Description:FORM 2
THE PATENT ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)
Fast-Dissolving Films Loaded with Biocompatible Nanoparticles of dimethyl fumarate (DMF) for Improved Drug Absorption
G D Goenka University, Sohna Gurugram Road, Sohna, Haryana, India, 122103
The following specification fully and particularly describes the invention and a method to carry out the same.
FIELD OF INVENTION
The present invention relates to the biotechnology field, particularly relates to a Chitosan-alginate core-shell-corona shaped nanoparticles of dimethyl fumarate in orodispersible film to improve bioavailability in treatment ofmultiple sclerosis.
BACKGROUND OF INVENTION
Fast-dissolving films (FDFs) represent a promising dosage form for oral drug delivery, offering several advantages such as ease of administration, rapid disintegration in the oral cavity without the need for water, and improved patient compliance. To further enhance the therapeutic potential of FDFs, the incorporation of biocompatible nanoparticles presents an innovative approach to improve drug delivery efficiency. This article explores the development and potential applications of fast-dissolving films loaded with biocompatible nanoparticles.
Biocompatible nanoparticles, such as those composed of polymers like chitosan, alginate, poly(lactic-co-glycolic acid) (PLGA), and lipid-based materials, have gained significant attention in drug delivery due to their favorable biocompatibility, controlled release properties, and ability to protect drugs from degradation. These nanoparticles can encapsulate a wide range of drugs, including hydrophobic and hydrophilic compounds, and enable controlled release kinetics.
Fast-dissolving films are thin, flexible films that rapidly disintegrate upon contact with saliva, releasing the encapsulated drug for oral absorption. These films are typically prepared using techniques such as solvent casting, hot melt extrusion, or printing, allowing for precise control over film composition and drug content. FDFs offer advantages over conventional oral dosage forms, particularly in populations with swallowing difficulties or those requiring convenient and discreet drug administration.
Integration of Biocompatible Nanoparticles into Fast-Dissolving Films:
The integration of biocompatible nanoparticles into fast-dissolving films offers several potential benefits:
Enhanced Drug Stability: Biocompatible nanoparticles can protect drugs from degradation and enhance their stability during formulation and storage, preserving the therapeutic efficacy of the drug.
Controlled Release: Nanoparticles can modulate the release kinetics of drugs, enabling sustained or targeted drug delivery, which is particularly beneficial for drugs with narrow therapeutic windows or those requiring prolonged action.
Improved Bioavailability: The incorporation of nanoparticles into FDFs can enhance drug solubility, permeability, and absorption, leading to improved bioavailability and therapeutic outcomes.
Targeted Delivery: Nanoparticles can be engineered to target specific tissues or cells, allowing for site-specific drug delivery and minimizing off-target effects.
Fast-dissolving films loaded with biocompatible nanoparticles have potential applications across various therapeutic areas, including but not limited to:
Oral drug delivery: Rapid absorption of drugs through the oral mucosa can bypass first-pass metabolism, resulting in improved bioavailability and onset of action.
Pediatric and geriatric populations: FDFs offer a convenient dosage form for patients with swallowing difficulties or those requiring precise dosing, making them particularly suitable for pediatric and geriatric populations.
Precision medicine: The ability to tailor drug release kinetics and target specific tissues or cells enables the development of personalized medicine approaches, optimizing therapeutic outcomes while minimizing side effects.
Fast-dissolving films loaded with biocompatible nanoparticles represent a promising platform for enhancing drug delivery efficiency and therapeutic efficacy. By leveraging the unique properties of both FDFs and nanoparticles, this innovative dosage form has the potential to address unmet clinical needs and improve patient outcomes across a wide range of therapeutic applications. Further research and development in this area are warranted to fully realize the clinical benefits of this novel drug delivery strategy.
The present invention relates to orodispersible films (ODFs) loaded with chitosan-alginate nanoparticles for improving the bioavailability, safety, and efficacy of drugs. More specifically, the invention pertains to a novel method of preparing polymeric film dosage forms containing chitosan-alginate nanoparticles of drugs, which exhibit sustained release properties and enhanced stability.
Orodispersible films (ODFs) are thin, flexible films that disintegrate rapidly upon contact with saliva, facilitating easy administration without the need for water. Various technologies, including solvent casting, hot melt extrusion, and printing techniques, have been utilized for the commercial preparation of ODFs. However, the choice of manufacturing method depends on the physicochemical properties of the active ingredient.
