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Title:  Nasal administration of agents for the treatment of gastroparesis

United States Patent:  6,770,262

Issued:  August 3, 2004

Inventors:  Lehman; Laura S. (Palo Alto, CA); Tierney; David (Shrewsbury, NJ); Retzios; Anastassios D. (San Ramon, CA); Petrone; Michael (Voorhees, NJ); Young; David (Ellicott City, MD); Trapnell; Carol B. (Ellicott City, MD); Oliver; Ruth (Maidenhead, GB)

Assignee:  Questcor Pharmaceuticals, Inc. (Union City, CA)

Appl. No.:  821139

Filed:  March 29, 2001

Abstract

The present invention is directed to a method for the treatment of gastroparesis by the use of metoclopramide nasal formulation.

SUMMARY OF THE INVENTION

The present invention is directed to providing a method for treating gastroparesis by using a dosage form of MCP that avoids or reduces the incidence of patient non-compliance. Another object of the present invention is to provide a method for treating gastroparesis by nasally administering MCP which avoids or reduces the incidence of side-effects experienced by patients.

Yet another Object of the present invention is to provide a method for treating gastroparesis caused by diabetes by using a dosage form of MCP that avoids or reduces the problem of patient non-compliance.

It is still another object of the present invention to provide a method for treating gastroparesis caused by type 1 or type 2 diabetes by using a dosage form of MCP that avoids or reduces the problem of patient non-compliance.

It is yet still another object of the present invention to provide a method for sufficiently treating gastroparesis caused by diabetes using a dosage form of MCP that avoids or reduces the incidence of side-effects experienced by patients.

It is even yet still another object of the present invention to provide a method for sufficiently treating gastroparesis caused by type 1 or type 2 diabetes using MCP nasal spray that avoids or reduces the severity of side-effects experienced by patients.

It is further an object of the present invention to provide a method for sufficiently controlling gastroparesis caused by diabetes by nasally administering MCP that avoids or reduces the problems associated with patient non-compliance.

These and other objectives of the present invention are accomplished by administering intranasally to patients suffering from gastroparesis a therapeutically effective dosage of MCP in a pharmaceutically acceptable dosage form which is therapeutically and medically acceptable.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a method for treating and controlling gastroparesis by nasally administering MCP or a pharmaceutically acceptable salt thereof. MCP is formulated to contain a therapeutically effective amount of MCP such that upon administration by the intranasal route, a therapeutically effective amount of MCP is delivered to the patient. In addition, the therapeutically effective amount of MCP, in both aqueous and non-aqueous formulations, is chosen to minimize the severity and incidence of untoward side-effects and drug-interactions encountered with MCP. Compared to the injectable form and oral form of MCP, intranasal administration of MCP has the advantage of being painless, effective, safe, and consistent, particularly for patients with gastroparesis.

5.1 Pharmacokinetic Data: Selection of Doses in the Study

The pharmacokinetic data from three single dose, crossover pharmacokinetic studies in healthy patients vas evaluated to determine appropriate dose selection for the clinical study described in sections 6 and 7.

In one study (data not shown), the relative bioavailability (nasal versus oral) was determined to be 52/57% in terms of AUC0-inf (area under the plasma concentration-time curve extrapolated to infinity) and 31/41% in terms of Cmax (maximum observed concentration). The absolute bioavailability (nasal versus IV) in terms of AUC0-inf was 42/45% (two different nasal spray concentrations were evaluated, 200 mg/ml and 400 mg/ml).

In a second study (data not shown), the relative bioavailability (nasal versus oral) was determined to be 97% in terms of AUC0-inf and 72% in terms of Cmax. The absolute bioavailability (nasal versus IV) in terms of AUC0-inf was also 97%.

In a third study (data not shown), the absolute bioavailability of the nasal spray (nasal versus IV) was determined to be 69%.

Given the disparity in these studies, a pooled analysis of the data from the first and second study was performed. This resulted in a relative bioavailability of 58% (90% CI: 49%-68%) for AUC0-inf and 45% (90% CI: 36%-57%) for Cmax.

It was therefore determined appropriate to study safety and efficacy of both 10 mg and 20 mg doses of nasal spray for the treatment of diabetic gastroparesis.

