COMPOSITION OF SUSPOEMULSION FORMULATION OF ANTHELMINTIC DRUGS WITH ESSENTIAL OILS FOR NASO-PULMONARY ADMINISTRATION

Abstract

A suspo-emulsion dosage form of anthelmintic drug such as Ivermectin or niclosamide with essential oils was proposed to be used for administration to the nasal cavity and lungs. The suspo-emulsion formulation is to be administered using a suitable medical device. The composition may be used to treat or prevent viral infections such as Covid-19.

Claims

1. A composition of a suspo-emulsion dosage form for naso-pulmonary administration, comprising: (i) therapeutically effective or prophylactic amount of at least one anthelmintic drug; (ii) therapeutically effective or prophylactic amount of at least one essential oil; (iii) at least one surfactant and (iv) pharmaceutically acceptable excipients; wherein the D90 value of the suspended particles and emulsified globules is less than or equal to 25 microns; wherein at least one anthelmintic drug is ivermectin.

2. A composition of a suspo-emulsion dosage form for naso-pulmonary administration according to claim 1, wherein the anthelmintic compound is selected from the group consisting of ivermectin, albendazole, mebendazole, thiabendazole, fenbendazole, benzimidazole, praziquantel, triclabendazole, flubendazole, abamectin, salicylanilide, nitazoxanide, niclosamide, octadepsipeptides, monepantel, spiroindoles, oxamniquine, piperazine, morantel, pyrantel, levamisole, and tribendimidine.

3. A composition of a suspo-emulsion dosage form for naso-pulmonary administration according to claim 1, wherein the essential oil is selected from the group consisting of tea tree oil, eucalyptus oil, lemongrass oil, cinnamon oil, oils from grapefruit, orange, tangerine, mandarine, lemon, pine, peppermint, lavender, clove, thyme, and oregano.

4. A composition of a suspo-emulsion dosage form for naso-pulmonary administration according to claim 1, wherein the surfactant is of anionic, cationic, non-ionic nature and a mixture thereof.

5. A composition of a suspo-emulsion dosage form for naso-pulmonary administration, comprising: (i) therapeutically effective amounts or prophylactic amounts of at least one anthelmintic drug; (ii) therapeutically effective or prophylactic amount of at least one essential oil; (iii) at least one surfactant and (iv) pharmaceutically acceptable excipients; wherein the D90 value of the suspended particles and emulsified globules is less than or equal to 25 microns; wherein at least one anthelmintic drug is niclosamide.

6. A composition of a suspo-emulsion dosage form for naso-pulmonary administration according to claim 5, wherein the anthelmintic compounds are selected from the group consisting of ivermectin, albendazole, mebendazole, thiabendazole, fenbendazole, benzimidazole, praziquantel, triclabendazole, flubendazole, abamectin, salicylanilide, nitazoxanide, niclosamide, octadepsipeptides, monepantel, spiroindoles, oxamniquine, piperazine, morantel, pyrantel, levamisole, and tribendimidine.

7. A composition of a suspo-emulsion dosage form for naso-pulmonary administration according to claim 5, wherein the essential oil is selected from the group consisting of tea tree oil, eucalyptus oil, lemongrass oil, cinnamon oil, oil from grapefruit, orange, tangerine, mandarine, lemon, pine, peppermint, lavender, clove, thyme, and oregano.

8. A composition of a suspo-emulsion dosage form for naso-pulmonary administration according to claim 5, wherein the surfactant is of anionic, cationic, non-ionic nature and a mixture thereof.

9. A composition of a suspo-emulsion dosage form for naso-pulmonary administration, comprising: (i) therapeutically effective amounts or prophylactic amounts of at least anthelmintic drug; (ii) therapeutically effective or prophylactic amounts of at least two essential oils; (iii) at least one surfactant and (iv) pharmaceutically acceptable excipients; wherein the D90 value of the suspended particles and emulsified globules is less than or equal to 25 microns.