In recent years, there has been a growing interest in utilizing biodegradable polymers for formulating ODFs, aiming to enhance patient compliance and minimize environmental impact. Despite extensive research, there is a lack of evidence regarding the use of biodegradable polymer combinations, such as chitosan and alginate, to prepare nanoparticles of drugs for loading onto thin film matrices using solvent casting technology.
Chitosan and alginate are biocompatible polymers known for their mucoadhesive properties and ability to form nanoparticles through ionotropic gelation. These nanoparticles can encapsulate drugs, protecting them from degradation and facilitating controlled release. However, challenges remain in stabilizing these nanoparticles and preventing aggregation during formulation and storage.
BR112020020851A2discloses an orodispersible thin film for providing a substrate for printing at least one active ingredient on its surface that remains free of cavities after printing, a method of making the film, the substrate for printing and a hydrophobic edible ink , comprising at least one Active Ingredient for printing; the invention includes all films with orodispersibility property; including rectal, vaginal, ocular film and any other film intended for oral or transmucosal administration; one or more of the ingredients that make up the substrate of this invention acts (s) as an adsorbent (s) and gives (m) the necessary roughness to the surface of the substrate; The ink does not crystallize on drying and remains stable for at least six months at 40 ° C and 75% RH; and can be printed on a continuous inkjet printer.
The present invention addresses these challenges by incorporating chitosan-alginate nanoparticles of drugs into polymeric film matrices prepared using solvent casting technology. The polymeric films act as carriers, stabilizing the nanoparticles and preventing their aggregation. Upon administration, the ODFs rapidly disintegrate,
releasing the nanoparticles and facilitating their sustained release, thereby enhancing the bioavailability, safety, and efficacy of the drugs.
The innovative aspect of this invention lies in the combination of chitosan-alginate nanoparticles with polymeric film matrices, resulting in a novel drug delivery system with improved therapeutic outcomes. The sustained release properties of the nanoparticles, coupled with the rapid disintegration of the ODFs, offer significant advantages in terms of patient convenience and dosage administration.
In summary, the present invention provides a platform technology for the development of orodispersible films loaded with chitosan-alginate nanoparticles, offering enhanced bioavailability, safety, and efficacy of drugs. This invention represents a significant advancement in the field of dosage form design, with potential applications across various therapeutic areas.
OBJECTIVES OF THE INVENTION
The present invention has been developed in response to the present state of the art, and in particular, in response to the problems and needs in the art that have not yet been fully solved by currently available techniques and processes.
Accordingly, the present invention has been developed to provide a method of preparing the Fast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF)
Therefore, the current invention successfully overcoming all of the above-discussed shortcomings present in the art.
o It is an object of the invention toDevelop an innovative formulation of fast-dissolving films loaded with biocompatible nanoparticles of DMF to enhance the bioavailability of the drug for the treatment of multiple sclerosis.
o It is an object of the invention toOptimize the composition of the fast-dissolving films to achieve a suitable balance between DMF content, polymer matrices, plasticizers, and stabilizers, ensuring efficient drug
delivery and rapid disintegration in the oral cavity.
o It is an object of the invention toFabricate chitosan-alginate core-shell-corona shaped nanoparticles of DMF and incorporate them into the orodispersible film matrix to improve drug stability, release kinetics, and therapeutic efficacy.
o It is an object of the invention toEvaluate the in vitro drug release profile of the nanoparticles within the film matrix to confirm sustained release characteristics, providing a prolonged therapeutic effect compared to conventional oral film formulations.
o It is an object of the invention toAssess the bioavailability of DMF from the fast-dissolving films loaded with biocompatible nanoparticles, including determination of key pharmacokinetic parameters such as C max, T max, t1/2, and AUC, to demonstrate enhanced drug absorption and systemic exposure.
o It is an object of the invention toDevelop a reproducible and scalable method for the preparation of the fast-dissolving films loaded with biocompatible nanoparticles of DMF, ensuring uniform particle size distribution, stability, and consistent film quality for pharmaceutical applications.
o It is an object of the invention toValidate the proposed method of preparation through comprehensive physicochemical characterization, including particle size analysis, zeta potential measurement, scanning electron microscopy, and stability studies, to confirm the suitability of the formulation for clinical use.
o It is an object of the invention toProvide a detailed protocol for the manufacturing process of the fast-dissolving films, including step-by-step instructions for the preparation of chitosan-alginate nanoparticles, formulation of the film matrix, casting, drying, cutting, and storage
conditions, ensuring reproducibility and compliance with regulatory standards.
o It is an object of the invention toDemonstrate the feasibility and potential advantages of the proposed formulation and manufacturing method through comparative studies with conventional oral film formulations, highlighting the superior bioavailability, sustained release, and therapeutic efficacy of the fast-dissolving films loaded with biocompatible nanoparticles of DMF.