In one embodiment of the present invention, gastroparesis is treated by intranasally administering a pharmaceutically acceptable MCP nasal dosage form at a therapeutic dosage level of between about 20 mg/day to about 160 mg/day for about 1 to about 8 weeks. The duration of treatment is preferably about 5 weeks to about 8 weeks, and most preferably about 6 weeks.

In another embodiment of the invention, a method for treating gastroparesis is provided by intranasally administering a pharmaceutically acceptable MCP nasal dosage form at a therapeutic dosage level of between about 40 mg/day to about 160 mg/day in 3 to 4 smaller dosages at equally spaced intervals within 24 hours for about 1 to about 8 weeks. It is understood that the daily dosing is varied with the particular needs of the patients to be treated and that one of skill in the art is expected to modify dosing in a manner most suitable for a particular patient, i.e., one dose per day, two, three, four, five or any other regime most efficacious for the patient's needs. Thus, any suitable number of doses per day may be used. Further, all therapeutic dosage levels from about 20 mg/day to about 160 mg/day, are encompassed in the invention, including but not limited to, dosage levels of 30 mg/day, 35 mg/day, 40 mg/day, 45 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, and 160 mg/day. These daily dosages may be administered in smaller doses. Preferred smaller doses are 10 mg, 20 mg, and 30 mg. Preferred times for administration are 3-4 smaller dosages at equally spaced intervals within a 24-hour period or about 1-8 weeks. Alternative preferred times for administration are before meals, assuming 2 to 4 meals per day, and before bedtime. The duration of treatment is preferably about 5 weeks to about 8 weeks, and most preferably about 6 weeks.

In still another embodiment of the invention, a method for treating gastroparesis is provided by intranasally administering a pharmaceutically acceptable MCP nasal dosage form at a therapeutic dosage level of between about 40 mg/day to about 80 mg/day for about 1 to about 8 weeks. The duration of treatment is preferably about 5 weeks to about 8 weeks, and most preferably about 6 weeks.

In an additional embodiment of the invention, a method for treating gastroparesis is provided by intranasally administering a pharmaceutically acceptable MCP nasal dosage form at a therapeutic dosage level of about 80 mg/day in 3 to 4 smaller dosages at equally spaced intervals within 24 hours for about 1 to about 8 weeks. The duration of treatment is preferably about 5 weeks to about 8 weeks, and most preferably about 6 weeks.

In particular, the invention is directed to a method for treating gastroparesis caused by a number of origins, including but not limited to, diabetes (including type 1 and type 2), postviral syndromes, anorexia nervosa, surgery on the on the stomach or vagus nerve, medications, particularly anticholinergics and narcotics which slow contractions in the intestine, gastroesophageal reflux disease, smooth muscle disorders such as amyloidosis and scleroderma, nervous system diseases (including abdominal migraine and Parkinson's disease), or metabolic disorders (including hypothyroidism).

In a preferred embodiment, the gastroparesis is of diabetic origin, including type 1 and type 2 diabetes. Treatment generally involves intranasally administering a pharmaceutically acceptable MCP nasal spray dosage form at a therapeutic dosage level of between about 40 mg/day to about 160 mg/day in 3 to 4 smaller dosages at equally spaced intervals within 24 hours for about 1 to about 8 weeks, preferably for about 2 weeks to about 8 weeks, and most preferably for about 6 weeks.

In a preferred embodiment, treatment involves intranasally administering a pharmaceutically acceptable MCP nasal dosage form at a therapeutic dosage level of between about 40 mg/day to about 80 mg/day in 3 to 4 smaller dosages at equally spaced intervals within 24 hours for about 1 to about 8 weeks, preferably for about 5 weeks to about 8 weeks, and most preferably for about 6 weeks.

