least 30 minutes before breakfast. Patients should have daily bowel movement symptom severity, daily abdominal symptom severity, weekly constipation severity, weekly IBS symptom severity, weekly adequate relief and perpro control rescue medication or other An evaluation of the use of laxatives, suppositories or enemas continued to be provided, in principle, in case of an event.

  In this study, daily and weekly assessment data for patients in each treatment group were aggregated to determine the following major and secondary regulatory authorities defined by the US and European regulatory authorities for testing IBS-c efficacy. Treatment efficacy parameters were given.

Key efficacy parameters:

  Weekly change from baseline in abdominal pain,

  Weekly change from baseline in CSBM frequency, and

  Abdominal pain and constipation (APC) +1 responder at 6/12 weeks. Patients were classified as 6/12 weeks abdominal pain and constipation (APC) +1 responders if they were weekly APC + 1 responders for ≧ 6 weeks of the 12 weeks of treatment. A weekly APC + 1 responder was defined as a patient who met both the weekly CSBM + 1 responder and the weekly abdominal pain responder criteria in a given week.

Secondary efficacy parameters:

  6/12 Week CSBM + 1 Responders; Patients were classified as 6/12 Week CSBM + 1 Responders if they were weekly CSBM + 1 Responders for ≧ 6 weeks of the 12 weeks of treatment. Weekly CSBM + 1 Responders were defined as patients with an increase in at least 1 from baseline in the weekly rate of CSBM for a given week.

  6/12 Week Abdominal Pain Responder; Patients were classified as 6/12 Week Abdominal Pain Responders if they were weekly Abdominal Pain Responders for ≧ 6 weeks of the 12 weeks of treatment. Weekly abdominal pain responders were defined as patients with at least 30% reduction from baseline in mean abdominal pain score for a given week.

  Change from baseline in abdominal pain at 12 weeks (total treatment period);

  Change from baseline in CSBM frequency rate at 12 weeks (total treatment period);

  Change from baseline in SBM frequency rate at 12 weeks (total treatment period);

  Change from baseline in stool consistency (BSFS) at 12 weeks (total treatment period);

  Change from baseline in stomach belly at 12 weeks (total treatment period);

  Change from baseline in abdominal discomfort at 12 weeks (total treatment period);

  Change from baseline in abdominal distension at 12 weeks (total treatment period);

  Change from baseline in constipation severity at 12 weeks (total treatment period);

  Change from baseline in abdominal symptom score at 12 weeks (total treatment period); and

  Change from baseline in IBS symptom severity at 12 weeks (total treatment period);

  Change from baseline in percent of days of use of Perpro Control rescue medication at 12 weeks (total treatment period);

  Treatment satisfaction; and

  Appropriate mitigation assessment.

Trial results:

  The results of the efficacy parameters of the trial are shown in Figures 2-13, 17 and 21. The data in these figures show that clinically meaningful and statistically significant improvements were achieved for IBS-c patients treated with the delayed release linaclotide composition compared to placebo and immediate release linaclotide groups. It clearly shows what was done. Improvements were shown across all three: primary efficacy parameter, secondary efficacy parameter and incidence of adverse events.

  The results of the trial demonstrate that administration of the DR1 composition has efficacy across primary and secondary efficacy parameters. The results of the trial also show that administration of the DR2 composition has no effect on constipation as demonstrated by CSBM and BSFS data (eg, FIGS. 5 and 11), but administration of the DR2 composition does not affect the abdomen in patients. Demonstrate improved symptoms of pain (very low incidence of adverse events), suggesting that DR2 compositions are useful in reducing abdominal symptoms (pain, discomfort, bloating) in non-constipated patients To do.

  FIG. 2 shows the results for the 6/12 week APC + 1 parameter. 300 μg of the DR1 composition showed a similar improvement over the IR composition (38.8% vs. 31.8%). The other DR1 and DR2 compositions showed improvement over placebo.

  Figure 3 shows weekly changes from baseline in SBM frequency.

  Figure 4 shows weekly changes from baseline in abdominal pain for each week over the 12 week treatment period. Again, 300 μg of DR1 composition outperformed comparable IR compositions, and other DR compositions outperformed placebo. Furthermore, 30 μg of the DR2 composition showed a similar change in abdominal pain level as the IR composition.

  5-13 show clinical trial results for secondary efficacy parameters, where the delayed release composition demonstrated an overall improvement in patient performance. In previous studies, the Bristol stool quality scale was found to be one of the most reliable and stable endpoints for efficacy in the IBS-c trial. As shown in FIG. 11, DR1 appears to show a dose-dependent improvement in BSFS scores.