10. A composition of a suspo-emulsion dosage form for naso-pulmonary administration according to claim 9, wherein the anthelmintic compound is selected from the group consisting of ivermectin, albendazole, mebendazole, thiabendazole, fenbendazole, benzimidazole, praziquantel, triclabendazole, flubendazole, abamectin, salicylanilide, nitazoxanide, niclosamide, octadepsipeptides, monepantel, spiroindoles, oxamniquine, piperazine, morantel, pyrantel, levamisole, and tribendimidine.

11. A composition of a suspo-emulsion dosage form for naso-pulmonary administration according to claim 9, wherein the essential oils are selected from the group consisting of tea tree oil, eucalyptus oil, lemongrass oil, cinnamon oil, oil from grapefruit, orange, tangerine, mandarine, lemon, pine, peppermint, lavender, clove, thyme, and oregano.

12. A composition of a suspo-emulsion dosage form for naso-pulmonary administration according to claim 9, wherein the surfactant is of anionic, cationic, non-ionic nature and a mixture thereof.

Description

DETAILED DESCRIPTION

Definition of Terms Used

[0031] A drug is “a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being. Medicament is a medicine, or a substance used in a therapy.

[0032] A “medicinal agent” is a pharmaceutical agent that includes drugs, biological products, and medical devices under the regulatory authority of the Food and Drug Administration (FDA). A “medicinal agent” shows pharmacological activity in human subjects and can be “allopathic drug molecules” or “natural drug products”.

[0033] Anthelmintic is the term used in this patent describes drugs used to treat infections of animals with parasitic worms. This includes both flat worms, e.g., flukes (trematodes) and tapeworms (cestodes) as well as round worms (nematodes).

[0034] “Nasal delivery” is the is a route of administration in which drugs are insufflated or inhaled through the nose. Nasal delivery of drugs circumvents gastrointestinal degradation and hepatic first-pass metabolism of drugs. Nasal delivery can be used to deliver drugs locally or for systemic applications.

[0035] “Pulmonary delivery” is a non-invasive means to deliver drugs into nose, nasal cavity and in lungs. In this patent, we used the term “Naso-pulmonary delivery” to indicate delivery to the nasal area and lungs.

[0036] “Dosage Form” is the physical form of a dose of a chemical compound used as a drug or medication intended for administration or consumption. A “compound” is a drug substance with intended medicinal action.

[0037] “Formulation” is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product or a dosage form.

[0038] A “Suspo-emulsion” is a formulation in which oil droplets and particles of a water-insoluble drug are dispersed and suspended together in water. A drug or an active may be dissolved in an inert oil, which is then emulsified in the system. If the drug is an oily form, it can be directly emulsified in the system or it can be diluted in an inert oil before emulsification. There is a need that these ingredients are stable when dispersed together in water not only immediately after production, but also after storage under suitable conditions. The solid particles to be suspended can be of a drug substance or of a combination of drugs. Even though, active molecules are suspended in the dosage form, a small portion of drug molecules can be in a molecularly dissolved state and can be considered as a solution. Thus, the active water-insoluble drug molecules are mostly in a suspended state, and a small portion in a dissolved state and oily components are in the emulsified state. This patent does not specify and claim the quantification of drugs in the dissolved, suspended or in emulsified state.

[0039] “Novel Formulation” means any new formulation, which is different than the existing formulation.

[0040] A “humectant” is a substance, which retains moisture in the formulation or keep thing moist. Humectants are found in moisturizers. Humectants are used in some of the formulation and are selected from the group consisting of sorbitol, propylene glycol, polyethylene glycol, glycerin and mixtures thereof.

[0041] We examined the effect of medium chain triglycerides on the evaporation rates of essential oils. A mixture of cinnamon oil, tea tree oil and lemon grass oil (210.1 mg, 175.5 mg and 178.6 mg, respectively) was prepared. About 25 to 30 mg of the mixture was weighed in 10 empty vials to which different amounts of medium chain triglyceride (MCT) were added (0 to 350% of the weight of mixture of essential oils). The samples were weighed over 5 days at intermittent intervals. The weight-loss values were determined. After 9.1 hrs, the weight loss values for the sample without MCT and for the samples with 349% MCT were 8.4% and 1.8%, respectively. There was a qualitative correlation between the weight-loss values and the percent MCT added to each sample throughout the experiment. Overall, it became evident that MCT reduced the evaporation rate of the mixture of essential oil used.

Examples of Various Formulations

[0042] With the following examples, one skilled in the art, can understand and use the present invention. In general, all the formulation contained one or two anthelmintic compounds, a mixture of EOs, medium chain triglyceride, a humectant, surfactants and water.

[0043] Composition 1—It contained Albendazole as the active anthelmintic drug. The formulation contained very small percentage of oils. Thus, the water-insoluble active. Albendazole, may have some solubility in oils. But the amount of albendazole dissolved in the oil phase can be considered as insignificant.

TABLE-US-00001 TABLE 1 Composition for 100 g naso-suspension formulation Ingredient Amount, w/w Albendazole  5.0% Tea tree oil 0.01% Cinnamon oil 0.01% Lemongrass oil 0.01% Sorbitol   1% Medium chain triglyceride  0.5% Tween 80 0.25% Span 80  0.1% Water 93.12% 

[0044] The preceding formulation is prepared by mixing the various constituents and stirring. The formulation was homogenized with Polytron 3000 to form a pre-emulsion. Then formulation was then passed through a microfluidizer. A microfluidizer from Microfluidics (Model 110P) was used in these experiments. Particle size distribution (PSD) values were determined after completion of predetermined number of passes. Normally, PSD was determined after 1 to 2 passes. PSD values were determined using Malvern 2000.

[0045] Composition 2—It contained Niclosamide as the active anthelmintic drug. The percent of niclosamide can be altered once more in vivo studies are performed.

TABLE-US-00002 TABLE 2 Composition for 100 g suspo-emulsion formulation containing niclosamide. Ingredient Amount, w/w Niclosamide 10.0% Peppermint oil 0.05% Grapefruit oil 0.05% Eucaplyptus oil 0.05% Propylene glycol  1.5% Medium chain triglyceride  0.8% Tween 80   1% Span 80  0.1% Water 86.45% 

[0046] The procedure to prepare compositions 2 and 3 is similar, which involved dissolution of essential oils in medium chain triglyceride, emulsification followed by an addition of solid water-insoluble drug to form a suspo-emulsion.

[0047] Composition 3—It contained Ivermectin as the active anthelmintic drug and three different essential oil dissolved in MCT.

TABLE-US-00003 TABLE 3 Composition for 100 g suspo-emulsion formulation containing ivermectin. Ingredient Amount, w/w Ivermectin 1.0% Pine oil 0.05% Thyme oil 0.05% Oregano oil 0.05% Propylene glycol 1.5% Medium chain triglyceride 0.8% Tween 80 0.5% Span 80 0.3% Water 95.75%

[0048] Composition 4—This formulation contained two anthelmintic actives—mebendazole and ivermectin along with three essential oils.

TABLE-US-00004 TABLE 4 Composition for 100 g suspo-emulsion formulation containing a combination of anthelmintic drugs - mebendazole and ivermectin. Ingredient Amount, w/w Mebendazole 2.5% Ivermectin 1.0% Eucalyptus oil 0.05% Peppermint oil 0.05% Pine oil 0.05% Propylene glycol 1.5% Medium chain triglyceride 1.0% Tween 80 0.5% Span 80 0.3% Water 93.05%

[0049] Composition 5—This formulation contained two anthelmintic actives—niclosamide and ivermectin along with three essential oils.

TABLE-US-00005 TABLE 5 Composition for 100 g suspo-emulsion formulation containing a combination of anthelmintic drugs. Ingredient Amount, w/w Niclosamide  10% Ivermectin 0.5% Peppermint oil 0.05%  Eucalyptus oil 0.05%  Cinnamon oil 0.05%  Propylene glycol 1.5% Medium chain triglyceride 1.0% Tween 80 0.5% Span 80 0.3% Water 86.05% 

[0050] Particle Size Distribution in Suspo-Emulsion Formulation

[0051] In the case of naso-pulmonary drug delivery for systemic absorption, aerosols with small particle size are required to ensure penetration of drug. Particles <3 μm have an approximately 80% chance of reaching the lower airways with 50-60% being deposited in the alveoli. Two batches of drug along with essential oils were prepared. Both the batches were first homogenized and then passed through a microfluidizer. Table 5 lists the particle size distribution (PSD) achieved for a representative suspo-emulsion formulation of ivermectin with essential oils. The particle size distribution is a combination of PSD for the suspended particles and PSD for the oil globules for the emulsion.

TABLE-US-00006 TABLE 6 Particle Size Distribution for a Suspo-emulsion formulation. The particle size values are in microns. Weighted D (0.1) D (0.5) D (0.9) D (1.0) D [3, 2] D [4, 3] Residual Initial 0.112 0.568 2.104 20.000 0.277 0.952 3.521 After 3 passes 0.068 0.144 0.543 7.962 0.125 0.280 2.028 After 5 passes 0.066 0.135 0.409 7.962 0.117 0.252 1.733

[0052] Prior to microfluidization, a primary emulsion was formed using Polytron 3000 homogenizer. The D90 values were 2.1 microns. After microfluidization, the D10, D50 and D90 values found to be 66 nm, 135 nm and 409 nm, respectively. These PSD values were satisfactory. No settling of suspended particle forming a cake or breaking of the emulsion were observed. The suspo-emulsion of Ivermectin with essential oils were satisfactory.

[0053] Theoretically, in nanosuspensions or in nanoemulsions, one expects the D90 value (90% units are below this value) of particles or globules to be less than 200 nm. Some references define nanosuspension or nanoemulsion dosage forms as those with D90 value of 1 micron or less. Some references define microsuspension or microemulsion dosage forms as those with D90 value of 25 micron or less. In this patent, we have not defined our system as a nanosuspo-emulsion or microsuspo-emulsion. But our intend is to prepare either nanosuspo-emulsion or microsuspo-emulsion dosage forms. The product will be sprayed in the naso-pulmonary cavity and it is important to achieve lower particle size distribution for two reasons. The dissolution rate of the suspended drug is significantly higher for micro- and nano-particles as the surface area for dissolution increases with a reduction in the particle size. Secondly, the particle size affect the reach of particles in the respiratory system. We observed that we could easily produce nanosuspo-emulsion or microsuspo-emulsion products. For convenience, we termed our system as a suspo-emulsion dosage form.

[0054] Concluding Remarks

[0055] In this patent, we prepared a suspo-emulsion dosage form for naso-pulmonary delivery of drugs. We used a combination of an allopathic drug(s) a and natural products. A suspo-emulsion dosage form of anthelmintic drug(s) such as Ivermectin with essential oils was prepared. The particle size was reduced using a microfluidizer and a D90 value of less than 1 micron was observed. We want to claim the D90 value of less than 23 microns for the formulations. The dosage form is proposed to be used for administration to the nasal cavity and lungs (naso-pulmonary administration). Essential oils can reach up to sinuses where the viruses tend to reside during the first couple of days after invasion into the nasal cavity. The intention of this dosage form is to achieve therapeutically or pharmacologically effective levels or prophylactic levels of actives locally in the naso-pulmonary regions. Any formulation scientist skilled in the art will be able to develop these formulations.

[0056] The description of formulations and concept in the present invention has been presented for purposes of illustration, but it is not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations may become apparent to those of ordinary skill in the art without departing from the scope and spirit of the invention. The description in the patent explains the principles of the invention and the practical applications, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated.

REFERENCES

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