In one embodiment, the MCP nasal formulation administered to deliver a dose of 10 mg four times a day comprises:

             10 mg/0.1 ml       metoclopramide hydrochloride
            1.5 mg              benzyl alcohol
            0.8 mg              NaCl
          0.320 mg              glacial acetic acid
          0.077 mg              sodium acetate
          6.425 mg              sorbitol
          0.8-1 mg/ml           menthol
              1 mg/ml           edetate disodium
            0.1 ml              purified water (qs ad to 0.1 ml)

The MCP nasal formulation is given to patients as either 1 puff in one and only one nostril (i.e., 1 puff at 10 mg/puff (10 mg/0.1 ml and 0.1 ml/puff)) four times a day (1 puff QID for about 1, 2, 3, 4, 5, 6, 7, or 8 weeks), or 1 puff per nostril in both nostrils (i.e., 2 puffs at 5 mg/puff (10 mg/0.1 ml and 0.05 ml/puff)) four times a day (2 puffs QID for about 1, 2, 3, 4, 5, 6, 7, or 8 weeks). The above formulation is sterile with a bacteria count of 10 below the level allowed by the U.S. Patent on a per ml basis. In addition, pathogens are absent. The pH of the above formulation is about 4.0.

In other embodiment, the MCP nasal formulation administered to deliver a dose of 20 mg four times a day comprises (formulation per 0.1 ml of MCP nasal (MCP n=metoclopramide nasal dosage form)):

             20 mg/0.1 ml       metoclopramide hydrochloride
            1.5 mg              benzyl alcohol
            0.8 mg              NaCl
          0.320 mg              glacial acetic acid
          0.077 mg              sodium acetate
          6.425 mg              sorbitol
          0.8-1 mg/ml           menthol
              1 mg/ml           edetate disodium
            0.1 ml              purified water (qs ad to 0.1 ml).

The MCP nasal formulation is given to patients as either 1 puff in one and only one nostril (i.e., 1 puff at 20 mg/puff (20 mg/0.1 ml and 0.1 ml/puff)) four times a day (1 puff QID for about 1, 2, 3, 4, 5, 6, 7, or 8 weeks), or 1 puff per nostril in both nostrils (i.e., 2 puffs at 10 mg/puff (20 mg/0.1 ml and 0.05 ml/puff)) four times a day (2 puffs QID for about 1, 2, 3, 4, 5, 6, 7, or 8 weeks). The above formulation is sterile with a bacteria count of 10 below the level allowed by the U.S. Patent on a per ml basis. In addition, pathogens are absent. The pH of the above formulation is about 4.0.

In yet another embodiment, the MCP nasal formulation administered to deliver a dose of 30 mg four times a day comprises (formulation per 0.1 ml of MCP nasal spray (MCP n=metoclopramide nasal dosage form)):

             30 mg/0.1 ml       metoclopramide hydrochloride
            1.5 mg              benzyl alcohol
            0.8 mg              NaCl
          0.320 mg              glacial acetic acid
          0.077 mg              sodium acetate
          6.425 mg              sorbitol
          0.8-1 mg/ml           menthol
              1 mg/ml           edetate disodium
            0.1 ml              purified water (qs ad to 0.1 ml)

The MCP nasal formulation is given to patients as either 1 puff in one and only one nostril (i.e., 1 puff at 30 mg/puff (30 mg/0.1 ml and 0.1 ml/puff)) four times a day (1 puff QID for about 1, 2, 3, 4, 5, 6, 7, or 8 weeks), or 1 puff per nostril in both nostrils (i.e., 2 puffs at 15 mg/puff (20 mg/0.1 ml and 0.075 ml/puff)) four times a day (2 puffs QID for about 1, 2, 3, 4, 5, 6, 7, or 8 weeks). The above formulation is sterile with a bacteria count of 10 below the level allowed by the U.S. Patent on a per ml basis. In addition, pathogens are absent. The pH of the above formulation is about 4.0.

Additional formulations may be prepared to deliver other doses of metoclopramide for nasal administration and may be formulated as above, substituting the amount of metoclopramide per milliliter, i.e., a dose of 15 mg would be 15 mg/0.1 ml, a dose of 30 mg would be 30 mg/0.1 ml, etc.

Thus, it is expected that one of ordinary skill would be able to formulate nasal formulations having different concentrations of MCP such as, for example, formulations where 1 puff of 0.1 ml/puff would deliver 25 mg/puff, 35 mg/puff, 40 mg/puff, etc. Also, one of skill in the art is presumed to know the appropriate concentration of MCP/puff depending on the desired administration i.e., 1 puff/nostril for one nostril or, alternatively, both nostrils and is expected to adjust the concentrations of MCP accordingly.