  FIG. 17 compares between the study DR1 composition 300 μg, the IR composition 290 μg, the placebo and the Linzess® Phase III trial IR composition 290 μg and the Linzes® Phase III trial placebo. The results of the selected efficacy parameters are shown. The DR1 composition results are comparable to those of the Linzess® Phase III clinical trial IR composition.

  FIG. 21 is a plot of percent change from baseline in weekly abdominal pain at Week 12 for DR1 composition, IR composition and placebo.

  An early clinical trial examined immediate release doses of 72 mcg to 579 mcg of linaclotide to test for improvement in abdominal pain. No difference was observed between weekly abdominal pain scores between the 290 and 579 mcg doses. In view of this, the excellent pain relief at the 300 mcg dose of DR1 (designated CR1 in FIG. 21) is surprising and unexpected.

Adverse event:

The incidence of adverse events was also monitored during the trial. A summary of the adverse events (TEAEs) that occurred under the study treatments is listed in Table 39. SAE means serious adverse event. ADO means diarrhea that causes withdrawal (ie, discontinuation of treatment).

Further data on adverse events are shown in Figures 14-16, 18 and 19. 14-16 show that the tested doses of DR1 and DR2 delayed release compositions all had a lower proportion of diarrhea (total and ADO) and lower moderate to severe diarrhea compared to the IR composition group. Ratios are included (Figure 16). FIGS. 18 and 19 show the percentage of diarrhea compared to Linzess® Phase III cure, which also improved the adverse diarrhea events of 300 μg of DR1 composition compared to the Linzess® Phase III results. Indicated.
(Example 19)
Studying the effects of food

  To determine the effect of ingestion of the delayed release composition on a full stomach (with food) compared to an empty stomach (after fasting), a study of the effect of food with the delayed release composition of the invention was performed. The patients were separated into two groups. Patients in Group 1 received a 300 μg dose of the linaclotide DR1 or DR2 delayed release composition under fed conditions. Specifically, patients in Group 1 received the composition 30 minutes after starting a high fat, high calorie breakfast with 8 ounces of water. Patients in group 2 received the same composition (DR1 or DR2) but no food under fasting conditions. Specifically, patients in Group 2 received the composition with about 8 ounces of water after an overnight fast of at least 10 hours. In both groups, food was not consumed for 4 hours after receiving the therapeutic agent. After a washout period of 7 days, patients in group 1 were then given the composition under fasted conditions and patients in group 2 were given the composition under fed conditions.

The results of the study demonstrated that administration of the DR1 composition to patients under fasting conditions did not cause diarrhea. Diarrhea developed in some patients who ingested the DR1 composition under fed conditions. Patients receiving the DR2 composition did not develop diarrhea under fed and fasted conditions. These results show that using the immediate release dosage form of linaclotide in healthy subjects, administration of a dose of 290 μg causes diarrhea in 100% of fed subjects and 94.7% in fasted subjects, respectively. In contrast to previous studies. Thus, DR1 and DR2 formulations designed to release in the lower GI have diarrhea only observed in the fed subjects in the DR1 formulation compared to the upper GI release in the immediate release formulation and The diarrhea incidence rate is significantly reduced to the extent that no diarrhea is observed in the target group. Therefore, the site of drug release plays a very effective role in modulating adverse events such as diarrhea.
Other embodiments

  The present invention is not limited in scope by the particular embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. It should be further understood that the values are all approximate and are provided for illustration.

  All patents, patent applications, publications, product descriptions, and protocols are cited throughout this application, the disclosures of which are incorporated herein by reference in their entireties for all purposes.

Claims (58)