How the foregoing objects are achieved will be clear from the following brief description. In this context, it is clarified that the description provided is non-limiting and is only by way of explanation. Other objects and advantages of the invention will become apparent as the foregoing description proceeds, taken together with the accompanying drawings and the appended claims.
SUMMARY OF THE INVENTION
This summary is provided to introduce a selection of concepts in a simplified format that is further described in the detailed description of the invention. This summary is neither intended to identify key or essential inventive concepts of the invention and nor is it intended for determining the scope of the invention.
According to an aspect of the present invention relates to develop oral film containing biocompatible and biodegradable chitosan-alginate nanoparticles of DMF to improve oral bioavailability in multiple sclerosis treatment. The film formulationscontaining DMF are optimized through design of experiments using full factorial design, and impact of varyinglevels of independent factors on critical quality attributes of films are made. The orodispersible film ofchitosan-alginate core-shell-corona shaped nanoparticles of DMF is prepared by ionotropic pre-gelation ofalginate core followed by chitosan polyelectrolyte complexation, the obtained colloidal nanosuspension isadded to the optimized polymer matrix composition by simple process integration and then cast to films bysolvent casting process. The films are characterized for their critical quality attributes like pH, tensile strength,disintegration time, in-vitro drug release, ex-vivo permeation study through porcine buccal mucosa and in-vivopharmacokinetic study in wistar rats. The
in-vitro drug release profile from chitosan-alginate core-shell-coronashaped nanoparticles in film evidenced a sustained release with initial 18.39% release in 30 min followed bysustained release up to 6h in comparison to DMF oral film formulations which released more than 80% drugwithin 15 min. The in-vivo pharmacokinetic study confirmed that nanoparticles of DMF in orodispersible films(DMF051) are 0.6-fold more bioavailable even at very low drug concentration (2 mg/film) in comparison toconventional oral film formulation (DMF023) (30 mg of drug/film). The C max values obtained for DMF023 is19.21 ± 0.46 µ g/ml in comparison to 21.90 ± 0.38 µ g/ml for DMF051 and 1.02 µ g/ml for drug suspension, T maxvalues obtained for DMF023 is 4.00h in comparison to 2.00 h for DMF051, t 1/2 values 3.81 ± 0.03 for DMF023in comparison to 6.59 ± 0.36 for DMF051, AUC 0-t values for DMF023 was 142.02 ± 1.17 µ g/ml*h in comparisonto 231.49 ± 3.49 µ g/ml*h for DMF051 and AUC 0-inf_obs values 153.67 ± 1.27 µ g/ml*h for DMF023 in comparison to 251.21 ± 3.48 µ g/ml*h for DMF051.
To further clarify the advantages and features of the present invention, a more particular description of the invention will be rendered by reference to specific embodiments thereof, which is illustrated in the appended figures. It is appreciated that this figure depicts only typical embodiments of the invention and are therefore not to be considered limiting of its scope. The invention will be described and explained with additional specificity and detail with the accompanying figure.
BRIEF DESCRIPTION OF FIGURES
These and other features, aspects, and advantages of the present invention will become better understood when the following detailed description is read with reference to the accompanying figures in which like characters represent like parts throughout the figures, wherein:
Figure 1, illustrates a view of (A) FTIR images of pure DMF, (B) DMF loaded oral film, (C) placebo oral film and (D) DMF loaded nanoparticles in oral filmfor the present invention.
Figure 2, illustrates a view of XRD overlay image of free DMF, DMF 023 (DMF
loaded oral film) and DMF 051 (DMF loaded nanoparticles in oral film)for the present invention.
Figure 3, illustrates a view of (A) Particles size of DMF loaded chitosan-alginate core-shell-corona nanoparticles, (B) zeta potential of DMF loaded chitosan-alginate core-shell-corona nanoparticles, (C) SEM image of DMF in oral film, and (D) SEM image of chitosan-alginate core-shell-corona nanoparticles of DMF in oral film, respectivelyfor the present invention.
Figure 4, illustrates a view of Cumulative percentage drug release from DMF loaded oral films formulationsfor the present invention.
Figure 5, illustrates a view of Graphical representation of ex-vivo permeation profile for oral film, nanoparticle in oral film and drug substancefor the present invention.
Figure 6, illustrates a view of Plasma drug concentration of DMF loaded DMF023 and DMF051 formulations, after oral delivery of DMF at dose of 30 mg/film and 2 mg/film, respectively (n = 6)for the present invention.
Further, skilled artisans will appreciate that elements in the figures are illustrated for simplicity and may not have been necessarily been drawn to scale. For example, the flowcharts illustrate the method in terms of the most prominent steps involved to help to improve understanding of aspects of the present invention. Furthermore, in terms of the construction of the device, one or more components of the device may have been represented in the figures by conventional symbols, and the figures may show only those specific details that are pertinent to understanding the embodiments of the present invention so as not to obscure the figures with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
DETAILED DESCRIPTION OF THE INVENTION
For the purpose of promoting an understanding of the principles of the invention, reference will now be made to the embodiment illustrated in the figures and specific language will be used to describe the same. It will nevertheless be understood that
no limitation of the scope of the invention is thereby intended, such alterations and further modifications in the illustrated system, and such further applications of the principles of the invention as illustrated therein being contemplated as would normally occur to one skilled in the art to which the invention relates.
It will be understood by those skilled in the art that the foregoing general description and the following detailed description are exemplary and explanatory of the invention and are not intended to be restrictive thereof.
Reference throughout this specification to “an aspect”, “another aspect” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrase “in an embodiment”, “in another embodiment” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.
The terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such process or method. Similarly, one or more devices or systems or elements or structures or components proceeded by "comprises... a" does not, without more constraints, preclude the existence of other devices or other systems or other elements or other structures or other components or additional devices or additional systems or additional elements or additional structures or additional components.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The system, methods, and examples provided herein are illustrative only and not intended to be limiting.
The terms “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items.
The terms “having”, “comprising”, “including”, and variations thereof signify the presence of a component.
Now the present invention will be described below in detail with reference to the following embodiment.
EXAMPLES
Example 1: Preparation of orodispersible film of DMF with different variables
The conventional fast-dissolving orodispersible films of DMF is prepared by solvent-casting method. In brief, aqueous solutions ofmaltodextrin, mannitol and PVA are prepared separately. Maltodextrin (10% w/v) and mannitol (10% w/v) are prepared in distilledwater, separately under stirring at room temperature. PVA (2% w/v)is dissolved in distilled water under stirring and mild heating to 40? C.According to the Table 1, all the three aqueous solutions aretaken in beaker and HPMC (E15) is added to it under the stirring at room temperature. Accurately weighed amount of PEG 600, aspartameand glycerine are added to the mixture under stirring condition. A 3.0g of DMF is dispersed in 10 ml of ethanol and peppermint oil isadded into it. The prepared drug dispersion is added into polymericfilm matrix prepared above, and the mixture is kept under stirring for30 min at room temperature. The prepared mixture is allowed toremain undisturbed for 1h to remove all bubbles and then casted ontoglass plate as films using a micrometre film applicator and dried overnight or at 40 ? C for 12h. The dried film is carefully peeled from glass plate, checked for anyimperfections, and cut according to the size and weight required fortesting (approximately square film: 3.1 cm length, 2.1 cm width). Theprepared film samples are stored in a glass container at 25 ± 2 ? C ofand relative humidity 60 ± 5%.
