Pharmaceutical formulations and production method used in pediatric anesthesia premedication

Abstract

The invention relates to fast-acting, multi-layered, orally disintegrating, and film-shaped pharmaceutical formulations containing anesthetic drugs (midazolam, ketamine, atropine, or a combination thereof) used to provide sedation in children prior to surgical operations or interventions, and the production method of these formulations.

Description

PHARMACEUTICAL FORMULATIONS AND PRODUCTION METHOD USED IN PEDIATRIC ANESTHESIA PREMEDICATIONTechnical FieldThe invention relates to fast acting, multi-layered, orally disintegrating, and film-shaped pharmaceutical formulations containing anesthetic drugs (midazolam, ketamine, atropine, or a combination thereof) used to provide sedation in children prior to surgical operations or interventions, and the production method of these formulations.BackgroundSurgical operations, hospital settings, doctors, especially the operating room and anesthesia procedure, induce a significant anxiety and fear in children. These fears encompass separation from parents, fear of painful procedures such as injections and IV insertion, fear of unfamiliar environments and people, fear of anesthesia, and fear of surgery, f1’5’8] Eliminating these fears, reducing anxiety, and facilitating easy and comfortable anesthesia administration require preoperative preparation of children. While preoperative consultations with patients and their families by anesthesia doctors are particularly effective in reducing preoperative anxiety and fear within the family, additional methods are needed for children. Pharmacologically, sedation through premedication plays a fundamental role in this regard.Premedication is routinely administered in children before surgery and is effective in alleviating preoperative anxiety. Sedative drugs commonly used in routine premedication can be administered orally, rectally, or intravenously. [7] Although the most suitable and easiest route for children among these is oral administration of these drugs, there is currently no oral preparation available for atropine. When referring to the FDA Orange Book and DailyMed databases [2-3], the market preparations of ketamine, midazolam, and atropine are as follows:- Ketamine-containing syrup, injectable solution, or nasal spray- Midazolam-containing syrup, injectable solution, or nasal spray Ketamine-Midazolam-Hydroxyzine lozenge- Midazolam-Ketamine HCl-Ondansetron lozengeAtropine-containing injectable and ophthalmic solution, aerosol, ointment, tablet, or chewable tabletInjectable solution, elixir, tablet, capsule, syrup, and liquid dosage forms containing a combination of atropine with other active pharmaceutical ingredients.When looking at the list above, it is noted that there are syrup formulations for ketamine and midazolam, while atropine is available in chewable tablet form. However, achieving accurate dosing with these dosage forms can be challenging, especially in young children (particularly around the age of 3), due to the resistance that can be encountered. For instance, a portion of the drug is lost due to spitting after administration. Additionally, in clinical practice, dosages of injectable products are often adjusted and then mixed into fruit juice for consumption. [4’n] However, under these conditions, the use is not practical and may not provide sufficient effectiveness due to the following issues:Concerns about consuming food before surgery.In cases where the entire fruit juice is not consumed, adequate effectiveness of the active pharmaceutical ingredients may not be achieved.Some drugs may have an unpleasant taste that cannot be masked.- Due to the unknown chemical stabilities of the active pharmaceutical ingredients in the fruit juice, if degradation occurs, both the effectiveness may decrease, and side effects may occur due to the impurities formed.The application may not be practical for healthcare personnel.In addition to fruit juice application, products in the form of lollipops have also been used in practice. [6 10] However, for the lollipop to be effective, it needs to be in contact with the buccal mucosa, which may not be feasible, especially in young children, thus limiting its effectiveness. Furthermore, pastilles may not be suitable for children due to their size and requirement for sucking and / or chewing.In addition to the application issues, syrup formulations can pose challenges in terms of chemical stability and transportation, and generally, solid dosage forms demonstrate higher stability compared to liquid forms. [9] Furthermore, studies conducted in children have observed that mini oral tablets are preferred more by both parents and children compared to syrups.