  A method of reducing the incidence or severity of adverse events associated with administration of linaclotide, comprising the step of orally administering to a subject a delayed release pharmaceutical tablet composition comprising linaclotide, said tablet comprising an immediate release dosage form. The delayed release pharmaceutical tablet composition comprising an enteric coating comprising a pH sensitive polymer that releases linaclotide in the lower GI of the subject when compared to administration of an equal dose of linaclotide, wherein the delayed release pharmaceutical tablet composition causes constipation and / or pain in the subject. The method further comprising a therapeutically effective amount of linaclotide for treating.   A method of reducing the incidence or severity of adverse events associated with administration of linaclotide in a subject, comprising orally administering a delayed release pharmaceutical tablet composition comprising linaclotide, said tablet comprising a pH sensitive polymer A method comprising an enteric coating, wherein said delayed release pharmaceutical tablet composition releases a therapeutically effective amount of linaclotide for treating constipation and / or pain in said subject.   3. The reduction in incidence or severity of the adverse event is a reduction in incidence or severity of the adverse event as compared to administration of an equal dose of linaclotide in an immediate release dosage form. Method.   The method according to any of the preceding claims, wherein the adverse event is diarrhea.   The method according to any of the preceding claims, wherein the incidence of the adverse event is reduced.   The method according to any of the preceding claims, wherein the severity of the adverse event is reduced.   A method of reducing the intestinal fluid secretagogue effect of linaclotide, comprising the step of orally administering to a subject a delayed release pharmaceutical tablet composition comprising linaclotide, said tablet releasing linaclotide in the lower GI of said subject. The method further comprising an enteric coating comprising.   A method of treating visceral or abdominal pain in a non-constipated subject comprising the step of orally administering a delayed release pharmaceutical tablet composition comprising linaclotide, wherein the tablet comprises a subtherapeutically effective amount of linaclotide in the stomach of the subject. The method further comprising a release enteric coating and a pH sensitive polymer.   A method of treating irritable bowel syndrome constipation (IBS-c), comprising the step of orally administering to a patient in need thereof a delayed release pharmaceutical tablet composition comprising a therapeutically effective amount of linaclotide.   A method of treating abdominal pain, comprising the step of orally administering a delayed release pharmaceutical tablet composition comprising a therapeutically effective amount of linaclotide to a patient in need thereof.   7. The method of any of the preceding claims, wherein the delayed release pharmaceutical tablet composition comprises a therapeutically effective amount of linaclotide to reduce, prevent or reduce pain or constipation in the subject.   8. The method of any of the preceding claims, wherein the delayed release pharmaceutical tablet composition comprises a therapeutically effective amount of linaclotide that reduces, prevents or reduces pain in the subject but does not affect bowel habits.   13. The method of claim 12, wherein the bowel habit is selected from CSBM rate, SBM rate or stool consistency.   8. The method of any of the preceding claims, wherein the delayed release pharmaceutical tablet composition provides less than an effective amount of linaclotide to substantially affect bowel habits.   The method according to any of the preceding claims, wherein the subject is diagnosed with constipation irritable bowel syndrome (IBS-c).   10. The method of any of the preceding claims, wherein the delayed release pharmaceutical tablet composition comprising linaclotide releases less than 50%, less than 40%, less than 25% or less than 10% of the linaclotide in the stomach.   The method according to any of the preceding claims, wherein the linaclotide is present in the delayed release pharmaceutical tablet composition in an amount between 30 μg and 1,000 μg.   18. The linaclotide is present in an amount of about 30 μg, about 100 μg, about 300 μg, about 500 μg, about 600 μg or about 1,000 μg, or is present in an amount of 100 μg, 300 μg, 500 μg, 600 μg or 1,000 μg. The method described in.   The delayed release pharmaceutical tablet composition comprises between 0% and 2% by weight of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine. The method according to any of the preceding claims, further comprising an amino acid selected from the group consisting of: threonine, tryptophan, tyrosine and valine, or any mixture thereof.   The method according to any of the preceding claims, wherein the delayed release pharmaceutical tablet composition further comprises between 0% and 2% by weight or between 0.5% and 1.5% by weight histidine.   Said delayed release pharmaceutical tablet composition comprises between 0% and 3% by weight of calcium, potassium, magnesium, zinc, aluminum, manganese, chromium, cobalt, nickel, barium and sodium, or any combination thereof or The method according to any of the preceding claims, further comprising a cationic salt selected from the group consisting of a mixture.   