Example 2:Preparation of chitosan-alginate core-shell-corona shaped nanoparticles of DMF
In brief, the solution of sodium alginate (0.05% w/v) and calcium chloride (18 mM) is prepared using the required quantity in doubledistilled water, separately. The pH of the sodium alginate solution isadjusted to 5.1 using diluted hydrochloric acid solution. An accuratelyweighed amount of chitosan (0.05% w/v) is dissolved in 1% aceticacid solution and pH is adjusted to 5.4 (slightly acidic pH) usingdiluted sodium hydroxide solution. 200 mg of DMF is dissolved in 10ml of dimethylformamide, this solution is added to 9.5 ml of sodiumalginate solution (0.05% w/v) and 0.5 ml calcium chloride mixtureunder stirring condition at drop-wise rate (15 drops per minutes) at1200 rpm using a magnetic stirrer. This colloidal suspension is thenadded to 15 ml of chitosan solution (0.05% w/v) at drop-wise rate undercontinuous stirring at 1200 rpm. The suspension is stirred for anadditional 1 h. The resultant opalescent suspension containing colloidalnanoparticles is kept overnight at room temperature to allow nanoparticles to stabilize and form uniform particle size. The prepared nanosuspension formulation is then added to the polymeric filmsolution containing plasticizer and stabilizer (a mixture of maltodextrin,HPMC E15, PVA, mannitol, aspartame, glycerol and PEG 600) underslow stirring. The formulation is casted onto glass plates as films usinga micrometre film applicator and dried overnight or at 40 ? C for 12 h.The dried film is carefully peeled from glass plate, checked for anyimperfections, and cut according to the size and weight required fortesting (approximately square film: 2.7
cm length and 2.1 cm width).The prepared film samples are wrapped in aluminium foils and storedin glass container.
Example 3: Optimization of DMF loaded orodispersible film
The three independent factors like the two polymers (HPMC E15 and PVA) and plasticizer (PEG 600) concentrations areevaluated at 2 levels. The HPMC E15 is studied at two different concentrations (12 mg/film and 18 mg/film), PVA is studied at 4mg/filmand 8 mg/film, while the plasticizer PEG 600, is studied at 3 mg/filmand 5 mg/film. The experiments are performed based on the trialssuggested by Minitab® software (details mentioned in Table 1) and theeffect on the dependent factors like disintegration time, tensile strengthand pH are observed (Table 2). Film formulation of orodispersible film of chitosan-alginate core-shell-corona shaped nanoparticles of DMF (DMF051) is then prepared using the same optimizedformula and compared with prepared convention orodispersible film.The detail formula for all the formulation trials have been enumerated inTable 1. The evaluation of all critical quality attribute for differentformulation trials have been detailed in Table 2.
Table 2
Example 4: Particle size, polydispersity index and zeta potential measurement
The piece of prepared DMF0023, and DMF051 orodispersible films are dispersed in 5 mL of deionized water followed by sonication for 3min. After that the obtained suspension is analysed for the averageparticle size, polydispersity index and zeta
potential measurement by aphoton correlation spectroscopy. The average particle size of the nanoparticles in DMF051 are found to be 561 ± 53.05 nm. The polydispersity index value of DMF051 is nearer to 0.4 which showed uniform distribution of nanoparticles in theorodispersible film. As obtained result is represented in Table 3 andFig. 5A, the disintegrated film with dispersed nanoparticles of drug inpurified water provided a zeta potential of - 27.2 ± 6.33 mV. It can be concluded that oral soluble films help to stabilize the nanoparticles and prevent aggregation.
Example 5: Drug content determination
The result obtained from drug content analysis have been recorded in Table 2 against standance calibration curve of DMF (Fig. 6A and B), thevalues are within S.D. of mean ± 0.6%, which indicates that oral fastdissolving film formulations as well as nanoparticle in oral film formulations exhibited uniformity of drug content for films cut from differentlocations based on area and weight.
Example 6: In-vitro dissolution study
The DMF051 exhibits an initial 18.39 cumulative percentage drug release at 30 min followed by sustained release of 26.29 ± 0.18% at 1 h,44.76 ± 0.32% at 2 h, 61.21 ± 0.10% at 4 h and 83.57 ± 0.11% at 6 h.While the drug release pattern from DMF07 formulation shows 79.06%and 98.6% of DMF release at 15 min and 30 min, respectively. TheDMF023 formulation released 73.74 ± 0.33% and 91.35% in 15 min and30 min, respectively. The obtained data may be attributed to the unetrapped DMF in the matrix of film while a slower diffusion of drug fromchitosan-alginate nanoparticle, since chitosan-alinate is known as for itsability to sustain the release of
the drug from its nanoparticles, therelease could be observed for more than 6 h (Fig. 7). The analysis of fitis carried out for in-vitro drug release for nanoparticle in oral film toverify the corresponding pharmacokinetic model for drug release from
film [19]. It was observed that the drug release from nanoparticles in the ordodispersible film exhibited a Higuchi model with linear equation asy = 4.2179x-1.1843 with R 2 was found to be 0.983.
