Oral formulation of clonidine and midazolam for sedation in dental procedures

Abstract

A liquid drug formulation comprising clonidine and midazolam. The amount of clonidine is in the range of 5.0-50 ?g/ml. The amount of midazolam is in the range of 0.5-10 mg/ml. The liquid drug formulation could be in the form of a syrup. The liquid drug formulation could be provided in a multi-use container or a single-use dispenser. Also disclosed is a method of inducing sedation in a patient using the liquid drug formulation.

Claims

1. A liquid drug formulation comprising: clonidine in an amount ranging from 5.0-50 ?g/ml; midazolam in an amount ranging from 0.5-10 mg/ml.

2. The liquid drug formulation of claim 1, wherein the amount of clonidine is 8.0-35 ?g/ml.

3. The liquid drug formulation of claim 1, wherein the amount of midazolam is 0.8-6.0 mg/ml.

4. The liquid drug formulation of claim 1, further comprising fentanyl in an amount ranging from 5-70 ?g/ml.

5. The liquid drug formulation of claim 1, being in form of a syrup.

6. The liquid drug formulation of claim 1, containing no other sedative agent other than the clonidine and the midazolam.

7. The liquid drug formulation of claim 6, not containing any opioid drug.

8. The liquid drug formulation of claim 6, being provided in a multi-use container that contains 25-400 ml of the liquid drug formulation.

9. The liquid drug formulation of claim 1, being provided in a single-use dispenser that contains 2.0-20 ml of the liquid drug formulation.

10. The liquid drug formulation of claim 9, wherein the single-use dispenser contains 2.0-20 ml of the liquid drug formulation.

11. A method of inducing sedation in a patient, comprising: having a liquid drug formulation of claim 1; administering an oral dose of the liquid drug formulation to the patient.

12. The method of claim 11, wherein the dose is a volume of less than 15 ml.

13. The method of claim 11, wherein the dose is a volume of less than 7 ml.

14. The method of claim 11, wherein the dose gives 1-10 ?g/kg clonidine to the patient.

15. The method of claim 11, wherein the dose gives 2-7 ?g/kg clonidine to the patient.

16. The method of claim 11, wherein the dose gives 0.1-4.0 mg/kg midazolam to the patient.

17. The method of claim 11, wherein the dose gives 0.2-2.0 mg/kg midazolam to the patient.

18. The method of claim 11, wherein the sedation is in preparation for a clinical procedure.

19. The method of claim 18, wherein the clinical procedure is performed after waiting a duration of 5-60 minutes duration from administering the liquid drug formulation to the patient.

20. The method of claim 18, wherein the clinical procedure is performed after waiting a duration of 10-45 minutes duration from administering the liquid drug formulation to the patient.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows a multi-dose bottle containing a medicated syrup.

(2) FIG. 2 shows a single-use syringe pre-filled with a medicated syrup.

(3) FIG. 3 shows a medicated lollipop.

(4) FIG. 4 shows a medicated lozenge.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

(5) Actual working examples of the drug composition were made and tested in a clinical trial setting. First, a medicated syrup formulation was made and clinically tested. Second, a medicated lollipop formulation was made and clinically tested.

(6) Medicated Syrup: The following is an example process that was used make the oral syrup formulation. Make stock preparation of clonidine HCl at 16 ?g/ml concentration. Do this by grinding clonidine HCl into fine powder. Mix the powder with 5 ml of flavored sucrose syrup to yield clonidine paste at 16 mg/ml concentration. Further add 100 ml of flavored sucrose syrup to yield clonidine solution at 16 ?g/ml concentration. For stock preparation of midazolam, use commercially-available midazolam liquid syrup with midazolam HCl 2.0 mg/ml concentration. Mix the two stock preparations together in an appropriate ratio for the desired drug concentration amounts (e.g. a 1:1 mixing ratio would give 8 ?g/ml of clonidine and 2 mg/ml of midazolam.

(7) This medicated syrup was tested in pediatric patients who were undergoing a routine dental procedure, such as tooth extractions, tooth fillings, root canals, and crowns. Prior to beginning the dental procedure, the patients were given the medicated syrup by mouth. The patients were instructed to swallow the medicated syrup. The patient's progress in sedation level was then assessed according to the Houpt scale. When sufficient sedation level was achieved, the dental procedure was started. If sufficient sedation level was not achieved or the sedation was ineffective in allowing the dental procedure to proceed, the study process was terminated for that patient.

(8) Table 1 below summarizes the results of the clinical study. Time indicates the wait duration after administering the medicated syrup and beginning the dental procedure. Sedation level is rated mild, moderate (mod), or deep. The patient's Houpt score is also indicated (abt means the dental treatment procedure was aborted).