22. The method of claim 21, wherein the delayed release pharmaceutical tablet composition further comprises between 0% and 3% by weight calcium salt.   23. The method of claim 22, wherein the delayed release pharmaceutical tablet composition further comprises between 0 wt% and 2 wt% or between 0.2 wt% and 0.8 wt% anhydrous calcium chloride.   The delayed release pharmaceutical tablet composition further comprises between 0% and 5% by weight, between 1% and 3% by weight or between 1% and 1.88% by weight polyvinyl alcohol (PVA), Method according to any of the preceding claims.   The method according to any of the preceding claims, wherein the pH sensitive polymer has a dissolution pH of at least 6.0, at least 6.5 or at least 7.0.   7. The method of any of the preceding claims, wherein the pH sensitive polymer comprises a methyl acrylate-methacrylic acid copolymer (e.g. Eudragit (R)).   The method according to any of the preceding claims, wherein the pH sensitive polymer comprises Eudragit S100.   The method according to any of the preceding claims, wherein the pH sensitive polymer comprises Eudragit L100.   The method according to any of the preceding claims, wherein the pH sensitive polymer consists essentially of Eudragit S100.   The method according to any of the preceding claims, wherein the pH sensitive polymer comprises a mixture of Eudragit S100 and Eudragit L100.   Wherein the pH sensitive polymer has a weight ratio of between 1: 1 and 6: 1 (S100: L100), a weight ratio of between 4.5: 1 and 5.5: 1 (S100: L100), or 4 31. The method of claim 30, comprising a mixture of Eudragit S100 and Eudragit L100 in a weight ratio between 0.875: 1 (S100: L100).   10. The method of any of the preceding claims, wherein the delayed release pharmaceutical tablet composition comprises enteric coated tablets. The delayed release pharmaceutical tablet composition comprises
Ca ²⁺ ;
Histidine; and Polyvinyl alcohol (PVA)
A method according to any of the preceding claims, comprising:   The method according to any of the preceding claims, further comprising a protective polymer film or subcoating.   35. The method of claim 34, wherein the subcoating comprises Opadry II (R).   The method according to any of the preceding claims, wherein the delayed release pharmaceutical tablet composition is administered once daily.   The method according to any of the preceding claims, wherein the delayed release pharmaceutical tablet composition is administered once a day in the morning.   The method according to any of the preceding claims, wherein the delayed release pharmaceutical tablet composition is administered once a day in the morning at least 30 minutes before breakfast.   10. The method of any of the preceding claims, wherein the delayed release pharmaceutical tablet composition is administered after the patient has fasted for at least 2 hours.   The method of any of the preceding claims, wherein the delayed release pharmaceutical tablet composition is administered for at least 12 weeks.   7. The method of any of the preceding claims, wherein the administering step increases the number of spontaneous defecation (CSBM) without sensation of bowel movements by the patient.   The method of any of the preceding claims, wherein the administering step reduces abdominal pain in the patient.   13. The method of claim 1, wherein the administering step increases the number of spontaneous defecation (CSBM) without sensation of stools by the patient from baseline at least once per week for at least 6 out of 12 weeks. The method described in either.   7. The method of any of the preceding claims, wherein the administering step reduces abdominal pain in the patient by at least 30% from baseline for at least 6 out of 12 weeks.   The step of administering increases the number of spontaneous defecation (CSBM) by the patient from the baseline for at least 6 weeks out of 12 weeks by at least once per week; 13. The method of any of the preceding claims, wherein at least 6 out of 12 weeks reduces abdominal pain in the patient from baseline by at least 30%.   The method according to any of the preceding claims, wherein said administering step ameliorates one or more of the following: abdominal pain, CSBM frequency rate, SBM frequency rate, stool consistency, tight belly, abdominal distress. Pleasure, abdominal bloating, abdominal symptom score, constipation severity, IBS symptom severity, days of use of per-protocol rescue medication, treatment satisfaction, and appropriate relief assessment.   47. The method of claim 46, wherein the administering step ameliorates two or more of the following: abdominal pain, CSBM frequency rate, SBM frequency rate, stool consistency, puffy belly, abdominal distress. Pleasure, abdominal bloating, abdominal symptom score, constipation severity, IBS symptom severity, days of use of per-protocol rescue medication, treatment satisfaction, and appropriate relief assessment.   The method of any of the preceding claims, wherein the administering step results in an improvement in one or more of the following efficacy parameters: weekly to baseline change in abdominal pain, baseline in CSBM frequency. From weekly, 6/12 week APC + 1 responder, 6/12 week CSBM + 1 responder, 9/12 week CSBM + 1 responder, 6/12 week abdominal pain responder, 9/12 week abdominal pain responder, week CSBM + 1 Responder by Week, Abdominal Pain Responder by Week, APC + 1 Responder by Week, Change from Baseline in Abdominal Pain at Week 12, Change from Baseline in CSBM Frequency at Week 12, SBM Frequency at Week 12 Change from baseline, of the 12 week flight Change from baseline in baseline, change from baseline in twelve week old belly, change from baseline in twelve week abdominal discomfort, change from baseline in twelve week bloating, twelve week abdomen. Change from baseline in symptom score, change from baseline in 12-week constipation severity, change from baseline in 12-week IBS symptom severity, base in percent of 12-day use of per protocol rescue medication Assessment of change from line, treatment satisfaction, and appropriate mitigation.   