CHRONIC, BOLUS ADMINISTRATION OF D-threo METHYLPHENIDATE

ES 2 289 787 T3

DESCRIPTION

Long-term bolus administration of D-threo-methylphenidate.

Field of the invention

The present invention is directed to uses for treating attention deficit disorder, attention deficit hyperactivity disorder, and cognitive decline associated with acquired immunodeficiency syndrome. Background of the invention

Attention deficit disorder (ADD), a disease of the nervous system commonly diagnosed in children, is generally treated with methylphenidate hydrochloride (commercially available, for example, as Ritalin^®). Symptoms of ADD include distraction and impulsivity. A related disorder called Attention Deficit Hyperactivity Disorder (ADHD) is also characterized by symptoms of hyperactivity, and is also treated with methylphenidate hydrochloride. Methylphenidate drugs have also been used to treat cognitive decline in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related disorders. See, for example, Brown, G., Intl. J. Psych. Med., 25 (1): 21-37 (1995); Holmes et al., J. Clin. Psychiatry, 50: 5-8 (1989).

Methylphenidate exists as four distinct optical isomers, as follows:

<img file="ES2289787T3_D0001.tif" />

in which R₂ is phenyl. The pharmaceutically acceptable salts are generally administered clinically. Other phenidate drugs, which can also be administered according to the invention, include those in which the methyl group in the above structures is replaced by C-alkyl.₂-C₄, and those in which R₂ is optionally substituted with Ci-C alkyl₄.

Clinically, the enantiomeric pair of methylphenidate hydrochloride is generally administered for the treatment of ADD and ADHD. The hydrochloride salt is usually simply referred to as "methylphenidate." Unless otherwise indicated, the term "methylphenidate" is used herein broadly to include methylphenidate and its pharmaceutically acceptable salts, including methylphenidate hydrochloride.

The threo racemate (pair of enantiomers) of methylphenidate is a mild stimulant of the central nervous system with a pharmacological activity qualitatively similar to that of amphetamines. Undesirable side effects associated with the use of methylphenidate D, L-threo racemate include anorexia, weight loss, insomnia, dizziness, and dysphoria. Furthermore, the racemate, which is an Appendix II controlled substance, produces a euphoric effect when administered intravenously or by inhalation or ingestion and therefore has a high potential for abuse.

ES 2 289 787 T3

Srinivas et al. studied the administration of D, L-threo-, D-threo- and L-threo-methylphenidate to children with ADHD, and indicated that the pharmacodynamic activity of D, L-threo-methylphenidate resides in the D-threo isomer (Clin Pharmacol Ther., 52: 561-568 (1992)). While D, L-threo-methylphenidate is generally used therapeutically, this racemate includes the L isomer which does not appear to contribute significantly to the pharmacological efficacy of the drug. However, the removal of the L isomer is expensive and there has been no reason to do so.

Another problem is that, in general, children being treated with d, l-threo-methylphenidate must take one or more doses during the day to receive the optimal benefit from treatment. This creates a problem for school managers, who must keep a controlled substance within the school's facilities, with the associated risk that it may be stolen for illicit use. In addition, children can be traumatized by the ridicule of being watched while taking medication at the center.

Sustained-release formulations of D, L-threo-methylphenidate have been developed, which provide a slow release of the drug throughout the day. However, peak plasma drug concentrations have been observed to be lower when sustained-release formulations are used, compared to conventional dosage forms administered throughout the day. In some studies, sustained release formulations of D, L-threo-methylphenidate have been shown to be less effective than conventional dosage forms.

Pulsed release dosage forms, in which a unit dosage form contains two doses, one of which is released soon after ingestion, and the other is released after a delay of several hours, have been proposed, recently, as a procedure to administer a most effective dose regimen. Although pulsed dosage forms provide effective delivery of multiple doses of medication at predetermined intervals, these dosage forms can be complex and expensive to manufacture. Furthermore, although pulse release dosage forms are suitable for the administration of medications, such as methylphenidate, to children, a multiple release of the medication is not required for all patients. However, it is desirable to administer the most effective and efficient dosage of medication to all patients and, in the case of methylphenidate, it is now believed that this goal is best achieved by administering the single effective isomer, i.e., D-threo- methylphenidate. WO9703671 describes the use of D-threo-methylphenidate for the treatment of attention deficit hyperactivity disorder in combination with another drug that undergoes or interferes with P450 metabolism. Preferably, the formulation used is a sustained release formulation that achieves a serum level of D-threo-methylphenidate of at least 50% of the C_max over a period of at least 8 hours. According to WO9703671, the serum level of D-threo-methylphenidate can be controlled so that it remains elevated during the day, after taking the dosage in the morning, and is lowered in the evening, before it can cause undesirable effects in sleep patterns. In WO9703672 it was found that patients showing or susceptible to liver dysfunction can be successfully treated with D-threo-methylphenidate, because it is less hepatotoxic than racemic methylphenidate. As in WO9703671, D-threo-methylphenidate can be administered in a sustained release formulation with characteristics similar to those described therein. WO9703673 describes a sustained release formulation (eg, a coated tablet) of D-threo-methylphenidate, preferably at least 95% in the D-threo form for the treatment of ADD or ADHD. A serum level of D-threo-methylphenidate of at least 50% of the C can be achieved._max for a period of at least 8 hours.

Although the D-threo isomer of methylphenidate has been shown to be the pharmacodynamically active isomer, the administration of the individual isomer has not been studied nor has it been administered clinically on a chronic basis. WO-A-9903471, which is a reference under Article 54 (3), describes the use of the D-threo isomer, although its use is quite different from the present invention. Thus, the effects of administering a single isomer on a chronic basis, compared to the racemate administered in a conventional manner, has hitherto not been recognized or understood.

There is a need for procedures to administer methylphenidate with maximum efficacy and minimum potential for abuse. In addition, there is a need for a dosage form that provides, in a single administration, the patient's requirement for an optimally effective daily dose of methylphenidate, eliminating the need to take a second dose, while minimizing undesirable side effects. and ease of administration is maximized.

Summary of the invention

The present invention provides a use, as set forth in claim 1, for treating at least one of the following disorders: attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), or AIDS-associated dementia . It is now believed that the L-threo isomer of methylphenidate probably contributes to the side effects associated with the commercial drug. Therefore, it is desirable to administer only the active D-threo form of the drug. D-threo-methylphenidate is administered in unit bolus dosages, with one dose being administered in each twenty-four hour period.

Administration of only the active pharmacodynamic D-threo form of methylphenidate can provide effective treatment for an entire day without undesirable side effects, such as interference with patterns.

ES 2 289 787 T3 patient sleep or anorexic behavior. It has been surprisingly and unexpectedly discovered that the beneficial effects of the D-threo isomer persist for a longer period of time when the D-threo isomer is administered alone than when it is administered in combination with the L-threo isomer.

Although the present invention is not intended to be limited by any particular theory, the lysomer is believed to act as an antagonist of the D-isomer. Thus, the inventors have also described methods for enhancing or counteracting the effects of methylphenidate drugs, which comprise administering L-threo-methylphenidate to a patient having a serum level of D-threo-methylphenidate.

The present inventors have observed that 6 to 8 hours after the administration of D, L-threo-methylphenidate, D-threo-methylphenidate, or a placebo, patients who received the D-threo isomer free from the L-isomer gave better results in objective trials, than patients who received racemate D, L-threo or a placebo. In contrast, patients who received the D racemate, L-threo did not perform better after that time period than those who received a placebo. Furthermore, subjective observations from the same patients indicate that those who received only the D-threo isomer experienced the beneficial effects of the drug for a longer period of time than those who received the D, L-threo racemate. Therefore, it is now believed that bolus administration of D-threo-methylphenidate may produce beneficial effects for a longer time than administration of the racemate. Furthermore, it is now possible for these effects to last for entire days of work or school after administration of a bolus dose on a chronic basis.

D-threo-methylphenidate is expected to be particularly useful in treating patients suffering from ADD, when they must act in a structured environment, such as an educational center or a job. Any formulation that provides a dosage sufficient to provide about 6 to about 8 hours of efficacy should allow an individual suffering from ADD to function in a structured environment without having to take another dose during the day.

According to one embodiment of the present invention, bolus dosage forms of D-threomethylphenidate are administered substantially free of L-threo-methylphenidate and erythro-methylphenidates. "Substantially free", as used herein, means that the dosage forms comprise at least about 95%, preferably at least 97%, and more preferably at least about 99% of the D-threo isomer, excluding the L-threo and erythro forms. The D-threo form can be isolated by procedures known to those of skill in the art.

"Chronic", as used herein, refers to a long-term, continuous and regular therapeutic administration, that is, a periodic administration without a substantial interruption, such as, for example, daily, over a period of time. from at least several weeks or months to several years, in order to treat a nervous disorder in a patient in need of treatment.

"Bolt", as used herein, refers to the administration of a drug as a single event. The term "bolus" is intended to exclude dosage forms such as sustained release, pulse release, and time release, and includes any dosage form that can be used to deliver a single dose. According to the present invention, a bolus dosage is administered to a patient in need of treatment once daily, preferably in the morning. The bolus dosages of the present invention can be administered in any conventional manner known to those of skill in the art. Suitable methods of administration include oral dosage forms, injection, and infusion.

For pharmaceutical use, the compounds described herein can be suspended in pharmaceutically acceptable carriers, such as, for example, solutions, suspensions, tablets, capsules, ointments, elixirs, and injectable compositions. Pharmaceutical preparations may generally contain from about 1% to about 90% by weight of the active ingredient. Preparations that are in a single dose form, "unit dosage form", preferably contain from about 20% to about 90% of the active ingredient. As used herein, the term "active ingredient" refers to compounds described herein, their salts, and mixtures of the compounds described herein with other pharmaceutically active compounds. Dosage unit forms, such as, for example, tablets or capsules, typically contain from about 0.001 to about 1.0 g of the active ingredient. The pharmaceutical preparations can be administered orally, parenterally, or topically.

Pharmaceutical preparations containing the compounds described herein can be prepared by procedures known to those skilled in the art, such as, for example, conventional mixing, granulating, dissolving, or lyophilization. Oral dosage forms include capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, and emulsions. The oral dosage forms provided by the invention may be in the form of tablets or oblong tablets, and may have any shape suitable for oral administration of a drug, such as a spheroid, cube, oval, bean or ellipsoid shape. For oral dosage forms, for example, the compounds can be combined with one or more solid pharmaceutically acceptable carriers, optionally granulating the resulting mixture. Pharmaceutically acceptable adjuvants may optionally be included, such as, for example, flow regulating agents and lubricants. Suitable carriers include, for example, fillers, such as sugars, cellulose preparations, calcium phosphates; and binders, such as methylcellulose, hydroxymethylcellulose, and starches, such as, for example, cornstarch,

ES 2 289 787 T3 potato starch, rice starch and wheat starch. The dosage form can be in the form of granules, which can have an irregular shape. The dosage form may comprise a capsule containing particles. Examples of orally administrable pharmaceutical preparations are dry-filled capsules consisting of gelatin, and soft sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. Dry-filled capsules can contain the active ingredient in the form of a granulate, for example, in admixture with fillers, binders, glidants and stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable liquid adjuvant, such as, for example, a fatty oil, paraffin oil, or liquid polyethylene glycol, optionally in the presence of stabilizers. Other orally administrable forms include syrups containing the active ingredient, for example, in suspended form at a concentration of about 0.01% to 20%, or a similar concentration that provides a suitable single dose when administered, for example, in measures of approximately 2 to approximately 5 milliliters. Suitable excipients for use in oral liquid dosage forms include diluents, such as water and alcohols, for example ethanol, benzyl alcohol and polyethylene alcohols, with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Powdered or liquid concentrates are also suitable for combining with liquids, such as milk. These concentrates can also be packaged in single dose amounts.

The compounds described herein can be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier. Solutions for parenteral administration may be in the form of infusion solutions. A pharmaceutical carrier can be, for example, a sterile liquid or mixture of liquids, such as water, saline, aqueous dextrose and solutions of related sugars, an alcohol, such as ethanol, glycol, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-1,3-dioxolan4-methanol, ethers, such as polyethylene glycol 400, oils, fatty acids, glycerides or fatty acid esters, with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or detergent, a suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or an emulsifying agent or other pharmaceutically acceptable adjuvants. Examples of oils that can be used in parenteral formulations include petroleum, animal, vegetable or synthetic oils, such as, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petroleum jelly, and mineral oil. Suitable fatty acids include, for example, oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters include ethyl oleate and isopropyl myristate. Suitable soaps include alkali metal, ammonium and triethanolamine salts of fatty acids. Suitable detergents include cationic detergents, such as dimethyldialkylammonium halides and alkylpyridinium halides; anionic detergents, such as alkyl, aryl and olefin sulfonates, monoglyceride sulfates and sulfosuccinates; nonionic detergents, such as fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepropylene copolymers; and amphoteric detergents, such as alkyl (-amino) propionates and 2-alkylimidazoline quaternary ammonium salts; as well as blends of detergents. Parenteral preparations will typically contain at least about 0.01% by weight of the active ingredient in solution. Preservatives and buffers can also be used to advantage. Injection suspensions can include viscosity-increasing substances such as, for example, sodium carboxymethyl cellulose, sorbitol, or dextran, and can also include stabilizers. To minimize irritation at the injection site, injectable compositions may contain a nonionic surfactant having a hydro-lipophilic ratio (HLB) of from about 20 to about 17. The amount of surfactants in these formulations ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB, or a mixture of two or more components having the desired HLB. Particular examples of useful surfactants include polyethylene sorbitan fatty acid esters, such as, for example, sorbitan monooleate.

The preferred amount of D-threo-methylphenidate to be used in a dosage to treat a particular patient can be readily determined by one of ordinary skill in the art. Factors that determine the appropriate dosage include the weight and age of the patient, the type and degree of the disorder being treated, and other conditions of the patient, including other disorders and medications, if any, that the patient is taking. In general, the dosage of D-threo-methylphenidate will be from about 0.01 mg / kg of patient body weight to about 1 mg / kg of patient body weight. Appropriate amounts can be determined by one of ordinary skill in the art. For example, a relatively young child will generally require a dose of about 0.03 to about 0.3 mg / kg, while an older child or adult may require a dose of about 0.1 mg / kg at about 0.4 or 0.5 mg / kg.

A physician treating a patient with ADD will generally titrate the dose of methylphenidate until the desired therapeutic effect is achieved. For example, a patient with ADD will start by taking 2.5 mg of D-MPH approximately 30 to 60 minutes before starting school or work. If this dose does not control the patient's behavior well after two or three days, and the patient has not experienced "disabling" anxiety, the dose will be increased to 5 mg. After two days, the lack of therapeutic effect will make it necessary to increase the dose to 10 mg or higher safe doses. When a dose of D-MPH is determined to be effective, this dose will remain stable unless the child is growing. It is not surprising that a dose of methylphenidate that was effective at seven years of age increases when the child is nine or ten years old. On the other hand, most adolescents can achieve appropriate efficacy from a particular dose for many years.

Response by patients with ADD or ADHD is generally determined by two types of measures: objective measures of a patient's ability to concentrate and stay focused on a task, such as

ES 2 289 787 T3 take a math test; and subjective scores of a patient's performance. The inventors have discovered that children who have been treated with racemic methylphenidate (D, L-threo-methylphenidate) show significantly better responses when treated with a formulation containing only the D enantiomer. Furthermore, it has been surprisingly observed that the beneficial effects of the administration of the D enantiomer alone, when measured by objective and subjective tests, persist for a significantly longer time than when the same patients are treated with the racemic mixture. .

Example 1

Double-blind, randomized study

A total of 35 children 9 to 12 years of age with ADHD (of whom 31 were evaluable) were enrolled, at three sites, in a double-blind, randomized, placebo-controlled crossover study consisting of nine consecutive weekly visits (ie a total of nine weeks in length). At each visit, serial blood samples were taken for pharmacological analysis. A battery of safety and pharmacodynamic measures was carried out.

At visit 1 (which is considered the baseline visit), all subjects received a single-blind placebo. For visits 2-8, subjects received one of two treatment regimens and a placebo in a randomized, double-blind fashion. Randomization occurs within each treatment regimen. One group of subjects received three single doses of D, L-methylphenidate (D, L-MPH) and then, in crossover, received three single doses of D-MPH; while the other group received three single doses of D-MPH, followed by three single doses of D, L-MPH. Placebo was administered at one of the visits within any treatment regimen. D-MPH was provided in 2.5, 5 and 10 µg capsules . D, L-MPH was matched and provided in 5, 10 and 20 mg capsules, representing the equimolar presence of the two isomers. A matched placebo was also provided. All capsules were administered orally.

At visit 9, subjects randomly received one of the treatments, unless they had not been to one of the study visits. In this case, visit 9 was used to repeat the missing study visit. A minimum of six days separate each of the 9 visits, during which the subjects received their conventional medication. Mean plasma concentration

D-MPH and D, L-MPH were found to have equivalent safety and pharmacokinetic profiles, and did not produce serious adverse effects. The amount of D-MPH delivered by a 2.5 mg dose of DMPH alone is approximately equal to the amount of D-MPH delivered by the 5 mg dose of racemic D, L-MPH. Similarly, a 5 mg dose of D-MPH alone provides the same amount of the D isomer as the 10 mg dose of the D, L racemic mixture. The mean plasma DMPH concentrations determined 4, 6, and 8 hours after ingestion are listed below.

TABLE 1

Mean plasma concentration, nanograms per milliliter (ng / ml) of D-MPH, after ingesting D-MPH

<td>Formulation</td><td>4 hours</td><td>6 hours</td><td>8 hours</td>

<td>2.5 mg D-MPH</td><td> 3,00</td><td> 1,82</td><td> 0,67</td>

<td>5 mg DL-MPH</td><td> 2,94</td><td> 1,91</td><td> 0,85</td>

<td>5 mg of D-MPH</td><td> 5,86</td><td> 3,75</td><td> 1, 84</td>

<td>10 mg DL-MPH</td><td> 7,66</td><td> 5,20</td><td> 2,66</td>

<td>10 mg D-MPH</td><td> 11,73</td><td> 7,65</td><td> 3,81</td>

<td>20 mg DL-MPH</td><td> 12,50</td><td> 8,15</td><td> 3,85</td>

Objective measure: math test

A computer-based math test provides a measure of attention, concentration, and job performance. This examination was carried out 30 minutes before, and 4 hours, 6 hours and 8 hours after the administration of the medication. Table 2 lists the statistical significance (p-values) for comparisons between the test results obtained after the administration of D-MPH or D, L-MPH, and the test results obtained after the administration of a placebo. Similar notations are used in other data tables below. The data in Table 2 were obtained 30 minutes before, and at 4.6 and 8 hours after the administration.

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Four hours after administration, 10 mg of the D isomer was as effective as 20 mg of the D, L racemate, as measured by an improvement in the math test. Efficacy, measured as an improvement in the math test, was evident only with 10 mg of D-MPH 6 and 8 hours after administration of the medication, and not with its equivalent dose contained within 20 mg of D, L -MPH. No superior efficacy was observed over placebo with doses of D-MPH less than 10 mg, and no significant effect was observed even with twice the dose of racemic D, L-MPH beyond 4 hours. At 6 and 8 hours after administration, no superior results were achieved over placebo with doses less than 10 mg of D-MPH or with any of the doses of D, L-MPH used in this study.

TABLE 2

P-Values ​​for Comparisons of Mathematics Scores Obtained at Various Time Intervals After Taking Placebo, with Mathematics Scores Obtained After Taking 20 mg D, L-threo-methylphenidate, or 10 mg D-threo-methylphenidate

<td></td><td>Exam 1 (-30 min)</td><td>Exam 4 (4 hours)</td><td>Exam 5 (6 hours)</td><td>Exam 6 (8 hours)</td>

<td>placebo - D, L 20 mg</td><td>NS *</td><td> &lt;0,001</td><td>NS</td><td>NS</td>

<td>placebo - D 10 mg</td><td>NS</td><td> &lt;0,001</td><td> &lt;0,001</td><td> 0,289</td>

<td>* NS, in this difference sign comparison are the value is listed</td><td colspan="4">cía and then indicates that there is no ificative. If the results of the statistically significant (p &lt;0.05), p.</td>

Connors, Loney and Milich Classification (CLAM)

The CLAM rating scale is a standard and subjective measure of inattention, hyperactivity, aggression, and defiance. Classification was performed 6 hours after drug administration by observers blind to the study medication that each subject was receiving. The scale contains 16 features:

1. Restless or hyperactive

2. Annoys other children

3. The mood changes quickly and in an extreme way

Four. Cries easily and frequently

5. Your demands must be met immediately

6. Annoys other children and interferes with their activities

7. Is agitated

8. Hums

9. Is excitable, impulsive

10. Inattentive, easily distracted

eleven. It does not end the things that it begins

12. Argue with others

13. He behaves as if he is smarter than the others

14. Has temper outbursts

fifteen. Is challenging

16. It does not cooperate.

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Although all three doses of D-MPH significantly reduced the overall CLAM score, indicating clinical benefit versus placebo, only the 10 mg and 20 mg doses of D, L-MPH remained effective six hours after drug administration.

TABLE 3

P-values ​​for comparison of global CLAM scores 6 hours after D-MPH or D, L-MPH administration, with global CLAM scores 6 hours after placebo administration

<td>placebo - D, L 5 mg</td><td>NS *</td><td></td><td>placebo - D 2.5 mg</td><td> 0,0065</td>

<td>placebo - D, L 10 mg</td><td> 0,216</td><td></td><td>placebo - D 5 mg</td><td> &lt;0,001</td>

<td>placebo - D, L 20 mg</td><td> &lt;0,0011</td><td></td><td>placebo - D 10 mg</td><td> &lt;0,001</td>

* NS, no significant difference; if it is statistically significant (p &lt;0.05), the p-value is listed

Two subscales were calculated from CLAM: the aggression / defiance subscale (A / D), and the inattention / hyperactivity subscale (F / H). All D-MPH doses were superior to placebo using the A / D subscale. However, only the highest dose (20 mg) of D, L-MPH was superior to placebo for the A / D subscale. The higher doses of the D-MPH and D, L-MPH formulations were superior to placebo on the F / H subscale. Although the 5 mg dose of D-MPH was also superior to placebo, the equivalent given in a 10 mg dose of D, LMPH was not.

The p-values ​​for the comparisons of scores on the two CLAM subscales obtained 6 hours after D, L- or D-MPH administration are shown below, with the scores obtained 6 hours after placebo administration.

TABLES 4 and 5

Comparison of CLAM Subscale Scores 6 Hours After D, Lo D-MPH, or Placebo Administration

Aggression-defiance score (A / D)

<td>placebo - D, L 5 mg</td><td>NS</td><td></td><td>placebo - D 2.5 mg</td><td> 0,0279</td>

<td>placebo - D, L 10 mg</td><td>NS</td><td></td><td>placebo - D 5 mg</td><td> &lt;0,001</td>

<td>placebo - D, L 20 mg</td><td> &lt;0,001</td><td></td><td>placebo - D 10 mg</td><td> &lt;0,001</td>

<td colspan="5">Inattention-hyperactivity score (F / H)</td>

<td>placebo - D, L 5 mg</td><td>NS</td><td></td><td>placebo - D 2.5 mg</td><td>NS</td>

<td>placebo - D, L 10 mg</td><td>NS</td><td></td><td>placebo - D 5 mg</td><td> &lt;0,0097</td>

<td>placebo - D, L 20 mg</td><td> &lt;0,001</td><td></td><td>placebo - D 10 mg</td><td> &lt;0,001</td>

Scores for individual behaviors were also determined. Based on various individual behaviors observed (is agitated, argues with others, and is defiant), 2.5 mg of D-MPH was determined to provide greater efficacy than placebo, but 5 mg of D, L-MPH is not effective in a similar way. Additionally, 5 mg of D-MPH provides greater efficacy than placebo, while 10 mg of D, L-MPH does not, for the following behaviors: annoying, demanding, agitated, excitable, inattentive, and challenging.

For two behaviors, you argue with others and behave as if you are smarter than others, 10 mg of D-MPH provides superior efficacy than placebo, while 20 mg of D, L-MPH does not.

The results for individual behaviors are summarized below. The table shows the p-values ​​for the comparisons of the individual behavior score results obtained 6 hours after the administration of D-MPH and D, L-MPH, with the results obtained 6 hours after the administration of a placebo.

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TABLES 6-13

P-Values ​​for Comparison of Efficacy of D-MPH and D, L-MPH with Placebo, Indicated by Individual Behaviors

<td colspan="5">Upset</td>

<td>placebo - D, L 5 mg</td><td>NS</td><td> —</td><td>placebo - D 2.5 mg</td><td>NS</td>

<td>placebo - D, L 10 mg</td><td>NS</td><td></td><td>placebo - D 5 mg</td><td> &lt;0,0280</td>

<td>placebo - D, L 20 mg</td><td> &lt;0,001</td><td></td><td>placebo - D 10 mg</td><td> &lt;0 ,001</td>

<td colspan="5">Demands</td>

<td>placebo - D, L 5 mg</td><td>NS</td><td></td><td>placebo - D 2.5 mg</td><td>NS</td>

<td>placebo - D, L 10 mg</td><td>NS</td><td></td><td>placebo - D 5 mg</td><td> 0,494</td>

<td>placebo - D, L 20 mg</td><td> 0,0335*</td><td></td><td>placebo - D 10 mg</td><td> 0,0011</td>

<td colspan="5">Is excited</td>

<td>placebo - D, L 5 mg</td><td>NS</td><td></td><td>placebo - D 2.5 mg</td><td> 0,0360</td>

<td>placebo - D, L 10 mg</td><td>NS</td><td></td><td>placebo - D 5 mg</td><td> 0,0067</td>

<td>placebo - D, L 20 mg</td><td> &lt;0,001</td><td></td><td>placebo - D 10 mg</td><td> &lt;0,001</td>

<td colspan="5">Is excitable</td>

<td>placebo - D, L 5 mg</td><td>NS</td><td></td><td>placebo - D 2.5 mg</td><td>NS</td>

<td>placebo - D, L 10 mg</td><td>NS</td><td></td><td>placebo - D 5 mg</td><td> 0,494</td>

<td>placebo - D, L 20 mg</td><td> 0,0014</td><td></td><td>placebo - D 10 mg</td><td> 0,001</td>

<td colspan="5">Not attentive</td>

<td>placebo - D, L 5 mg</td><td>NS</td><td></td><td>placebo - D 2.5 mg</td><td>NS</td>

<td>placebo - D, L 10 mg</td><td>NS</td><td></td><td>placebo - D 5 mg</td><td> 0 , 0149</td>

<td>placebo - D, L 20 mg</td><td> 0,0016</td><td></td><td>placebo - D 10 mg</td><td> &lt;0,001</td>

<td colspan="5">Argue with others</td>

<td>placebo - D, L 5 mg</td><td>NS</td><td></td><td>placebo - D 2.5 mg</td><td> 0,0115</td>

<td>placebo - D, L 10 mg</td><td>NS</td><td></td><td>placebo - D 5 mg</td><td>NS</td>

<td>placebo - D, L 20 mg</td><td>NS</td><td></td><td>placebo - D 10 mg</td><td> 0,0016</td>

<td colspan="3">It behaves as if it were more (</td><td colspan="2">.isto that the others</td>

<td>placebo - D, L 5 mg</td><td>NS</td><td></td><td>placebo - D 2.5 mg</td><td>NS</td>

<td>placebo - D, L 10 mg</td><td>NS</td><td></td><td>placebo - D 5 mg</td><td>NS</td>

<td>placebo - D, L 20 mg</td><td>NS</td><td></td><td>placebo - D 10 mg</td><td> 0,001</td>

<td colspan="5">Is challenging</td>

<td>placebo - D, L 5 mg</td><td>NS</td><td></td><td>placebo - D 2.5 mg</td><td> 0,0010</td>

<td>placebo - D, L 10 mg</td><td> 0,0038</td><td></td><td>placebo - D 5 mg</td><td> 0,0016</td>

<td>placebo - D, L 20 mg</td><td> &lt;0,001</td><td></td><td>placebo - D 10 mg</td><td> &lt;0,001</td>

At a dose of 5 mg, the D isomer provides efficacy for at least 6 hours after administration, compared to the D, L racemate, which requires twice the dosage to provide 6 hours of efficacy. Even more significantly, a 2.5 mg dose of the D isomer provides efficacy in controlling various behaviors, while even twice the dose of the D, L racemate was not effective against the same behaviors. For two behaviors (he is excited, and he argues with others), even four times the dose of the racemate, that is, 10 mg, did not show a statistically significant improvement compared to placebo, when compared to 2.5 mg of the D-isomer.

In conclusion, the data demonstrate that, on both objective and subjective measures, D-MPH is not only more effective than a placebo in controlling subjective behaviors and improving objective performance on a math test, but it clearly provides a efficacy for a period of time significantly greater than an equivalent dose of D, L-MPH.

ES 2 289 787 T3 D-MPH roll 2

<td>Formulations for 2.5 mg D-MPH</td><td colspan="3">Formulation (mg / tablet)</td>

<td>Ingredient</td><td>n ° 1</td><td>n ° 2</td><td>n ° 3</td>

<td>Starch 1500, NF (pregelatinized starch)</td><td> 30,0</td><td> 30, 0</td><td> 23,4</td>

<td>Active drug</td><td> 2,5</td><td> 2,5</td><td> 2,5</td>

<td>D&amp;C Yellow Lake n ° 10</td><td> 0,9</td><td> 0,6</td><td> 1,5</td>

<td>Lactose monohydrate, NF (from fast flow n ° 316)</td><td> 61,9</td><td> 61,6</td><td> 75,0</td>

<td>Sodium starch glycolate, NF</td><td> 1,5</td><td> 4,0</td><td> 27,35</td>

<td>Microcrystalline cellulose, NF</td><td> 42,7</td><td> 50,0</td><td> 30,0</td>

<td>Magnesium stearate, NF</td><td> 0,5</td><td> 1,3</td><td> 0,25</td>

<td>Total weight per tablet</td><td> 140</td><td> 150</td><td> 160</td>

<td>Formulations for 5 mg of D-MPH</td><td colspan="3">Formulation (mg / tablet)</td>

<td>Ingredient</td><td>n ° 1</td><td>n ° 2</td><td>n ° 3</td>

<td>Starch 1500, NF (pregelatinized starch)</td><td> 30,0</td><td> 30</td><td> 23,4</td>

<td>Active drug</td><td> 5</td><td> 5</td><td> 5</td>

<td>D&amp;C Yellow Lake n ° 10</td><td> 0,9</td><td> 0 , 6</td><td> 1,5</td>

<td>Lactose monohydrate, NF (from fast flow n ° 316)</td><td> 59,4</td><td> 61,6</td><td> 72,5</td>

<td>Sodium starch glycolate, NF</td><td> 1,5</td><td> 4,0</td><td> 27,35</td>

<td>Microcrystalline cellulose, NF</td><td> 42,7</td><td> 47,5</td><td> 30,0</td>

<td>Magnesium stearate, NF</td><td> 0,5</td><td> 1,3</td><td> 0,25</td>

<td>Total weight per tablet</td><td> 140</td><td> 150</td><td> 160</td>

<td>Formulations for 10 mg of D-MPH</td><td colspan="3">Formulation (mg / tablet)</td>

<td>Ingredient</td><td>n ° 1</td><td>n ° 2</td><td>n ° 3</td>

<td>Starch 1500, NF (pregelatinized starch)</td><td> 30,0</td><td> 30,0</td><td> 23,4</td>

<td>Active drug</td><td> 10</td><td> 10</td><td> 10</td>

<td>D&amp;C Yellow Lake n ° 10</td><td> 0,9</td><td> 0,6</td><td> 1,5</td>

<td>Lactose Monohydrate, NF (Fast Flow # 316)</td><td> 54,4</td><td> 61,6</td><td> 67,5</td>

<td>Sodium starch glycolate, NF</td><td> 1,5</td><td> 4,0</td><td> 27,35</td>

<td>Microcrystalline cellulose, NF</td><td> 42,7</td><td> 42,5</td><td> 30,0</td>

<td>Magnesium stearate, NF</td><td> 0,5</td><td> 1,3</td><td> 0,25</td>

<td>Total weight per tablet</td><td> 140</td><td> 150</td><td> 160</td>