(9) TABLE-US-00001 TABLE 1 Clinical Results, Medicated Syrup Patient Medication, Medication, Sedation Houpt # Age dose per kg weight dose amount Time Level Score 1 3 clonidine 4 ?g/ clonidine 56 ?g/ 30 mild 9 midazolam 0.5 mg midazolam 7 mg 2 4 clonidine 4 ?g/ clonidine 89 ?g/ 30 mild 5 midazolam 0.5 mg midazolam 9.4 mg 3 5 clonidine 4 ?g/ clonidine 72 ?g/ 50 mod 9 midazolam 0.5 mg midazolam 9 mg 4 5 clonidine 4 ?g/ clonidine 90 ?g/ 45 mild 7 midazolam 0.75 mg midazolam 15 mg 5 6 clonidine 4 ?g/ clonidine 112 ?g/ 45 mod 17 midazolam 0.75 mg midazolam 20 mg 6 5 clonidine 4 ?g/ clonidine 88 ?g/ 35 mild abt midazolam 0.75 mg midazolam 16.5 mg 7 2 clonidine 4 ?g/ clonidine 60 ?g/ 45 mild abt midazolam 0.75 mg/ midazolam 11.25 mg/ hydroxyzine hydroxyzine 16.25 mg 8 8 clonidine 4 ?g/ clonidine 140 ?g/ 45 mod 9 midazolam 0.6 mg/ midazolam 20 mg/ hydroxyzine hydroxyzine 77 mg 9 3 clonidine 3 ?g/ clonidine 53 ?g/ 47 mod 9 midazolam 0.6 mg/ midazolam 10.4 mg/ hydroxyzine hydroxyzine 18 mg 10 4 clonidine 3 ?g/ clonidine 64 ?g/ 45 mod 9 midazolam 0.6 mg/ midazolam 13 mg/ hydroxyzine hydroxyzine 21 mg 11 4 clonidine 3 ?g/ clonidine 86.7 mg/ 45 mod 9 midazolam 0.6 mg/ midazolam 17.4 mg/ hydroxyzine hydroxyzine 27 mg

(10) In patients #3, 8, and 10, sedation was sufficient for the procedure to continue to completion. In the other patients, the level of sedation achieved was not sufficient for the procedure to continue to completion. These cases were likely because of non-optimal compounding technique, which caused formulation instability and non-homogenous distribution of the drugs in the product. This non-homogenous preparation caused a clinically significant variation in drug concentrations. Vital signs were stable in all cases.

(11) Medicated Lollipop: The following is an example process that was used make the lollipop formulation. Make fentanyl citrate into finely ground (trituration) 1% powder mixture by adding fentanyl citrate to a similar particle-size excipient powder material (e.g. steviol glycosides, sugar, etc.) and a similar particle-size food color of choice in a quantity sufficient to make a 1% trituration. Mix with a powder blender (e.g. V-Blender or other pharmaceutical powder blender) to produce a homogenous powder mixture. Obtain an accurate weight from an aliquot. Make clonidine HCl into finely ground (trituration) 1% powder mixture by adding clonidine HCl to a similar particle-size excipient powder material (e.g. steviol glycosides, sugar, etc.) and a similar particle-size food color of choice in a quantity sufficient to make a 1% trituration. Mix with a powder blender (e.g. V-Blender or other pharmaceutical powder blender) to produce a homogenous powder mixture. Obtain an accurate weight from an aliquot. Have ready midazolam HCl powder.

(12) Calculate amount of sorbitol base needed to make 8.0 grams total weight (for each lollipop being made) when combined with all other ingredients (e.g. 7.9 grams of sorbitol base for each lollipop may be the calculated result). Put calculated amount of sorbitol base into a glass beaker and heat to about 160? C. on a hot plate. Optionally, measure water activity and maintain temperature of 160? C. until water activity is below 0.6. This is to ensure that the sorbitol base is anhydrous. Slowly cool the sorbitol base to about 90? C. Put stir bar into beaker and start slow mixing. Add 13.8 mg of the fentanyl 1% triturated powder per each lollipop being made. Add 11 mg of the clonidine 1% triturated powder per each lollipop being made. Add 20.6 mg of the midazolam powder per each lollipop being made. Add 12 mg of steviol glycosides per each lollipop being made. Add 160 ?l of stock bubblegum flavor per each lollipop being made. In an alternate processing technique, a rotor-stator homogenizer (instead of a stir bar) could be used for improved homogenization of the mixture and reduction of powder aggregation that can form when adding powders to the base. This forms finely micronized particles and a homogenous mixture (suspension).

(13) Coat metal lollipop molds with a light oil and heat to 90? C. Drain and remove excess oil. Pour the hot 90? C. mixture (of sorbitol base, active pharmaceutical ingredients, and inactive ingredients) into the lollipop molds (or use a 20 ml oral syringe to draw up the mixture and dispense into the molds). After filling the lollipop molds, let cool to room temperature over a 12 hour duration. After cooling, put mold in freezer for about 30 minutes and then remove the medicated lollipops from the mold.

(14) These medicated lollipops were tested in pediatric patients who were undergoing a routine dental procedure, such as tooth extractions, tooth fillings, root canals, and crowns. Prior to beginning the dental procedure, the lollipops were placed into the patient's mouth and dwelled therein for an appropriate wait time. The patient's progress in sedation level was then assessed according to the Houpt scale. When sufficient sedation level was achieved, the dental procedure was started. If sufficient sedation level was not achieved or the sedation was ineffective in allowing the dental procedure to proceed, the study process was terminated for that patient.

(15) Table 2 below summarizes the results of the clinical study. Time indicates the wait duration after administering the medicated syrup and beginning the dental procedure. Sedation level is rated mild, moderate (mod), or deep. The patient's Houpt score is also indicated.

(16) TABLE-US-00002 TABLE 2 Clinical Results, Medicated Lollipop Patient Medication, Medication, Sedation Houpt # Age Dose per kg weight Dose amount Time Level Score 12 6 clonidine 3.33 ?g/ clonidine 60 ?g/ 21 deep 17 midazolam 0.55 mg/ midazolam 10 mg/ fentanyl 5.55 ?g fentanyl 100 ?g 13 6 clonidine 3.06 ?g/ clonidine 60 ?g/ 14 mod 15 midazolam 0.5 mg/ midazolam 10 mg/ fentanyl 5 ?g fentanyl 100 ?g 14 5 clonidine 2.85 ?g/ clonidine 60 ?g/ 28 mod 13 midazolam 0.48 mg/ midazolam 10 mg/ fentanyl 4.76 ?g fentanyl 100 ?g 15 6 clonidine 2.4 ?g/ clonidine 60 ?g/ 27 mild 12 midazolam 0.4 mg/ midazolam 10 mg/ fentanyl 4 ?g fentanyl 100 ?g 16 4 clonidine 3.4 ?g/ clonidine 60 mg/ 29 mild 9 midazolam 0.6 mg/ midazolam 10 mg/ fentanyl 6 ?g fentanyl 100 ?g 17 3 clonidine 4.3 ?g/ clonidine 60 mg/ 37 mild 8 midazolam 0.71 mg/ midazolam 10 mg/ fentanyl 3.5 ?g fentanyl 50 ?g 18 3 clonidine 2.5 ?g/ clonidine 45 ?g/ 42 mod 15 midazolam 0.42 mg/ midazolam 7.5 mg/ fentanyl 4.2 ?g fentanyl 75 ?g 19 4 clonidine 2.75 ?g/ clonidine 45 ?g/ 33 mild 8 midazolam 0.45 ?g/ midazolam 7.5 mg/ fentanyl 4.6 ?g fentanyl 75 ?g 20 4 clonidine 3 ?g/ clonidine 45 ?g/ 20 mild 8 midazolam 0.51 mg/ midazolam 7.5 mg/ fentanyl 5 ?g fentanyl 75 ?g 21 3 clonidine 4.1 ?g/ clonidine 60 ?g/ 35 mild 8 midazolam 0.7 mg/ midazolam 10 mg/ fentanyl 6.9 ?g fentanyl 100 ?g 22 8 clonidine 4.12 ?g/ clonidine 130 mg/ 34 mod 14 midazolam 0.77 ?g/ midazolam 24.4 mg/ fentanyl 5.15 ?g fentanyl 162.5 ?g 23 5 clonidine 4.8 ?g/ clonidine 90 ?g/ 15 mod 15 midazolam 0.9 mg/ midazolam 16.9 mg/ fentanyl 6 ?g fentanyl 113 ?g 24 8 clonidine 4.24 ?g/ clonidine 110 ?g/ 25 mod 13 midazolam 0.8 mg/ midazolam 21 mg/ fentanyl 5.3 ?g fentanyl 138 ?g 25 5 clonidine 4 ?g/ clonidine 70 ?g/ 22 mild 8 midazolam 0.75 mg/ midazolam 13.1 mg/ fentanyl 5 ?g fentanyl 87.5 ?g 26 3 clonidine 4.4 ?g/ clonidine 70 ?g/ 24 mild 7 midazolam 0.83 mg/ midazolam 13.1 mg/ fentanyl 5.5 ?g fentanyl 87.5 ?g 27 7 clonidine 4.9 ?g/ clonidine 130 ?g/ 37 mod 17 midazolam 0.92 mg/ midazolam 24.4 mg/ fentanyl 5.2 ?g fentanyl 138 ?g 28 8 clonidine 4.24 ?g/ clonidine 110 ?g/ 21 mod 13 midazolam 0.8 ?g/ midazolam 20.6 mg/ fentanyl 5.3 ?g fentanyl 138 ?g 29 6 clonidine 5.5 ?g/ clonidine 110 ?g/ 22 mod 16 midazolam 0.96 mg/ midazolam 20.6 mg/ fentanyl 6.8 ?g fentanyl 138 ?g 30 3 clonidine 6 ?g/ clonidine 90 ?g/ 24 mod 16 midazolam 1.13 mg/ midazolam 17 mg/ fentanyl 7.55 ?g fentanyl 113 ?g 31 3 clonidine 5.3 ?g/ clonidine 90 ?g/ 25 mild 8 midazolam 0.99 ?g/ midazolam 17 mg/ fentanyl 6.6 ?g fentanyl 113 ?g 32 5 clonidine 4.2 ?g/ clonidine 90 ?g/ 30 mild 8 midazolam 0.79 mg/ midazolam 17 mg/ fentanyl 5.2 ?g fentanyl 113 ?g 33 6 clonidine 4.95 ?g/ clonidine 110 ?g/ 16 mod 16 midazolam 0.93 mg/ midazolam 20.6 mg/ fentanyl 6.2 ?g fentanyl 138 ?g 34 4 clonidine 4.7 ?g/ clonidine 90 ?g/ 23 mild 6 midazolam 0.88 mg/ midazolam 17 mg/ fentanyl 5.9 ?g fentanyl 113 ?g 35 9 clonidine 4.2 ?g/ clonidine 130 mg/ 36 mild 7 midazolam 0.8 mg/ midazolam 24.4 mg/ fentanyl 4.4 ?g fentanyl 138 ?g 36 6 clonidine 5.3 ?g/ clonidine 110 ?g/ 38 mild 9 midazolam 1 mg/ midazolam 20.6 mg/ fentanyl 6.6 ?g fentanyl 138 ?g 37 4 clonidine 4.4 ?g/ clonidine 70 ?g/ 21 mild 6 midazolam 0.83 mg/ midazolam 13.1 mg/ fentanyl 5.5 ?g fentanyl 87.5 ?g 38 3 clonidine 4.6 ?g/ clonidine 90 ?g/ 35 mod/deep 17 midazolam 0.87 mg/ midazolam 17 mg/ fentanyl 5.7 ?g fentanyl 113 ?g

(17) There was 100% compliance with the child accepting the lollipop. Notably, this is higher than the compliance rate for oral medications that are swallowed. Parental separation was excellent except in patients #16, 29, and 31. In patients #12-15, 18, 22-24, 27, 28, 30, 33, and 38, sedation was sufficient for the procedure to continue to completion. In the other patients, the level of sedation achieved was not sufficient for the procedure to continue to completion. In all cases, vital signs were stable and the patient had no memory of the procedure (amnesia).

(18) Compared to opioid drugs, benzodiazepines (such as midazolam) have a much better safety profile. Thus, being able to reduce the amount of fentanyl is an important benefit. Through synergistic effect with the clonidine and midazolam, the lollipops were able provide effective sedation despite having a reduced amount of fentanyl compared to the ACTIQ? lollipop product.

(19) Product Examples: Shown in the drawings are some examples of drug product forms in which this invention may be implemented. FIG. 1 shows a multi-dose bottle 10 containing a medicated syrup. There is a spoon 12 for orally administering the doses from the bottle 10. The patient swallows the medicated syrup. FIG. 2 shows a single-use syringe 20 pre-filled with a medicated syrup. The dispensing spout is closed with a cap 22. In use, cap 22 is removed and the contents of syringe 20 is squirted into the patient's mouth. The patient swallows the medicated syrup. FIG. 3 shows a medicated lollipop 30 on a stick 32. The patient puts the lollipop 30 in their mouth and lets it dwell therein for transmucosal absorption. FIG. 4 shows a medicated lozenge 40. The patient puts the lozenge 40 in their mouth and lets it dwell therein for transmucosal absorption.

(20) The descriptions and examples given herein are intended merely to illustrate the invention and are not intended to be limiting. Each of the disclosed aspects and embodiments of the invention may be considered individually or in combination with other aspects, embodiments, and variations of the invention. In addition, unless otherwise specified, the steps of the methods of the invention are not confined to any particular order of performance. Modifications of the disclosed embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, and such modifications are within the scope of the invention.

(21) Any use of the word or herein is intended to be inclusive and is equivalent to the expression and/or, unless the context clearly dictates otherwise. As such, for example, the expression A or B means A, or B, or both A and B. Similarly, for example, the expression A, B, or C means A, or B, or C, or any combination thereof.