49. The method of claim 48, wherein the administering step results in an improvement in two or more of the following efficacy parameters: weekly to baseline change in abdominal pain, baseline in CSBM frequency. From weekly, 6/12 week APC + 1 responder, 6/12 week CSBM + 1 responder, 9/12 week CSBM + 1 responder, 6/12 week abdominal pain responder, 9/12 week abdominal pain responder, week CSBM + 1 Responder by Week, Abdominal Pain Responder by Week, APC + 1 Responder by Week, Change from Baseline in Abdominal Pain at Week 12, Change from Baseline in CSBM Frequency at Week 12, SBM Frequency at Week 12 Change from baseline, of the 12 week flight Change from baseline in baseline, change from baseline in twelve week old belly, change from baseline in twelve week abdominal discomfort, change from baseline in twelve week bloating, twelve week abdomen. Change from baseline in symptom score, change from baseline in 12-week constipation severity, change from baseline in 12-week IBS symptom severity, base in percent of 12-day use of per protocol rescue medication Assessment of change from line, treatment satisfaction, and appropriate mitigation.   The method of any of the preceding claims, wherein said administering step improves one or more of the following as compared to treatment with an immediate release composition of linaclotide: abdominal pain, CSBM frequency rate, SBM frequency. Rate, stool consistency, abdominal discomfort, abdominal discomfort, abdominal distention, abdominal symptom score, constipation severity, IBS symptom severity, days of use of per-protocol rescue medication, treatment satisfaction, and appropriate relief assessment.   The method of any of the preceding claims, wherein the administering step results in an improvement in one or more of the following efficacy parameters as compared to treatment with an immediate release composition of linaclotide: base in abdominal pain Weekly change from line, weekly change in CSBM frequency from baseline, 6/12 week AP + 1 responders, 6/12 week CSBM + 1 responders, 9/12 week CSBM + 1 responders, 6/12 week abdomen Pain Responder, Week 9/12 Abdominal Pain Responder, Weekly CSBM + 1 Responder, Weekly Abdominal Pain Responder, Weekly APC + 1 Responder, Change from Baseline in Week 12 Abdominal Pain, at Week 12 CSBM Frequency Rate Change from baseline, 12 week SBM frequency Change from baseline in rate, change from baseline in 12-week stool hardness, change from baseline in 12-week hungry abdomen, change from baseline in 12-week abdominal discomfort, 12 weeks Change from baseline in abdominal distension, change from baseline in 12-week abdominal symptom score, change from baseline in 12-week constipation severity, change from baseline in 12-week IBS symptom severity, Evaluation of change from baseline, treatment satisfaction, and appropriate relief in percent of 12-week use of per protocol rescue medication.   7. The method of any of the preceding claims, wherein the administering step results in a reduction in the risk of an adverse event in the patient as compared to treatment with an immediate release composition of linaclotide.   53. The method of claim 52, wherein the administering step results in a reduction in diarrhea risk in the patient as compared to treatment with an immediate release composition of linaclotide.   53. The method of claim 52, wherein the administering step results in at least a 20% reduction in diarrhea risk in the patient as compared to treatment with an immediate release composition of linaclotide.   53. The method of claim 52, wherein the administering step results in a reduction in the risk of severe diarrhea in the patient as compared to treatment with an immediate release composition of linaclotide.   A method of treating or alleviating pain, comprising administering a therapeutically effective amount of a delayed release pharmaceutical tablet composition according to any of the preceding claims to a patient in need thereof.   57. The method of claim 56, wherein the pain is selected from visceral pain; diverticulitis pain; pelvic pain; abdominal pain; or pain associated with gastrointestinal disorders, sexually transmitted diseases, bladder pain syndrome or interstitial cystitis.   The pain may be whole abdominal pain, diverticulopathy, pain associated with irritable bowel syndrome (IBS), chronic or acute radiation rectal disease (also called radiation proctitis), rectal pain, chronic perianal pain, transient Rectal pain, anal pain, chronic anal fissure, postoperative anal pain, overactive bladder syndrome, stress incontinence, interstitial cystitis, bladder pain syndrome, cancer-related pain, gastrointestinal neoplasm-related pain, pelvis Associated with general pain, endometriosis, pudendal pain, chronic prostatitis, prostatic pain, vulvar pain, urethral syndrome, penile pain, perianal pain, and ulcerative colitis, ulcerative proctitis or Crohn's disease 57. The method of claim 56, wherein the method is selected from: