Pharmaceutical composition for mucosal administration, methods of manufacture and use thereof

Abstract

A pharmaceutical composition for mucosal administration is provided. It comprises microparticles comprising carboxyalkyl starch and one or more active pharmaceutical ingredients (API), wherein the carboxyalkyl starch is either uncrosslinked and having a degree of substitution with carboxyalkyl groups of less than about 0.25, or crosslinked and having crosslinking degree of at least about 25, wherein the carboxyalkyl starch adopts a V-type helix secondary structure defining an internal cavity within said helix, and wherein the molecules of the one or more active pharmaceutical ingredients are at least partially contained within said internal cavity of the carboxyalkyl starch. Methods of manufacture and use are also provided.

Description

PHARMACEUTICAL COMPOSITION FOR MUCOSAL ADMINISTRATION, METHODS OF MANUFACTURE AND USE THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit, under 35 U.S.C. § 119(e), of U.S. provisional application Serial No. 63 / 664,215, filed on June 26, 2024, and U.S. provisional application Serial No. 63 / 806,324, filed on May 14, 2025. All documents above are incorporated herein in their entirety by reference.FIELD OF THE INVENTION

[0002] The present invention relates to a pharmaceutical composition for mucosal administration. More specifically, the present invention is concerned with such a pharmaceutical composition that can be administered nasally, buccally, or vaginally.BACKGROUND OF THE INVENTIONOn Coronavirus Disease 19

[0003] Coronavirus disease 19 (COVID-19), caused by the highly transmissible and pathogenic SARS-CoV-2 virus, has led to a global pandemia. The recent severe acute respiratory syndrome known as the SARS-CoV-2 coronavirus (CoV-2) pandemia caused more than 600 million infected people worldwide, and more than 6 million deaths reported by the World Health Organization (WHO) (Tulimilli et al., 2022). With COVID-19 infections still frequent in 2024 in various regions, there is a continuous interest for fast and easy to apply antimicrobial materials to prevent contamination with respiratory viruses (with respiratory droplets as major route of dissemination). (Chen et al, 2021). While various vaccines have been developed, drugs against SARS-CoV-2 have been primarily focused on repurposing existing anti vi rals / anti m icrobi als. In addition, formulations with iodine such as povidone-iodine (PVP-I) were shown to be effective in inactivating SARS-CoV-2 virus.

[0004] Since its initial identification in late 2019, the causative agent of COVID-19, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Acter et al., 2020), has led to intensive research seeking to understand its properties, epidemiology, and pathogenic characteristics. SARS-CoV-2 and its variants have rapidly spread worldwide and there are no currently predefined standard treatments (Lother et al., 2020). Nonpharmaceutical measures have thus been promoted to prevent viral spread with different levels of success (Ayouni et al., 2021 ; Bohloli et al., 2023). For example, essential oils have been proposed as virucidal agents against SARS- CoV-2 (Elsebai et Albalawi, 2022; Wani et al., 2021).

[0005] SARS-CoV-2 is highly transmissible and infected individuals can be contagious days before and after the acute clinical phase of the disease (Mahyuddin et al., 2020). During infection, viral loads are elevated in the nasal cavity, nasopharynx, and oropharynx (Zou et al., 2020). Coronaviruses have a triple tropism within the body:respiratory, enteric, and neurological, which leads to variation in their clinical expression according to the dominant tropism in the host, reflected by respiratory, enteric, and / or demyelinating infections and symptoms (Barrantes, 2021; Vabret et Miszczak, 2010). The nasal cavity and the cells of the respiratory epithelium have the highest expression of ACE2 (angiotensin-converting enzyme) receptor, as the main receptor for the spike protein of SARS-CoV-2 (Sungnak et al., 2020). Viral shedding can thereby be detected with nasal swabs before, during, and after the onset of acute symptomatic illness, including convalescent individuals converted to seropositive (Wei et al., 2020). Numerous reports have demonstrated that in addition to the nasal cavity, the nasopharynx, and the oropharynx are important transmission routes (Chavda et al., 2023; Hoffmann, 2023).

[0006] In infected subjects, the virus is detected in saliva, nasal secretions, blood, and urine (Kampf et al., 2020; Meyerowitz et al., 2021). Thus, oral and nasopharyngeal decontamination, among other measures, can be of major relevance to prevent virus spreading. Exposure to aerosol and aerosol-generating devices can promote transmission through the nasopharyngeal airway, by the release of aerosol -associated viruses that can persist for several hours on surfaces (Al-Omiri et al., 2021 ; Krajewska et al., 2020). Indeed, SARS-CoV-2 can survive for hours or even days, for example on clothing and surfaces. Since infectious viruses can be transmitted from asymptomatic subclinical carriers, symptomatic infected carriers, and convalescent patients, there is a growing need to develop new and easy to apply approaches to reduce transmission of the virus. Standard precautions, including donning masks and gloves, may not be sufficient. Early experiences with COVID-19 outbreaks in hospitals and health care facilities have shown the added value of nasal / oral cavity disinfection. Recent studies have investigated the impact of iodine-based compounds for disinfection as part of a transmission reduction plan. Guidelines from the American Dental Association recommended the use of mouthwash with povidone-iodine PVP: I (also known as PVI) before any dental procedures, in order to minimize the risk of COVID-19 transmission (Tessema et al., 2020).

[0007] Various vaccines have been developed in the last 3 years from different technologies, such as Pfizer- BioNTech and Moderna (mRNA-based), Oxford-AstraZeneca (Ch AdOx 1 adenoviral vector), Sinovac and Bharat Biotech (inactivated virus) (Zimmer, 2021). However, developments in the field of antiviral drugs against SARS-CoV- 2 has been focused on repurposing of existing approved antiviral / antibacterial agents (Zhang et al., 2022).

[0008] Recent studies showed that chlorpromazine inhibits viral replication of coronaviruses in vitro (Plaze et al., 2020). Chloroquine phosphate, an older drug used primarily for the treatment of malaria, has shown efficacy against COVID-19-associated pneumonia in a few clinical trials (Silva Borba et al., 2020; Zhang, X.-l. et al., 2020). Remdesivir (RDV) exhibits a broad-spectrum antiviral activity against RNA viruses (Hendaus, 2021), and previous studies on Ebola virus (EBOV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have proven that RdRp (RNA-dependent RNA replicase) incorporates the triphosphate form of RDV into RNA, which stops the RNA synthesis (Hendaus, 2021). Furthermore, Paxlovid drug for SARS-CoV-2 marketed by Pfizer to be administered orally (Wen et al., 2022) blocks the activity of the SARS-CoV-2 3C-like protease necessary for the replication of the coronavirus (Amani et Amani, 2023).

[0009] As SARS-CoV-2 transmission occurs through contaminated surfaces, droplets and aerosol, improved antiseptic measures at sites of viral contamination (entry and replication) in humans has been identified as a key goalin reducing infections. Nasal and oral antiseptic formulations of povidone-iodine PVP-I at a concentration of 1 % to 5 % have been shown to be effective in inactivating SARS-CoV-2 after 60 seconds of exposure (Pelletier et al., 2021). In a previous study, the iodine complex Renessans inactivated SARS-CoV-2 with an EC50 value of 0.425 pg / mL and 0.505 pg / mL in syrup and capsule formulations, respectively (Altaf et al., 2021). Similar studies indicated that PVP-l-based handwashes, and PVP-I gargle / mouthwashes reduced viral load of Modified Vaccinia Ankara and MERS-CoV in the oral cavity and oropharynx by a factor of 4 log in different conditions, within one minute of application of each undiluted PVP-I product (Eggers, M. et al., 2015). In addition, iodine has also shown its virucidal potential against other enveloped and non-enveloped viruses (Edington et al., 2020).On Vaginal Infections

[0010] Postmenopausal women often complain of vaginal infections as well as genital and sexual symptoms, and climacteric syndromes such as hot flashes, insomnia, depression. Bacterial vaginosis (BV) and complicated vulvovaginal candidiasis (WC) are common postmenopausal vaginal infections (Vieira-Baptista et Bornstein, 2019) These vaginal infections can range from superficial skin infections to life-threatening infections, hence the need for prompt diagnosis and treatment. If not treated promptly, in the worst cases, they can cause pelvic inflammation, endometriosis, chronic vaginitis, and infertility.

[0011] Candida albicans (C. albicans) is the most important pathogen contributing to the development of vulvovaginal candidiasis (VVC) (Gongalves et al., 2016). Four or more VVC infections in a year are defined as recurrent vulvovaginal fungus (Blostein et al., 2017). Recurrent VVC (RVVC) is a chronic, widespread mucosal infection, often drug-resistant, that has a huge negative impact on patients' quality of life and work (Sobel, 2016) Each year, RWC has a serious impact on the reproductive health of approximately 138 million women worldwide (Nsenga et Bongomin, 2022). The Infectious Diseases Society of America guidelines recommend that patients with RVVC take fluconazole orally for at least six months (Phillips et al., 2022). However, under current drug treatment, the disease has a high recurrence rate of more than 60% (Foxman et al., 2013). The difficulty in treating RWC stems from the formation of antifungal-resistant biofilms; Thus, a new generation of antifungal drugs is urgently needed (McKloud, 2021). The eukaryotic characteristics of fungal cells and the dual permeability of the fungal cell wall and membrane significantly hinder the development of new antifungal drugs.

[0012] Escherichia Coli is one of the most common organisms in the genital tract of non-pregnant women (9 to 28%) and pregnant women (24 to 31%) (Saez-Lopez et al., 2016). Vaginal strains of E. coli (VEC) are considered a reservoir of vaginal and / or endocervical colonization in pregnant women, and an important step in the development of urinary tract, intra-amniotic and puerperal infections by "fecal-vaginal-urinary / neonatal" transmission. Histologically, subclinically or clinically diagnosed chorioamnionitis is an obstetric infection caused primarily by ascending microorganisms in the vagina that can lead to maternal or fetai complications, including postpartum endometritis, bacteremia, or sepsis (Casey et Cox, 1997). E. coli is considered to be normally involved in these infections. The most common antibiotic treatment in case of infection is ampicillin combined with an aminoglycoside, normally gentamicin are prescribed (Bergeron et Marois, 1986). Nevertheless, an increase in treatment failure wasobserved due to the high percentage of ampicillin resistance found among E. coli strains (Erb et al., 2007).On Iodine

[0013] In humans, iodine is an important element with antioxidant and antiproliferative characteristics, which helps maintain normal tissue physiology (Winkler, 2015). Iodine also has broad-spectrum bactericidal activity and causes DNA denaturation and oxidative stress (Krishnamoorthy et al., 2022). In fact, iodine has multimodal activities against pathogens, which include the oxidation of vital constituents, such as amino acids, nucleotides, and membrane components (Bigliardi et al., 2017).

[0014] Scanning Electron Microscopy and biochemical observations support the conclusion that iodine interacts with the cell wall of microorganisms, causing the formation of pores or generating solid-liquid interfaces at the lipid membrane, resulting in loss of cytosol material, in addition to enzymatic denaturation (Schreier et al., 1997).

[0015] For many decades, solutions of iodine have been used as dyes for identification of starch and of cellulosic fibers (Moulay, 2013). Several different formulations of iodine have been used, but they mostly rely on differential staining of cell wall polysaccharides for their function.

[0016] Topical and oral povidone-iodine (PVP-I) products have shown virucidal activity against SARS-CoV-2 (Eggers, 2019). PVP-I was found to disrupt microbial cell walls by inducing pore formation, resulting in cytosol leakage. It was also found that PVP: I treatment can inhibit human and avian influenza A virus infections of MDCK (Madin-Darby canine kidney) cells by 23-98% (Eggers, 2019). In fact, PVP-I preparations are well known to be effective against several bacteria, fungi and protozoa due to the antimicrobial properties of iodine (molecular l2). They have also been found to be effective against both enveloped and non-enveloped viruses.

[0017] A previous report has indicated that PVP-I can also functionally inhibit viral hemagglutinin (the most important antigen of influenza A virus), resulting in the loss of viral binding to host cell receptors (Bhowmik Aneek Das, 2023). By simultaneously targeting the critical aspects of the viral machinery required for replication, including essential viral enzymes, such as neuraminidase and the inhibition of vital protein function, PVP-I reduces the likelihood of the emergence of resistance through mutations, as in the case of the influenza virus (Eggers, 2019).

[0018] Previous results have also confirmed the use of iodopovidones to prevent the development of C. albicans biofilm (Cuellar-Rufino et al., 2022). The antibacterial activity of iodopovidones appears to be mediated by an oxidative influence on fatty acids and amino acids of the bacterial cell membrane, as well as cytosolic enzymes involved in the respiratory chain, causing the denaturation of biomolecules and the loss of cellular function (Cuellar- Rufino et al., 2022; Stawarz-Janeczek et al., 2021).

[0019] Currently, PVP: I solutions are used in microbiology due to their potential antibacterial activity. However, inhalation of low concentrations of N-vinyl-2-pyrrolidone has been reported to cause inflammation of the nasal cavity, atrophy of the olfactory epithelium, and hyperplasia of the respiratory basal cells, just as N-Vinyl-2-pyrrol idone, which is an irritant to the skin and mucous membranes, causes hepatotoxicity in rats and mice (Hartwig et Commission, 2002). In humans and laboratory animals, polyvinylpyrrolidone accumulates in the vacuoles of cells of various organsand is associated with pulmonary fibrosis and pneumonia (Cuellar-Rufino et al., 2022).On Starch

[0020] Starch is a biopolymer presenting non branched (amylose) and branched chains (amylopectin), the latter consisting of glucose mostly bound by a-(1-4) glycosidic links (Robyt, 1984). It may adopt B-type double helices and V-type single helix (Gibson et al., 1997; Moran Jr, 2021) coexisting with amorphous regions. Single helices may retain molecules in their central cavity (Cheetham et Tao, 1998; Daniels et Donald, 2004) forming “inclusion complexes” also known as “clathrates” such as the complexes with iodine which are largely used in analytical, health and domestic consumer products and devices (Crini, 2014).

[0021] Native starch is crystalline and insoluble at room temperature. For its use in the pharmaceutical field, some physical (gelatinization) and chemical (cross-linking, carboxymethylation) modifications are necessary to afford new properties and to obtain a matrix able to better retain molecules such as iodine with therapeutic or disinfecting effects (Radeloff et Beck, 2012; Singh et al., 2007). Starch materials are generally recognized as safe (GRAS) and products containing starch are nontoxic, biocompatible, quite stable and slowly biodegradable in the biological environment (Gill et al., 1998). Carboxymethyl-Starch (CMS) tablets and CMS microspheres have been previously investigated in different drug delivery applications (Mulhbacher et al, 2005; Calinescu et Mateescu, 2005; Lemieux et al., 2015;M alafay a et al., 2006).

[0022] Carboxymethylated starch was found to exhibit an enlarged V-type helix structure (due to hydration of the polar carboxyl functions) with a hydrophobic cavity capable of retaining iodine (Mateescu et al., 2014). It was also found to exhibit mucoadhesive properties (Juliano et al., 2004; Mulhbacher et al, 2006; Lemieux et al., 2015).

[0023] It was also previously found that cross-linked starch, even chemically modified, was still a substrate for alpha-amylase (Dumoulin et al., 1999; Mateescu et al., 1985).On Mucoadhesion

[0024] The Mucoadhesion or the formation of weak physical bonds between the polymer and tissues could be ensured by ionic, Van der Waals and / or hydrogen bonds. These physical interactions, weak when alone, when assembled, will produce a strong adhesion through many interaction sites.

[0025] The on-site release of a virucide combined with its mucoadhesion, is a major advantage because it may exert the virucidal effect against respiratory viruses locally, whereas other antiinfective agents may be dissipated through esophagus.SUMMARY OF THE INVENTION

[0026] In accordance with the present invention, there is provided:1. A pharmaceutical composition for mucosal administration comprising microparticles, said microparticles comprising carboxyalkyl starch and one or more active pharmaceutical ingredients (API),wherein the carboxyalkyl starch is either: uncrosslinked and having a degree of substitution with carboxyalkyl groups of less than about 0.25, or crosslinked and having crosslinking degree of at least about 25, wherein the carboxyalkyl starch adopts a V-type helix secondary structure defining an internal cavity within said helix, and wherein the molecules of the one or more active pharmaceutical ingredients are at least partially contained within said internal cavity of the carboxyalkyl starch. The pharmaceutical composition of embodiment 1 , wherein the mucosal administration is oropharyngeal, nasal, buccal, intraesophageal, or vaginal administration, preferably oropharyngeal, nasal, or buccal administration. The pharmaceutical composition of embodiment 1 or 2, further comprising one or more pharmaceutically acceptable excipients. The pharmaceutical composition of any one of embodiments 1 to 3, being formulated as an oral or nasal spray. The pharmaceutical composition of any one of embodiments 1 to 4, being in powder form, semi-liquid form, or in liquid form. The pharmaceutical composition of embodiment 5, being in powder form. The pharmaceutical composition of embodiment 5, being in semi-liquid form or in liquid form. The pharmaceutical composition of embodiment 7, wherein the microparticles are suspended in a semi-liquid or liquid pharmaceutically acceptable excipient. The pharmaceutical composition of embodiment 7 or 8, being an ointment, a cream, a gel, a paste, a foam, a solution, a suspension, an emulsion, a syrup, an elixir, or a nasal or oral liquid spray. The pharmaceutical composition of any one of embodiments 1 to 9, wherein the one or more active pharmaceutical ingredients is one or more of: an anti-infective including amebicides, aminoglycosides, anthelmintics, antiviral agents (including adamantane antivirals such as amantadine and rimantadine, antiviral boosters such as ritonavir and cobicistat, antiviral combinations, antiviral interferons, antiviral monoclonal antibodies, and virucidal agents blocking the viral replication), antifungals (including azole antifungals, echinocandins,polyenes, and other antifungals), antibacterial agents (including sulfonamides, tetracyclines, and other antibiotics); a genitourinary tract agent; a topical agent including mouth and throat products, nasal preparations (including nasal antihistamines and decongestants; or an alternative medicine (including herbal products, and probiotics).11 . The pharmaceutical composition of embodiment 10, wherein the one or more active pharmaceutical ingredients is an anti-infective.12. The pharmaceutical composition of embodiment 11, wherein the anti-infective is an antiviral agent, preferably one or more of an adamantane antiviral, such as amantadine, and rimantadine, an antiviral booster, such as ritonavir and cobicistat, an antiviral combination, iodine, or a virucidal agent blocking the viral replication.13. The pharmaceutical composition of embodiment 11, wherein the anti-infective is an antifungal agent, preferably one or more of an azole antifungal, an echinocandin, such as nystatin, amphotericin b, amphotericin b liposomal, and amphotericin b lipid complex, an aminosalicylate or an aminosalicylic acid, or a nicotinic acid derivative.14. The pharmaceutical composition of embodiment 11 , wherein the anti-infective is a sulfonamide, such as sulfamethoxazole / trimethoprim, and sulfadiazine.15. The pharmaceutical composition of embodiment 11 , wherein the anti-infective is a vaginal anti-infective agent for treating a bacterial or fungal vaginal infection; preferably a vaginal antifungal (such as for treating vaginal thrush), or a vaginal antibacterial for treating a bacterial infection such as bacterial vaginosis or for managing irritation or soreness.16. The pharmaceutical composition of embodiment 15, wherein the anti-infective is miconazole topical, tioconazole topical, metronidazole topical, clindamycin topical, terconazole topical, clotrimazole topical, iodine topical, butoconazole topical, hydroxyquinoline topical, sulfanilamide topical.17. The pharmaceutical composition of any one of embodiments 1 to 10, wherein the one or more active pharmaceutical ingredients is a vaginal agent, preferably a female sex hormone (for example a combination of estrogen and progestin or just estrogen) or a contraceptive agent, such as estradiol topical, citric acid / lactic acid / potassium bitartrate topical, conjugated estrogens topical.18. The pharmaceutical composition of any one of embodiments 1 to 17, wherein the microparticles consist of the carboxyalkyl starch and the one or more active pharmaceutical ingredients.19. The pharmaceutical composition of any one of embodiments 1 to 18, wherein the carboxyalkyl starch is carboxymethyl starch.20. The pharmaceutical composition of any one of embodiments 1 to 19, wherein the carboxyalkyl starch is crosslinked.21 . The pharmaceutical composition of embodiment 20, wherein said crosslinking degree is at least about 25, preferably at least about 40.22. The pharmaceutical composition of any one of embodiments 1 to 19, wherein the carboxyalkyl starch is uncrosslinked.23. The pharmaceutical composition of embodiment 22, wherein said degree of substitution with carboxyalkyl groups is less than about 0.25, preferably less than about 0.20, and more preferably about 0.1524. The pharmaceutical composition of any one of embodiments 1 to 23, wherein the microparticles are between about 1 pm and about 1000 pm in size.25. The pharmaceutical composition of any one of embodiments 1 to 24, wherein the microparticles up to about 500 pm, up to about 250 pm, preferably up to about 150, preferably up to about 100 pm in size.26. The pharmaceutical composition of any one of embodiments 1 to 25, wherein the microparticles are at least 5 pm, preferably at least 10 pm, preferably at least 25 pm, and preferably at least 50 pm in size.27. The pharmaceutical composition of any one of embodiments 1 to 26, wherein the microparticles are about 75 pm in size.28. The pharmaceutical composition of any one of embodiments 1 to 27, being mucoadhesive.29. The pharmaceutical composition of any one of embodiments 1 to 28, wherein the presence of iodine as an active pharmaceutical ingredient increases mucoadhesion, lowers viscosity, increases sprayability, and / or increases susceptibility to amylolysis.30. The pharmaceutical composition of any one of embodiments 1 to 29, wherein, when the pharmaceutical composition is hydrolysed by alpha-amylase, the pharmaceutical composition releases in situ the one or more active pharmaceutical ingredients, such as iodine exerting the anti-infective action.31 . An oral or nasal spray comprising the pharmaceutical composition of any one of embodiments 1 to 30, wherein the spray comprises a canister containing the pharmaceutical composition, an atomizer for dispersing the pharmaceutical composition into an aerosol, and an outlet to disperse the aerosol into the nose or mouth of a patient.32. A method of manufacture of the pharmaceutical composition of any one of embodiments 1 to 30, the method comprising the steps of: a) providing precursor microparticles, wherein said precursor microparticles comprises a carboxyalkyl starch, wherein the carboxyalkyl starch is either:• uncrosslinked and having a degree of substitution with carboxyalkyl groups of less than about 0.25, or• crosslinked and having crosslinking degree of at least about 25, and wherein the carboxyalkyl starch adopts a V-type helix secondary structure defining an internal cavity within said helix, and b) loading the precursor microparticles with one or more active pharmaceutical ingredients, thus allowing at least partial insertion of the molecules of the one or more active pharmaceutical ingredients within said internal cavity, thus yielding said microparticles comprising said one or more active pharmaceutical ingredients, c) formulating said microparticles comprising said one or more active pharmaceutical ingredients into said pharmaceutical composition.33. The method of embodiment 32, wherein step a) comprises carboxyalkylating a starch, fore example by reacting the starch with a carboxyalkylating agent, such as sodium monochloroacetate or monochloroacetic acid for carboxymethylation and sodium chloropropanoate or chloropropanoic acid for carboxyethylation.34. The method of embodiment 32 or 33, wherein step a) further comprises crosslinking the carboxyalkylated starch.35. The method of embodiment 34, wherein the crosslinking is achieved by emulsion crosslinking wherein: an emulsion of droplets of a first phase in a continuous second phase is prepared, the first phase being a liquid phase in which the carboxyalkylated starch is solubilized, the second phase being a liquid phase that does not comprise carboxy alkylated starch and a crosslinking agent is added to the emulsion to crosslink the carboxyalkylated starch and form the precursor microparticles.36. The method of embodiment 35, wherein the emulsion is a water-in-water emulsion, and wherein the first phase is a reaction mixture obtained by gelatinizing starch and the second phase is polyethylene glycol in water.37. The method of embodiment 35 or 36, wherein the crosslinking agent is sodium trimetaphosphate (STMP) or epichlorohydrin, preferably STMP.38. The method of any one of embodiments 32 to 37, wherein said loading at step b) is achieved by exposing the microparticles of the carboxyalkyl starch to a vapor, an aerosol or a spray of the active pharmaceutical ingredient, preferably iodine, preferably in a desiccator, preferably for 1 to 7 days, preferably for 7 days.39. The method of any one of embodiments 32 to 37, wherein said loading at step b) is achieved by impregnating the microparticles of the carboxyalkyl starch with a solution of the active pharmaceutical ingredient.40. Use of the pharmaceutical composition of any one of embodiments 1 to 30 for delivering said one or more active pharmaceutical ingredient to a mucosa of a patient in need thereof.41 . A method of delivering one or more active pharmaceutical ingredients to a mucosa of a patient in need thereof, the method comprising administering the pharmaceutical composition of any one of embodiments 1 to 30 to said mucosa of said patient.42. A method for mucosal administration of an active pharmaceutical ingredient to a patient in need thereof, the method comprising administering the pharmaceutical composition of any one of embodiments 1 to 30 to said mucosa of said patient.43. The use of embodiment 40 or the method of embodiment 41 or 42, wherein the mucosa is the oral mucosa, the nasal mucosal, the oropharyngeal mucosa, or the vaginal mucosa.44. The use of embodiment 40 or 43, wherein the pharmaceutical composition is for nasal, oropharyngeal, buccal, or vaginal administration.45. The method of any one of embodiments 41 to 43, wherein the pharmaceutical composition is administered nasally, oropharyngeally, buccally, or vaginally.46. The use / method of any one of embodiments 40 to 45, wherein the pharmaceutical composition is formulated as a spray.47. The use / method of any one of embodiments 40 to 46, wherein the active pharmaceutical ingredient is an anti-infective agent.48. Use of the pharmaceutical composition of any one or embodiments 1 to 30 as anti-infective agent for preventing and / or treating an infection.49. A method of preventing and / or treating an infection in a patient in need thereof, the method comprising administering the pharmaceutical composition of any one or embodiments 1 to 30 to a mucosa of said patient.50. The use / method of embodiments 48 or 49, wherein the anti-infective is an antiviral agent.51 . The use / method of any one of embodiments 48 to 50, wherein the infection is a viral infection.52. The use / method of embodiment 51 , wherein the viral infection is COVID-19, or an infection caused bySARS-CoV-2 virus or hCoV-OC43 virus.53. The use / method of embodiments 48 or 50, wherein the anti-infective is an antifungal agent.54. The use / method of any one of embodiments 48, 49, and 53, wherein, the infection is a fungal infection.55. The use / method of embodiment 54, wherein the fungal infection is an infection caused by Candida albicans.56. The use / method of embodiment 55, wherein the fungal infection is vaginal or buccal candidiasis.57. The use / method of embodiments 48 or 49, wherein the anti-infective is an antibacterial agent.58. The use / method of any one of embodiments 48, 49, and 57, wherein the infection is a bacterial infection.59. The use / method of embodiment 58, wherein the bacterial infection is an Escherichia coli. infection.60. Use of the pharmaceutical composition of any one of embodiments 1 to 30 as antiviral agent for preventing viral replication.61 . A method of preventing viral replication in a patient in need thereof, the method comprising administering the pharmaceutical composition of any one of embodiments 1 to 30 to a mucosa of said patient.62. The use / method of embodiment 61 , wherein the viral replication is replication of SARS-CoV-2 virus or hCoV-OC43 virus.63. The use / method of any one of embodiments 48 to 62, wherein the patient is an animal, preferably a mammal, and more preferably a human.DESCRIPTION OF THE DRAWINGS

[0027] In the appended drawings:Fig. 1 shows the manufacture and use of the pharmaceutical composition of the invention.Fig. 2 shows the iodine content in Starch derivatives samples as determined with the thiosulfate titration method.Data are presented as mean ± SD (n = 3). (**** p-value < 0.0001 , *** p-value < 0.001 , ** p-value < 0.01 , * p-value < 0.05, ns = not statistically significant).Fig. 3 shows powders of iodine-loaded starch derivatives after one week of incubation of starch materials withmolecular iodine.Fig. 4 shows the scanning electron microscopy micrographs of native (Hylon VII) and of modified starch powders at x1 ,80k magnification (the white bar is for 30 pm).Fig. 5 shows the FTIR spectra of starch materials not complexed (NC) and complexed (C) with iodine:. (A) CMS and (B) Hylon VII (native corn starch (Hylon VII).Fig. 6 shows X-Ray diffractograms of native starch (Hylon VII) and of various CM-starch materials not complexed (NC) and complexed (C) with iodine.Fig. 7 shows a mucoadhesion device to evaluate comparative bioadhesive materials (A) (from Robinson et al, 2021) and mucoadhesion of novel iodine complexes with various starch derivatives compared with some commercial iodinated materials (B) quantified as migration time to run 20 mm measured for various formulations in function of the contact time on gelatin-mucin support (n=3).Fig. 8 shows the viscosity and sprayability of the various composition tested in Example 1 .Fig. 9 shows reducing sugar production from various starch derivatives by (A) bacterial a-amylase, (B) commercial human salivary a-amylase and (C) crude saliva. The time of amylolysis was set at 3 minFig. 10 shows a comparison of the effect of CMS: l2, Betadine and Lugol on hCoV-OC43RLuc virus replication: (A) Viability of HRT 18 cells, (B) Infectivity with hCoV-OC43 [expressed as Relative Luciferase Units (RLU) in logarithmic form] and (C) Virucidal activity (normalized considering non-treated [NT] virus as 100 %) of Betadine, Lugol and CMS:l2 at different concentrations. The iodine compounds were incubated simultaneously with the virus for 30 min. The CMS:l2, Betadine and Lugol inhibited the early stages of infection. Mock: cells without the added virus; NT: nontreated virus added directly to cells. **** p < 0.0001; ns: non-significant.Fig. 11 shows the effect of increasing concentrations of CMS:l2 in presence of human crude saliva on hCoV- OC43RLuc replication: (A) Viability of HRT 18 cells, (B) Infectivity with hCoV-OC43 [expressed as Relative Luciferase Units (RLU) in logarithmic form] and (C) Virucidal activity (normalized considering non-treated [NT] virus as 100%) of CMS:l2 in presence / absence of crude saliva (home-made) at different concentrations. The CMS:l2 was incubated simultaneously with the hCoV-OC43 virus for 30 min. The CMS:l2 inhibited the early stages of infection. Mock: HRT 18 cells without the added virus; NT: non-treated virus added directly to the cell culture. **** p < 0.0001 ; ns: non-significant.Fig. 12 shows the effect of increasing concentrations of CMS:l2 in presence of commercial salivary alpha-amylase on hCoV-OC43R Luc replication: (A) Viability of HRT 18 cells, (B) Infectivity with hCoV-OC43 [expressed as Relative Luciferase Units (RLU) in logarithmic form and (C) Virucidal activity (normalized considering non-treated [NT] virus as 100%) of CMS:l2 in presence / absence of commercial human salivary a-amylase. The CMS:l2 was incubated simultaneously with the virus for 30 min. The CMS:l2 inhibited the early stages of infection. Mock: cells without the added virus; NT: non-treated virus added directly to the cell culture. **** p < 0.0001; ns: non-significant.Fig. 13 shows the effect of increasing concentrations of bacterial a-amylase, human a-amylase and human home-made saliva on hCoV-OC43RLuc replication: (A) Viability of HRT 18 cells, (B) Infectivity with hCoV-OC43 [expressed as Relative Luciferase Units (RLU) in logarithmic form]. Each amylase was incubated simultaneously with the virus for 30 min. None of the investigated amylases presented antiviral activity. Mock: cells without the added virus; NT: non-treated virus added directly to the cell culture.Fig. 14 shows representative images of the inhibition zone of Candida albicans and Escherichia coli after exposure to iodine samples: CMS:l2 discs (n = 3 different experiments).Fig. 15 shows the MTT viability tests of Candida albicans after exposure to iodine samples: CMS:l2 (1 % and 5%), commercial products (1 % and 5%), and Lugol. (Reported values of C. albicans viability are the mean ± SD; n = 3 different experiments). The relative viability was normalized considering 1 x 106CFUs / mL as 100 %.Fig. 16 shows the E. coli bacteria viability test after exposure to iodine samples: CMS:l2 (1% and 5%), commercial Betadine® products (1 % and 5%), and Lugol. Reported values of E. coli viability are the mean ± SD; n = 3 different experiments. The relative viability was normalized considering 1 x106CFUs / mL as 100 %.DETAILED DESCRIPTION OF THE INVENTION

[0028] Turning now to the invention in more details, there is provided a pharmaceutical composition for mucosal administration. Methods of manufacture and use of this composition are also provided.

[0029] The pharmaceutical composition for mucosal administration of the invention comprises microparticles, said microparticles comprising carboxyalkyl starch and one or more active pharmaceutical ingredients (API), wherein the carboxyalkyl starch is either: uncrosslinked and having a degree of substitution with carboxyalkyl groups of less than about 0.25 crosslinked and having crosslinking degree of at least about 25, wherein the carboxyalkyl starch adopts a V-type helix secondary structure defining an internal cavity within said helix, and wherein the molecules of the active pharmaceutical ingredient are at least partially contained within said internal cavity of the carboxyalkyl starch.

[0030] Herein, the microparticles comprising carboxyalkyl starch and an active pharmaceutical ingredient (API) are sometimes referred to as the “starch:API microparticles”.

[0031] The mucoadhesive starch derivatives e.g., carboxymethyl starch (CMS), loaded with anti-infective agents (e.g., iodine - CMS: I2), are to be administered on mucosa at risk of contamination, where they would release the antimicrobial agent on-site, following matrix hydrolysis by endogenous alpha-amylase. In the Examples below, the virucidal activity of CMS:l2 and of other iodine compounds was quantitatively assessed against the hCoV-OC43, a coronavirus representative of SARS-CoV-2. The anti-infectivity and viability of novel CMS:l2 have been assessed on epithelial cell target HRT-18 (representative for various human mucosa). This virucidal activity of CMS:l2 was found only upon the addition of salivary a-amylase by on-site hydrolysis of the CMS:l2 and release of iodine, supporting the assumption that the alpha-amylase is the main factor from saliva triggering its virucidal action.

[0032] The pharmaceutical composition of the invention presents several advantages.

[0033] First, compared to unmodified starch, the carboxyalkyl starch, whether crosslinked or not, has increased porosity and an expanded V-type helix secondary structure since its internal cavity is larger. This makes the starch:API microparticles of the invention better able to accommodate a variety of APIs. Furthermore, compared to unmodified starch, the carboxyalkyl starch, whether crosslinked or not, has increased retention of APIs, such as iodine, possibly due to the introduction of carboxyl groups. Crosslinking further increases API retention, possibly by increasing porosity. Both of these factors increase the usefulness of such modified starch microparticles as delivery vehicles for an API to a mucosa.

[0034] In addition, compared to unmodified starch, the carboxyalkyl starch, whether crosslinked or not, has increased susceptibility at amylolysis i.e., hydrolysis with a-amylase, possibly because of the disruption of the crystalline structure of the starch. Crosslinking further increases susceptibility at amylolysis, again possibly by disrupting the crystalline structure of the starch. This makes the starch:API microparticles of the invention particularly useful for mucosal administration, especially to a mucosa wetted with a significant endogenous a-amylase concentration, which will trigger the delivery of the API.Notably, this allows the starch:API microparticles to continuously release the API in a controlled manner over time through in-situ (on the mucosa) amylolysis.

[0035] Furthermore, compared to unmodified starch, the carboxyalkyl starch, whether crosslinked or not, has increased mucoadhesion and reduced viscosity, possibly due to the introduction of carboxylic groups. The increased mucoadhesion prolongs the time period during the starch:API microparticles are exposed to a-amylase and also increases delivery of microbicidal agent and, indeed, a response to infectious diseases necessitates treatments that can quickly and effectively inactivate pathogens. In addition to their antimicrobial / antiviral / antifungal efficacy, effective treatments for infectious diseases, when they are administered to a mucosa, must be able to adhere to mucosal surfaces to ensure prolonged contact and effectiveness. Adherence is particularly important for applications in the oral and nasopharyngeal cavities, where the presence of saliva and other fluids can quickly wash away applied treatments. The increased mucoadhesion of the starch:API microparticles of the invention are thus interesting in view of these needs. Additionally, the reduced viscosity increases sprayability of the starch:API microparticles, making particularly interesting for formulation into dosage forms where a powder or a suspension of a powder is sprayed onto a mucosa. These include e.g. oral and nasal sprays.

[0036] In addition, the starch:API microparticles are able to generate complexes with volatile APIs for example iodine. When starch microparticles are exposed to a gaseous API (i.e. I2), this gaseous API may spontaneously migrate inside the internal cavity of the V-type helix secondary structure.