[12] The document WO2019165208A1 discusses a transmucosal film composition and methods for its production and use.The document EP3912622A1 describes an oral film developed for the safe application of active pharmaceutical ingredients.The document W02020051317A1 mentions oral film compositions and dosage forms with precise active dissolution profiles.The document WO2022120263A1 discusses an oral formulation of clonidine and midazolam for sedation in dental procedures.Based on the existing studies in the field, there is a need for the development of fast acting, multi-layered, orally disintegrating, and film-shaped pharmaceutical formulations containing anesthetic drugs (midazolam, ketamine, atropine, or a combination thereof) for providing sedation in children before surgical operations or interventions, as well as the improvement of the production method of these formulations.Aims of the InventionThe aim of this invention is to develop fast-acting, multi-layered, orally disintegrating, and film-shaped pharmaceutical formulations containing anesthetic drugs (midazolam, ketamine, atropine, or a combination thereof) for providing sedation in children before surgical operations or interventions, as well as to improve the production method of these formulations.Another aim of this invention is to facilitate easy dosage adjustment by healthcare personnel based on the child's weight without the need for any liquid intake before surgery, and to develop orally disintegrating and film-shaped pharmaceutical formulations that can be easily administered to children.Detailed Description of the InventionThe invention pertains to the production method of fast-acting, multi-layered, orally disintegrating, and film-shaped pharmaceutical formulations containing anesthetic drug / drugs for providing sedation in children before surgical operations or interventions. The method includes the following steps:- Preparation of an aqueous solution of Polyvinyl Alcohol (PVA) by adding the polymer to distilled water.- Mixing the prepared aqueous solution with PEG 400, xylitol, citric acid, and banana flavor in a magnetic stirrer.Addition of benzoic acid dissolved in ethanol to the solution.Conversion of the solution into a film using the electrospinning method (First layer).- Dispersing midazolam in distilled water and preparing an aqueous solution by clarifying with Hydrochloric acid (HC1).Again, preparation of an aqueous solution of Polyvinyl Alcohol (PVA) by adding the polymer to distilled water.- Mixing midazolam and Polyvinyl Alcohol (PVA) aqueous solutions.Addition of acetic acid to the mixture.Spraying the solution, to which acetic acid has been added and pH adjusted with Sodium hydroxide (NaOH), onto the first polymer layer obtained in step 4 using the electrospinning method (Second layer).- Preparation of the polymer solution by repeating the first 3 steps and spraying onto the second active pharmaceutical ingredient layer obtained in step 9 using the electrospinning method (Third layer) to obtain the pharmaceutical formulation.In the method subject of the invention, for a 10 mL polymer solution, 10 mL of distilled water is placed on a magnetic stirrer in a water bath, and it is left for a while until its temperature reaches 80°C. Then, 1.5 g of PVA is added gradually to ensure its dispersion in water. This mixture is left to stir in this way for approximately 10 hours.After the PVA solution has cooled down to room temperature, PEG 400, xylitol, citric acid, and banana flavor are added to it and mixed on a magnetic stirrer. Distilled water is added to bring the mixture to a total volume of 10 mL in a graduated cylinder. Benzoic acid is dissolved in 1 mL of ethanol and added to the PVA solution obtained in the previous step.Using 1 mL of the obtained solution, a film is formed via the electrospinning method. As a result of this process, the first layer is obtained. During the procedure, the voltage of the device, the distance between the spray head and the collector, and the solution flow rate are adjusted. These values are set to 25 kV for voltage, 150 mm for the distance between the spray head and the collector, and 0.3-1 mL / h for the solution flow rate, respectively.In the process of obtaining the second layer in the method subject of the invention, 0.6 g of midazolam is dispersed in 1.6 mL of distilled water, and approximately 20 drops of HC1 are added to it to clarify.For a 5 mL polymer solution, 5 mL of distilled water is placed on a magnetic stirrer in a water bath and left for a while until its temperature reaches 80°C. Then, 1.5 g of PVA is added gradually to ensure its dispersion in water. This mixture is left to stir in this way for approximately 10 hours. Afterwards, midazolam and PVA solutions are mixed. Then, acetic acid is added to the mixture. The pH value is adjusted to 3.5 with NaOH, and the volume is brought to 10 mL with distilled water.1 mL of the obtained solution is sprayed onto the first layer using the electrospinning method to form the second layer. During the process, the voltage of the device, the distance between the spray head and the collector, and the solution flow rate are adjusted. These values are set to 25 kV for voltage, 150 mm for the distance between the spray head and the collector, and 0.3-1 mL / h for the solution flow rate, respectively.In the method subject of the invention, the polymer solution prepared during the creation of the first layer is sprayed onto the second layer using the electrospinning method to form the third layer. As a result of this process, the third layer is obtained. During the preparation of the PVA solution, the solution temperature can vary between 70-90°C, and the waiting time can range from 8 to 24 hours. During the electrospinning process, the voltage value can range from 20 to 30 kV, the distance between the spray head and the collector can vary between 140 and 170 mm, and the solution flow rate can range from 0.2 to 1.5 mL / hour. A drum or flat collector can be used as the collector. When using a flat collector, the homogenization process can be activated.The formulation obtained by the method subject of the invention contains:2% by weight of midazolam as the active pharmaceutical ingredient (can be used in the range of 0.5-20% by weight).15% by weight of polyvinyl alcohol (PVA) as the polymer (can be used in the range of 7.5-30% by weight).1.67% by weight of Polyethylene Glycol 400 (PEG 400) as the plasticizer (can be used in the range of 1-5% by weight).0.17% by weight of xylitol as the sweetener (can be used in the range of 0.1-1% by weight).0.33% by weight of citric acid as the saliva secretion enhancer (can be used in the range of 0.1-1% by weight).0.017% by weight of benzoic acid as the antimicrobial preservative (can be used in the range of 0.01-0.05% by weight).0.17% by weight of banana flavor as the flavoring agent (can be used in the range of 0.1-1% by weight). pH adjusting agents such as HC1, NaOH, and acetic acid (as needed).6.67% by weight of ethanol as the co- solvent (can be used in the range of 5-10% by weight).- Distilled water as the solvent (as needed).Midazolam is the active pharmaceutical ingredient responsible for the sedative effect. Polyvinyl alcohol (PVA) acts as the film-forming agent and serves as the carrier for the active pharmaceutical ingredient. Although there are various molecular weight derivatives of PVA, those with molecular weights ranging mostly between 40,000-70,000 and 80, GOO- 125, 000 are commonly used. Polyethylene glycol 400 (PEG 400) is included in the formulation as a plasticizer. It is used to improve the flexibility and mechanical resistance of the film. Xylitol and banana flavor are used as sweetener and flavoring agent, respectively, to leave a pleasant taste when the film dissolves in the mouth. Citric acid is added to act as a saliva secretion enhancer, aiding in the disintegration of the film in the mouth. Benzoic acid, an antimicrobial agent, is added to improve microbiological stability of the film. Ethanol is included in the polymer solution to dissolve benzoic acid and facilitate the electrospinning process. Hydrochloric acid (HC1) is added to dissolve midazolam. As HC1 is added to the dispersion of midazolam in water, midazolam hydrochloride salt forms, enhancing its solubility in water. Sodium hydroxide (NaOH) is used to adjust the pH of the midazolam solution to a level suitable for oral administration while not adversely affecting its solubility. Acetic acid is used to increase the conductivity of the active pharmaceutical ingredient-polymer solution and facilitate the electrospinning process. Distilled water is preferred as the main solvent for the polymer and substances.Alternative components can be used. Other active pharmaceutical ingredients with similar purposes, such as ketamine or atropine, or various combinations of midazolam, ketamine, and atropine, can be utilized. Active pharmaceutical ingredients belonging to the antiemetic,anticonvulsant, sedative, and analgesic groups can also be employed. Additionally, nanoparticulate forms of the active pharmaceutical ingredients can be utilized, in addition to their solution forms.As an alternative to PVA as the film-forming agent, cellulose and its derivatives, and pullulan, as well as their combinations with PVA and each other, can be used.As an alternative to PEG 400 as the plasticizer, glycerin, sorbitol, propylene glycol, or various combinations thereof can be utilized.For sweetening purposes, mannitol, sorbitol, acesulfame potassium K, sodium saccharin can be used.As an alternative to benzoic acid as antimicrobial preservatives, methylparaben, propylparaben, sodium benzoate, potassium benzoate, or various combinations thereof can be used.For flavoring, substances such as strawberry, vanilla, chocolate, apple, or mint can be used.The final formulation contains midazolam, ketamine, and atropine alone or in combination (2 -way, 3 -way), and it easily disperses with saliva upon contact with the oral mucosa (within 3 minutes). It cannot be expelled by spitting, as it will be at least 2x2 cm2in size, with an acceptable taste and easily dispersed in the mouth. Since the film contains active pharmaceutical ingredients in certain proportions relative to its weight, dosing based on the child's weight can be achieved by adjusting the weight of the film. Also drinking of water is not required for administration, thus, the essential fasting state before surgery can be safely maintained. The bitter taste of the active pharmaceutical ingredients will be masked by the multilayered film production, with the active ingredient layer positioned as an intermediate layer within the film.References:[1] Cihangir-Altay, N. 2008. “ ocuklarda ameliyat bncesi hazirhk”, Hacettepe Universitesi, Saghk Bilimleri Fakiiltesi Hem§irelik Dergisi, 68-76.[2] FDA OrangeBook. OrangeBook: Approved Drug Products with Therapeutic Equivalence Evaluations”, https: / / www.accessdata.fda.gov / scripts / cder / ob / index.cfm Last access date: July 15, 2023.[3] Dailymed. “U.S. National Library Of Medicine”. https: / / dailymed.nlm.nih.gov / dailymed / Last access date: July 15, 2023.[4] Gbksu, S., Oner, U, Tahtaci, N., Gbgii§, D., Gungor, G. 1997. “Pediartik anestezide oral midazolam ve ketamin premedikasyonunun kar§ila§tinlmasi”. AUTD, 29, 495-499.[5] Harter, V., Barkmann, C., Wiessner C., Rupprecht, M., Reinshagen, K., Trah, J. 2021. “Effects of educational video on pre-operative anxiety in children- A randomized clinical trial”, Frontiers in Pediatrics, 9, 640236.[6] Horiuchi, T., Kawaguchi, M., Kurehara, K., Kawaraguchi, Y., Furuya, H. 2003. “Evaluation of oral transmucosal ketamine (lollipop) premedication in children: a comparison with oral midazolam”, Anesthesiology, 99, A1383.[7] Kain, Z. N., Mayes, L. C., Bell, C., Weisman, S., Hofstadter, M. B., Rimar, S. 1997. “Premedication in the United States: A status report”, AnesthAnalg., 84(2), 427-432.[8] Kain, Z. N., Mayes, L. C., Caldwell-Andrews, A. A., Karas, D. E., McClain, B. C. 2006. “Preoperative anxiety, postoperative pain, and behavioral recovery in young children undergoing surgery”, Pediatrics, 118(2), 651-658.[9] Lopez, F. L., Ernest, T. B., Tuleu, C., Gul, M. O. 2015. “Formulation approaches to pediatric oral drug delivery: benefits and limitations of current platforms”, Expert Opinion on Drug Delivery, 12(11), 1727-1740.

[0010] Shigemi, K., Kanbayashi, Y., Ohta, T., Nakamura, Y., Ashida, H., Hayashida, K., Nishida, K., Tanaka, Y. 2000. “Midazolam-atropine lollipop for pediatric premedication”, Masui. The Japanese Journal of Anesthesiology, 49(5):496-503.

[0011] §entiirk, Z., Kuvaki, B., Arkan, A. 1997. “ ocuklarda oral premedikasyonda midazolam ve midazolam-ketamin kombinasyonunun solunumsal ve hemodinamik etkilerinin kar§ila§tinlmasi”, SDU Tip Fakiiltesi Dergisi, 4(2), 21-29.

[0012] vanRiet-Nales, D. A., de Neef, B. J., Schobben, A. F., Ferreira, J. A., Egberts, T. C., Rademaker, C. M.2013. “Acceptability of different oral formulations in infants and preschool children”, Archives of Disease in Childhood, 98(9), 725-731.

Claims

CLAIMS1. A production method of fast-acting, multi-layered, orally disintegrating, and filmshaped pharmaceutical formulations containing anesthetic drugs for providing sedation in children before surgical operations or interventions characterized by comprising the following steps:- Preparation of an aqueous solution of Polyvinyl Alcohol (PVA) by adding the polymer to distilled water.- Mixing the prepared aqueous solution with PEG 400, xylitol, citric acid, and banana flavor in a magnetic stirrer.Addition of benzoic acid dissolved in ethanol to the solution.Conversion of the solution into a film using the electrospinning method (First layer).- Dispersing midazolam in distilled water and preparing an aqueous solution by clarifying with HC1.Again, preparation of an aqueous solution of Polyvinyl Alcohol (PVA) by adding the polymer to distilled water.- Mixing midazolam and Polyvinyl Alcohol (PVA) aqueous solutions.Addition of acetic acid to the mixture.Spraying the solution, to which acetic acid has been added and pH adjusted with NaOH, onto the first polymer layer obtained in step 4 using the electrospinning method (Second layer).- Preparation of the polymer solution by repeating the first 3 steps and spraying onto the second active pharmaceutical ingredient layer obtained in step 9 using the electrospinning method (Third layer) to obtain the pharmaceutical formulation.

2. The method according to claim 1, wherein the preparation of the aqueous solution by adding polyvinyl alcohol (PVA) polymer to distilled water is characterized by allowing the solution to stand for 8-24 hours.

3. A pharmaceutical formulation in the form of a multilayered, orally disintegrating film, characterized by its ability to provide rapid sedation in children prior to surgical procedures or interventions, comprising:Midazolam,Polyvinyl alcohol (PVA),Polyethylene glycol 400 (PEG 400),Xylitol,Citric acid,- Benzoic acid,- Banana flavoring,- HC1, NaOH, and acetic acid, Ethanol,- Distilled water.

4. The pharmaceutical formulation according to claim 3, characterized by the weight percentage of midazolam ranging from 0.5% to 20%.

5. The pharmaceutical formulation according to claim 3, characterized by the weight percentage of polyvinyl alcohol ranging from 7.5% to 30%.

6. The pharmaceutical formulation according to claim 3, characterized by the weight percentage of polyethylene glycol 400 ranging from 1% to 5%.

7. The pharmaceutical formulation according to claim 3, characterized by the weight percentage of xylitol ranging from 0.1% to 1%.

8. The pharmaceutical formulation according to claim 3, characterized by the weight percentage of citric acid ranging from 0.1% to 1%.

9. The pharmaceutical formulation according to claim 3, characterized by the weight percentage of benzoic acid ranging from 0.01% to 0.05%.

10. The pharmaceutical formulation as according to claim 3, characterized by the weight percentage of banana flavoring ranging from 0.1% to 1%.