Example 7: Stability study
The stability study of the optimized formulations (i.e., DMF023 andDMF051) was carried out at normal room conditions (25 ± 2 ? C temperature and 60 ± 5% relative humidity) and at accelerated conditions(40 ± 2 ? C temperature and 75 ± 5% relative humidity) for a period ofthree months. The films were characterized for any change in appearance, tensile strength, drug content, surface pH and dissolution. Theresults have been tabulated in Table 4. It was observed that there is nosignificant change in assay, tensile strength, dissolution, at the end ofthree months when compared with initial values, i.e., were within ±5%for both type formulations; i.e., DMF023 and DMF051. The obtainedresults of the stability studies indicated that oral films were able toprevent aggregation of nanoparticles as there was no significant changein drug release at all time points. It can be concluded that oral thin filmformulation has a potential for stabilization of nanosuspensions.
Example 8: Ex-vivo permeation studies
It can be observed that the oral films have 10% more permeability than pure drug at 5 min, 20% more permeability than pure drug at 15min and 56% more permeability than pure drug at 30 min (Table 5 andFig. 8) [53–55]. The steady state flux obtained for oral film is0.659/min, steady state flux for DMF051 film was 0.233/min and steadystate flux for pure drug was 0.047/min. Hence it can be concluded thatboth DMF023 and DMF051oral films exhibit enhanced ex vivo permeability in comparison to pure DMFn-vivo pharmacokinetic study of DMF loaded formulations3.13.
Example 9:In-vivo pharmacokinetic study of DMF loaded formulations
The plasma concentration of DMF is plotted versus time as shownin Fig. 9. The key pharmacokinetic parameters were estimated by a non-compartmental fitting model. In Fig. 9 and Table 6, the DMF051group showed higher C max and lower t max than DMF023. The increasedAUC 0–72h suggested the better rate and extent of absorption of DMF fromDMF051 orodispersible film than DMF023 orodispersible film. Thereason is ascertained to the fact that the administration route throughbuccal and tongue avoids the influences of gastrointestinal tract and the first pass metabolism effect of liver. When DMF nanoparticles areencapsulated into OFDF formulation, its AUC 0–72h are much higherthan that of the DMF023 formulation. The obtained data are shownC max of DMF51 (21.90 ± 0.38 µ g/mL) in comparison to DMF023 (19.21± 0.46 µ g/mL). The AUC 0-t values for DMF023 was found to be 142.02± 1.17 µ g/ml*h in comparison to 231.49 ± 3.49 µ g/ml*h for DMF051and AUC 0-8 values 153.67 ± 1.27 µ g/ml*h for DMF023 in comparisonto 251.21 ± 3.48 µ g/ml*h for DMF051, The T max (h) of DMF51 isobserved to be 2 h faster than the T max of DMF023. Therefore, the rate and extent of drug absorption are further enhanced by combination ofdrug nanoparticles and OFDF techniques. It can be further inferred thatthis smart dosage form design provided an advantage of fast dissolutionand absorption, especially for drugs with poor bioavailability due tohigh first pass metabolism like DMF. The in-vivo performance of nanoparticles in film was improved in comparison to in-vitro release performance. This could be
attributed to the huge difference of circumstancefor film disintegration and drug dissolution between in vivo and in vitrostudy. The in vitro release study was performed in simulated saliva at pH6.8 and 500 ml media to ensure the sink condition. However, theamount of saliva during the in vivo study was highly restricted.Besides owing to the nanosize the drug particles have a high surface areafor dissolution, permeation and hence have enhanced absorption and
biodistribution. The pharmacokinetic study revealed that the preapared DMF051 orodispersible film showed significant improvementin Cmax, AUC 0-t , and AUC 0-8 in comparison to prepared DMF023 orodispersible film. DMF051 was 0.6-fold more bioavailable even at verylow concentration (2 mg drug per unit film) in comparison to DMF023(30 mg drug per unit film) (DMF023). This results may attributed due tomucoadhesive properties of chitosan which was used for the preparationof DMF nanoparticles, it may have provided high surface area andresulted to increased contact time with buccal mucosa.
While the invention has been described with respect to specific composition which include presently preferred modes of carrying out the invention, those skilled in the art will appreciate that there are numerous variations and permutations of the above described embodiments that fall within the spirit and scope of the invention. It should be understood that the invention is not limited in its application to the details of construction and arrangements of the components set forth herein.