Further, suitable nontoxic pharmaceutically acceptable nasal carriers for MCP will be apparent to those skilled in the art of nasal pharmaceutical formulations. Also see REMINGTON'S PHARMACEUTICAL SCIENCES, any edition. Obviously, the choice of suitable carriers will depend on the exact nature of the particular nasal dosage form required, e.g., whether the drug is to be formulated into a nasal solution (for use as drops or as a spray, can be either oil or aqueous-based), a nasal suspension, a nasal ointment, a nasal gel or another nasal form, all of which are encompassed by the present invention. Preferred nasal dosage forms are solutions, suspensions and gels. Minor amounts of ingredients such as pH adjusters (e.g., a base such as NaOH), emulsifiers or dispersing agents, buffering agents, preservatives such as agents which prevent degradation of MCP and in particular the oxidation of MCP, wetting agents, jelling agents (e.g., methylcellulose) and flavoring agents may also be present. Preferably about 1 mg/ml of edetate disodium (or another agent which prevents oxidation of metoclopramide) and about 0.08-1 mg/ml of menthol or menthol crystals is added.

Most preferably, the nasal composition is isotonic. If desired, sustained release nasal compositions, e.g., sustained release gels, or when a more highly insoluble form is desired, a long chain carboxylic acid salt of the drug can be conveniently employed. The carboxylic acid portion of the salt preferably contains 10 to 20 carbon atoms. Alternatively, equimolar amounts of the drug free base and the long chain carboxylic acid are combined in methanol. That mixture is then added to a small volume of water, causing the desired salt (e.g., drug stearate) to precipitate out. One of skill in the art is presumed to be aware of other suitable aqueous and non-aqueous embodiments for sustained release formulations.

Those skilled in the art will be aware that a systemic, therapeutically effective amount of MCP for treating gastroparesis will vary with the age, size, weight and general physical condition of the patient as well as the severity of the disease. Frequency of administration will likewise vary with the formulation of nasal metoclopramide (i.e., the concentration of MCP, whether it is in the form of sustained release, etc.) and can be adjusted so that any suitable number of doses per day may be used.

As a practical matter the selected therapeutic compositions will normally be prepared in dosage unit forms to contain systemic, therapeutically effective amounts of the selected MCP.

Typical MCP nasal dosage forms are solutions or suspensions that can be administered as a nasal spray. However, nasal drops may also be used. Nasal spray or nasal drops may comprise aqueous or non-aqueous solutions or suspensions of MCP. The MCP nasal spray dosage formulation contains the active agent in any suitable form and pharmaceutically acceptable salt thereof (e.g. metoclopramide hydrochloride).

A typical MCP nasal formulation is in solution form having a light amber color and being non-cloudy to the naked eye with an pH of between about 3.0-5.0. The typical formulation may contain benzyl alcohol of at least about 13.5 mg/ml containing practically no impurities as determined by high pressure liquid chromatography (HPLC) and having a bacterial count of less than 250 ufc/ml and free of pathogens sufficient to form an acceptable pharmaceutical nasal spray dosage form. The solvent may be purified water suitable for use in nasal dosage forms or any equivalent water (e.g. injectable water) that is allowed for use in such nasal dosage forms. See REMINGTON'S PHARMACEUTICAL SCIENCES, any edition from 1980-1996. For the adequate and/or sufficient treatment and control of gastroparesis, a typical dose is that dose which is therapeutically effective and which minimizes side-effects and drug interactions.

The formulations used in the methods of the invention also include one or more other drugs being co-administered with the nasal metoclopramide. These drugs can be administered concurrently with metoclopramide or at separate time intervals. Alternatively, one or more other drugs may be incorporated into the metoclopramide nasal formulation. These drugs include pain relievers, insulin and other drugs useful in the management of diabetes, steroids, especially steroids that prevent nasal irritation, and antidepressants. It is preferred that the co-administered drug be one that is not known to cause adverse side effects when administered with metoclopramide.

A typical nasal dosage of MCP for the treatment and control of gastroparesis depends upon the degree and severity of gastroparesis experienced by a typical patient (e.g. caused by diabetes). Some individuals with diabetic gastroparesis may experience symptom-free periods interspersed with intermittent acute exacerbations. Others may have chronic, ongoing symptoms that wax and wane over time. Disease severity falls along a wide continuum. Some diabetics may be completely asymptomatic despite measurable delays in gastric emptying. Others may have symptoms that affect their lifestyles or daily activities to varying degrees. Although rare, complete gastric atony can be a life-threatening complication of diabetic gastroparesis, requiring hospitalization and supportive measures of intravenous hydration or nutrition. All of the above states of gastroparesis disease are encompassed by the invention.

The dosage of the nasally administered MCP may be varied between about 20 mg/day to about 160 mg/day. Above about 160 mg/day, the dosage may be undesirable due to untoward side effects experienced by patients receiving more than about 160 mg/day from the MCP nasal dosage form. A preferred dosage of MCP nasal spray is 40 to 80 mg/day. Typically, administration of, for example, 80 mg/day is given as 20 mg four times a day (for example, either (1) 2 puffs of 10 mg/0.1 ml of MCP nasal spray, one puff per nostril, (2) 2 puffs of 10 mg/0.05 ml of MCP nasal spray, one puff per nostril, or (3) 1 puff of 20 mg/0.1 ml of MCP nasal spray in one and only one nostril).

Various techniques may be used to assess the severity of the gastroparesis and gastric emptying. Methods well known in this art include, for example, questioning the patient on symptoms related to the disease as well as techniques such as radioscintigraphy, ultrasonography, and techniques using radiopaque markers such as barium. Radioscintigraphy appears to be the preferred method, due to its relatively high sensitivity and specificity, ease of use, and low exposure to radiation. All of these methods can be used to determine, together with teachings of the present invention, the appropriate dosage for a particular patient.

The weight of the patient may also affect the dosage to be administered. Typically, a dose of between about 0.1 mg/kg to about 2.5 mg/kg is given to a patient suffering from gastroparesis. The dosages can be either about 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1.0 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg, 2.3 mg/kg, 2.4 mg/kg, 2.5 mg/kg. A preferred nasal dosage is between about 0.06 to about 1.2 mg/kg of body weight. Other preferred nasal dosages are about 0.06 mg/kg, 0.08 mg/kg, 1.0 mg/kg, 1.2 mg/kg and 1.4 mg/kg.

The aforementioned dosages for the treatment and control of gastroparesis are usually given before meals and before bed time.

The expected benefit of an intranasal formulation of metoclopramide for gastroparesis is to provide an alternative route of administration for this agent to patients who have uncomfortable gastrointestinal symptoms of gastroparesis. The intranasal formulation of metoclopramide will spare patients with active symptoms the potential additional discomfort of having to swallow an oral formulation and serves as an alternative to injectable formulations. As presented in greater detail below in Section 6, the nasal administration of metoclopramide treatment of gastroparesis offers many benefits, some of which are unexpected. For example, as illustrated below, one unexpected benefit is that while patents receiving the nasal form of the drug were exposed to less drug overall, 10 mg of nasal metoclopramide was superior to 10 mg oral metoclopramide in reducing symptoms with particular significance in the categories of feeling full after eating and persistent fullness. Further, less exposure to metoclopramide reduces the opportunity for central nervous system (CNS) side effects (see the data relating to AUC0-inf for 10 mg oral versus nasal). Also, the benefit of the 20 mg nasal (80 mg/day) was superior than 10 mg oral in for all symptoms studied and was well tolerated for six weeks. In contrast, 80 mg/day of oral metoclopramide would be expected to result in significant CNS side effects and is not indicated for such duration. However, nasal doses of 80 mg/day were well tolerated for an extended period of six weeks. Further, because of its rapid onset of action, nasal metoclopramide may be substituted for intravenous administration in patients with severe gastroparesis for whom the oral form is not indicated. The benefits of nasal administration over intravenous administration being obvious to the skilled practitioner. In sum, the nasal form of metoclopramide, as demonstrated herein, provides heretofore unexpected benefits in the treatment of gastroparesis.

Claim 1 of 35 Claims

What is claimed is:

1. A method for treating or reducing the symptoms of gastroparesis in a patient comprising:

administering metoclopramide or a pharmaceutically acceptable salt thereof to a patient in need of gastroparesis treatment, wherein said metoclopramide is in a pharmaceutically acceptable nasal spray formulation and administered intranasally in a therapeutically effective amount at a daily dosage of about 40 mg/day to about 160 mg/day for about 2 weeks to about 8 weeks, so that one or more symptoms of gastroparesis is treated or reduced.



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