Variations and modifications of the foregoing are within the scope of the present invention. Accordingly, many variations of these embodiments are envisaged within the scope of the present invention.
The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, and to thereby enable others skilled in the art to best utilize the present invention and various embodiments with
various modifications as are suited to the particular use contemplated. It is understood that various omissions and substitutions of equivalents are contemplated as circumstances may suggest or render expedient, but such omissions and substitutions are intended to cover the application or implementation without departing from the spirit or scope of the present invention.
CLAIMS
We Claim,
1. A fast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF)to improve bioavailability in treatment of multiple sclerosis comprises of;
a. DMF: 0-30 mg/film
b. DMF-NPs: 0-2 mg/film
c. HPMC E-15: 12-18 mg/film
d. PVA (2%w/v): 3-5 mg/film
e. Mannitol (10%w/v): 5 mg/film
f. PEG 600: 4-8 mg/film
g. Glycerol: 3 mg/film
h. Aspartame: 4 mg/film
i. Maltodextrin (10%w/v): 44-78 mg/film
2. The fast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF) as claimed in claim 1, wherein saidfast-dissolving films loaded with biocompatible nanoparticles are Chitosan-alginate core-shell-corona shaped nanoparticles of dimethyl fumarate in orodispersible film to improve bioavailability in treatment ofmultiple sclerosis.
3. The fast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF) as claimed in claim 1,whereinin-vitro drug release profile from chitosan-alginate core-shell-coronashaped nanoparticles in film shows a sustained release with initial 18.39% release in 30 min followed bysustained release up to 6 h in comparison to DMF oral film formulations which released more than 80% drugwithin 15 min.
4. The fast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF) as claimed in claim 1, wherein thenanoparticles of DMF in orodispersible films are 0.6-fold more bioavailable even at very low drug concentration (2 mg/film) in comparison toconventional oral film formulation (30 mg of drug/film).
5. The fast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF) as claimed in claim 1, wherein the C max values is 21.90 ± 0.38 µ g/ml, T max is 2.00 h, t 1/2 values is 6.59 ± 0.36, and AUC 0-t values is 231.49 ± 3.49 µ g/ml*h.
6. AmethodofpreparingtheFast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF) claimedinclaim1,comprisingthesteps of;
(i) Dissolving 200 mg of DMF in 10 ml of dimethylformamide (DMF) to obtain a DMF solution,
(ii) Adding the DMF solution prepared in step 1 to 9.5 ml of sodium alginate solution (0.05% w/v),
(iii) Mixing the solutions under stirring conditions at 1200 rpm using a magnetic stirrer,
(iv) Maintaining a drop-wise addition rate of 15 drops per minute,
(v) adding 0.5 ml of calcium chloride mixture in drop-wise manner to the stirring solution,
(vi) Transferring the colloidal suspension obtained in step 2 to 15 ml of chitosan solution (0.05% w/v),
(vii) Continue stirring the suspension at 1200 rpm while adding drop-wise.
(viii) Stirring the resulting suspension for an additional 1 hour to ensure thorough mixing and stabilization of nanoparticles,
(ix) Allowing the suspension to stand overnight at room temperature to promote the formation of uniform particle size and stabilization of nanoparticles,
(x) Introducing the prepared nanosuspension formulation into the polymeric film solution containing a plasticizer and stabilizer mixture.
(xi) Ensuring slow stirring to achieve homogeneity in the film-forming solution.
(xii) Casting the film-forming solution onto glass plates using a micrometre film applicator,
(xiii) Drying the casted films overnight or at 40°C for 12 hours to remove solvent and solidify the films,
(xiv) peeling the dried film from the glass plate and cut the film into desired sizes and weights suitable for testing, approximately square films measuring 2.7 cm in length and 2.1 cm in width,
(xv) Wrapping the prepared film samples in aluminium foil and stored in a glass container.
Dated,this 10/04/2024 GD Goenka University
Applicant
ABSTRACT
Fast-Dissolving Films Loaded with Biocompatible Nanoparticles of dimethyl fumarate (DMF) for Improved Drug Absorption
The present invention relates to oral film containing biocompatible and biodegradable chitosan-alginate nanoparticles of DMF to improve oral bioavailability in multiple sclerosis treatment. The orodispersible film ofchitosan-alginate core-shell-corona shaped nanoparticles of DMF is prepared by ionotropic pre-gelation ofalginate core followed by chitosan polyelectrolyte complexation, the obtained colloidal nanosuspension isadded to the optimized polymer matrix composition by simple process integration and then cast to films bysolvent casting process. The in-vitro drug release profile from chitosan-alginate core-shell-corona shaped nanoparticles in film evidenced a sustained release with initial 18.39% release in 30 min followed bysustained release up to 6h in comparison to DMF oral film formulations which released more than 80% drugwithin 15 min. The in-vivo result confirmed that nanoparticles of DMF in orodispersible films(DMF051) are 0.6-fold more bioavailable even at very low drug concentration (2 mg/film) in comparison toconventional oral film formulation (DMF023) (30 mg of drug/film). This indicates enhanced bioavailability from this promising dosage form, prompting dose reduction and reduced side effects. , Claims:We Claim,
1. A fast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF)to improve bioavailability in treatment of multiple sclerosis comprises of;
a. DMF: 0-30 mg/film
b. DMF-NPs: 0-2 mg/film
c. HPMC E-15: 12-18 mg/film
d. PVA (2%w/v): 3-5 mg/film
e. Mannitol (10%w/v): 5 mg/film
f. PEG 600: 4-8 mg/film
g. Glycerol: 3 mg/film
h. Aspartame: 4 mg/film
i. Maltodextrin (10%w/v): 44-78 mg/film
2. The fast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF) as claimed in claim 1, wherein saidfast-dissolving films loaded with biocompatible nanoparticles are Chitosan-alginate core-shell-corona shaped nanoparticles of dimethyl fumarate in orodispersible film to improve bioavailability in treatment ofmultiple sclerosis.
3. The fast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF) as claimed in claim 1,whereinin-vitro drug release profile from chitosan-alginate core-shell-coronashaped nanoparticles in film shows a sustained release with initial 18.39% release in 30 min followed bysustained release up to 6 h in comparison to DMF oral film formulations which released more than 80% drugwithin 15 min.
4. The fast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF) as claimed in claim 1, wherein thenanoparticles of DMF in orodispersible films are 0.6-fold more bioavailable even at very low drug concentration (2 mg/film) in comparison toconventional oral film formulation (30 mg of drug/film).
5. The fast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF) as claimed in claim 1, wherein the C max values is 21.90 ± 0.38 µ g/ml, T max is 2.00 h, t 1/2 values is 6.59 ± 0.36, and AUC 0-t values is 231.49 ± 3.49 µ g/ml*h.
6. AmethodofpreparingtheFast-dissolving films loaded with biocompatible nanoparticles of dimethyl fumarate (DMF) claimedinclaim1,comprisingthesteps of;
(i) Dissolving 200 mg of DMF in 10 ml of dimethylformamide (DMF) to obtain a DMF solution,
(ii) Adding the DMF solution prepared in step 1 to 9.5 ml of sodium alginate solution (0.05% w/v),
(iii) Mixing the solutions under stirring conditions at 1200 rpm using a magnetic stirrer,
(iv) Maintaining a drop-wise addition rate of 15 drops per minute,
(v) adding 0.5 ml of calcium chloride mixture in drop-wise manner to the stirring solution,
(vi) Transferring the colloidal suspension obtained in step 2 to 15 ml of chitosan solution (0.05% w/v),
(vii) Continue stirring the suspension at 1200 rpm while adding drop-wise.
(viii) Stirring the resulting suspension for an additional 1 hour to ensure thorough mixing and stabilization of nanoparticles,
(ix) Allowing the suspension to stand overnight at room temperature to promote the formation of uniform particle size and stabilization of nanoparticles,
(x) Introducing the prepared nanosuspension formulation into the polymeric film solution containing a plasticizer and stabilizer mixture.
(xi) Ensuring slow stirring to achieve homogeneity in the film-forming solution.
(xii) Casting the film-forming solution onto glass plates using a micrometre film applicator,
(xiii) Drying the casted films overnight or at 40°C for 12 hours to remove solvent and solidify the films,
(xiv) peeling the dried film from the glass plate and cut the film into desired sizes and weights suitable for testing, approximately square films measuring 2.7 cm in length and 2.1 cm in width,
(xv) Wrapping the prepared film samples in aluminium foil and stored in a glass container.