[0037] When used for oropharyngeal administration, the on-site release of iodine by the microparticles combined with their mucoadhesion, is a major advantage because it may exert the virucidal effect against respiratory viruses locally, whereas other anti-infective agents may be dissipated through the esophagus. When used for vaginal administration, these same properties favor vaginal application against various infections. Local alpha-amylasetrigger the liberation of e.g., anti-infective agents. To the best of the inventor’s knowledge, the Examples below report the first observation of mucoadhesive agents that will liberate in situ virucidal agents by fast hydrolysis with an endogenous enzyme. The mucoadhesive formulations reported in the Examples are based on a carboxymethyl starch:iodine complex (CMS:h) that, if oropharyngeally administered, is expected to liberate iodine by its hydrolysis with salivary amylase. It was found that this amylolysis was fast and that the released iodine exerted a strong virucidal effect, but did not affect cell viability.

[0038] Furthermore, the insertion of an API, such as iodine, in the internal cavity of the V-type helix secondary structure, surprisingly:• further increases the mucoadhesion of the starch:API microparticles, and• further reduces viscosity of the starch:API microparticles powder, and thus increases its sprayability.

[0039] Furthermore, the starch:API microparticles have been shown below to preserve the therapeutic activity of APIs, such as anti-infectives. In fact, for iodine as the API, the starch:API microparticles exhibit a virucidal activity superior to Betadine™ - see the Examples below.

[0040] There is a need for antimicrobial treatments that can effectively treat bacterial and fungal infections in various mucosal and other biological environments. For instance, vaginal infections such as bacterial vaginosis (BV) and vulvovaginal candidiasis (WC) are common and can lead to severe health issues if not promptly treated. Similarly, bacterial infections caused by organisms like Escherichia coii can result in serious complications, including urinary tract infections and sepsis. The increased mucoadhesion of the starch:API microparticles of the invention constituted a versatile anti-infective treatment that can address a wide range of pathogens, including viruses, bacteria, and fungi, while ensuring prolonged contact through enhanced adhesion properties.

[0041] Herein, mucosal administration refers to the delivery of the active pharmaceutical ingredient onto or across a mucous membrane, and the effect can be local or systemic. In preferred embodiments, the active pharmaceutical ingredient is delivered onto the mucosa but not across the mucosa.

[0042] In preferred embodiments, the mucosal administration is:• oropharyngeal administration in which the pharmaceutical composition is put into contact with the oropharyngeal mucosa, which lines the back of the mouth and the upper part of the throat;• nasal administration in which the pharmaceutical composition is put into contact with the nasal mucosa and / or the olfactory mucosa, which lines the nasal cavity;• buccal administration in which the pharmaceutical composition is put into contact with the oral mucosa, which lines the inside of the mouth, typically by being placed between the gums and the inner lining of the cheek; or intraesophageal administration in which the pharmaceutical composition is put into contact with the esophageal mucosa, orvaginal administration in which the pharmaceutical composition is put into contact with the vaginal mucosa, which lines the inside of the vagina, typically by being inserted into the vagina.

[0043] In most preferred embodiments, the mucosal administration is oropharyngeal, nasal, or buccal administration.

[0044] The pharmaceutical composition of the invention can be formulated as an oral or nasal spray. In embodiments, there is therefore provided an oral or nasal spray comprising the pharmaceutical composition of the invention. Preferably, the spray comprises a canister containing the pharmaceutical composition, and an atomizer for dispersing the pharmaceutical composition into an aerosol, and an outlet to disperse the aerosol into the nose or mouth of a patient.

[0045] As noted above, the pharmaceutical composition for mucosal administration of the invention comprises the starch:API microparticles. Typically, they also comprise one or more pharmaceutically acceptable excipient. These will be defined further below.

[0046] The pharmaceutical composition of the invention may be in powder, semi-liquid, or liquid form. In powder form, the pharmaceutical composition may consist of the starch:API microparticles only or comprise the starch:API microparticles together with one or more pharmaceutically acceptable excipients also in powder form. In semi-liquid or liquid form, the starch:API microparticles can be suspended in a semi-liquid or liquid pharmaceutically acceptable excipients. Non-limiting examples of semi-liquid formulations include ointments, creams, gels, pastes, and foams. Non-limiting examples of liquid formulations include solutions, suspensions, emulsions, syrups, elixirs, and oral and nasal liquid sprays.

[0047] As noted above, the pharmaceutical composition of the invention comprises an active pharmaceutical ingredient. It should be understood that it may comprise a combination of such active pharmaceutical ingredient.

[0048] The active pharmaceutical ingredient(s) can be any such ingredient used in human or veterinary medicine. Non-limiting examples of classes of active pharmaceutical ingredients that can be comprised in the pharmaceutical composition of the invention include one or more:• an anti-infective including amebicides, aminoglycosides, anthelmintics, antiviral agents (including adamantane antivirals such as amantadine and rimantadine, antiviral boosters such as ritonavir and cobicistat, antiviral combinations, antiviral interferons, antiviral monoclonal antibodies, and virucidal agents blocking the viral replication), antifungals (including azole antifungals, echinocandins, polyenes, and other antifungals), antibacterial agents (including sulfonamides, tetracyclines, and other antibiotics);• genitourinary tract agents;• topical agents including mouth and throat products, nasal preparations (including nasal antihistamines and decongestants; and• alternative medicines (including herbal products, and probiotics);All these pharmaceutical agents are well known and documented, for example, at https: / / www.druqs.com / druq- classes.html?tree=1 .

[0049] In embodiments, the pharmaceutical composition of the invention comprises an anti-infective such as• antiviral agents, which are used to inhibit production of viruses that cause disease, including: o adamantane antivirals, which are only active against influenza A virus, an RNA virus, but has no action against influenza B virus. Non-limiting examples include amantadine, and rimantadine. o antiviral boosters, which are drugs that are used in conjunction with other specific antiviral drugs to enhance or increase their effect. Non-limiting examples include ritonavir and cobicistat. o antiviral combinations, which have more than one antiviral agent in the one dosage form, or o a virucidal agent blocking the viral replication.• antifungal agents, also called antimycotic agents. They kill or inactivate fungi and are used to treat fungal infections (including yeast infections). Types of antifungal agents include: o azole antifungals, a group of medicines that contain an azole ring and inhibit the growth of a wide range of fungi. Azole antifungal agents can be used to treat fungal infections of the body and skin, including athlete's foot, onychomycosis (fungal nail infections), ringworm, and vaginal candidiasis; o echinocandins, a class of antifungal drugs that target the fungal cell wall. They are lipopeptide molecules nystatin, amphotericin b, amphotericin b liposomal, and amphotericin b lipid complex; o aminosalicylates or aminosalicylic acid is used with other drugs to treat tuberculosis; o iodine; or o nicotinic acid derivatives, which are highly specific antibacterial agents, typically active only against Mycobacterium;• sulfonamides, a group of medicines that contain the sulfonamide chemical group. They may also be called sulfa drugs. They have antibacterial properties but can also have antiviral and / or antifungal properties. Nonlimiting examples include sulfamethoxazole / trimethoprim, and sulfadiazine.• vaginal anti-infective agents, which are available as creams, pessaries (tablets), gels or solutions to treat either bacterial or fungal vaginal infections. Vaginal antifungal products can be used to treat e.g. vaginal thrush. Antibacterial vaginal products are used for bacterial infections such as bacterial vaginosis. Other products are used to manage irritation or minor soreness. Non-limiting examples include miconazole topical, tioconazole topical, metronidazole topical, clindamycin topical, terconazole topical, clotrimazole topical, iodine topical, butoconazole topical, hydroxyquinoline topical, sulfanilamide topical.

[0050] In embodiments, the pharmaceutical composition of the invention comprises another vaginal agents, which generally include products with female sex hormones (either a combination of estrogen and progestin or justestrogen). These agents work locally and may be absorbed systemically as well to replace low levels of hormones during menopause. These vaginal agents are used to treat menopausal symptoms such as vaginal dryness, itching and burning. Non-limiting examples include estradiol topical, citric acid / lactic acid / potassium bitartrate topical, conjugated estrogens topical.The starch:API microparticles

[0051] As noted above, the pharmaceutical composition of the invention comprises starch:API microparticles.These are microparticles comprising, preferably consisting of, the carboxyalkyl starch and the active pharmaceutical ingredient.

[0052] As is well known to the skilled person, starch is a polysaccharide composed of glucose units linked by glycosidic bonds. It has two components: amylose (non-branched) and amylopectin (branched), which can be found in varying ratios.Amylose: Amylopectin:

[0053] The amylose content of starch typically ranges from 20 wt% to 30 wt% with the remainder being amylopectin, which makes up about 70% to 80% of the starch. In preferred embodiments, the starch is a so-called high amylose starch (HAS). Herein, a high amylose starch comprises more than 30 wt% or more, preferably 50 wt% or more, and most preferably about 70 wt% of amylose, with the remainder being amylopectin.

[0054] A carboxyalkyl starch is a chemically modified starch where carboxyalkyl groups (-alkyl-COOH) are introduced attached to the hydroxyl groups of the glucose units in the starch molecule.Carboxy alky I starch:-alkyl-COOH.

[0055] In embodiments, the carboxyalkyl starch is carboxymethyl starch (R = -CH2COOH), or carboxyethyl starch (R = -CH2CH2COOH), preferably carboxymethyl starch.

[0056] Herein, the degree of substitution with carboxyalkyl groups (DS) of the carboxyalkyl starch (CMS) refers to the average number of carboxyalkyl groups attached to a glucose repeat unit of the starch. In the pharmaceuticalcomposition of the invention, when the carboxyalkyl starch is uncrosslinked, the degree of substitution is less than about 0.25, preferably less than about 0.20, and more preferably about 0.15. It has been found that a DS about 0.30 or more, undesirably slowed the reaction rate with alpha-amylase - see the Examples below. In embodiments, the degree of substitution is at least 0.05.

[0057] When the carboxyalkyl starch is uncrosslinked, the degree of substitution is not particularly limited. In preferred embodiments, the degree of substitution is between about 0.05 to about 0.30, preferably about 0.15.

[0058] As noted above, in the pharmaceutical composition of the invention, the carboxyalkyl starch can be crosslinked or uncrosslinked. Herein, crosslinking is the presence of bonds, for example diether bridges, linking together two starch macromolecules. In preferred embodiments, the carboxyalkyl starch is uncrosslinked.

[0059] In alternative embodiments, the carboxyalkyl starch is crosslinked. Herein, a “crosslinking degree” of X is defined as the amount of crosslinker used to cross-link 100 g of starch material (starch or carboxy alkylstarch as CMS), where cross-linker is STMP or epichlorohydrin or another cross-linking agent. As noted above, when crosslinked, the carboxyalkyl starch in the pharmaceutical composition of the invention, has a crosslinking degree of at least about 25, preferably at least about 30, more preferably at least about 35, and most preferably at least about 40. Indeed, it has been found that a crosslinking degree of less than 25 undesirably reduced the insertion of the active pharmaceutical ingredient in the internal cavity within the V-type helix of the carboxyalkyl starch - see the Examples below.

[0060] As noted above, in the pharmaceutical composition of the invention, the carboxyalkyl starch adopts a V-type single helix secondary structure. An example of a V-type helix is shown in Fig. 1. It is a single helical structure mostly formed by the amylose chains. In this structure, the starch chains adopt a helical conformation stabilized by hydrogen bonds. This helical conformation defined an internal cavity within the helix. In the pharmaceutical composition of the invention, many of the active pharmaceutical ingredient are at least in part contained within this internal cavity. This means at least part of each molecule of the active pharmaceutical ingredient (not necessarily the whole molecule) is contained within the internal cavity. More particularly, iodine can easily be contained within this cavity. In fact, any linear chain of an active pharmaceutical ingredient molecule (particularly, but not only hydrophobic) is easy to contain within this cavity. In fact, the inventors have found (results not shown) that up to three parallel hydrocarbon chains can be contained within this cavity. Therefore, among all the active pharmaceutical ingredients described above, those with hydrocarbon chains are preferred.

[0061] It has been found that, compared to unmodified starch, carboxyalkyl starch is more amorphous presenting fewer B-type (double) helices and more V-type helices. Further, it presents larger V-type helix than the nonmodified starch i.e., V-type helix with larger internal cavities, thus accommodating larger molecules of the active pharmaceutical ingredient. Thus, it can be said that the carboxyalkyl starch in the pharmaceutical composition of the invention is exhibits an enhanced V-helix structure.

[0062] Furthermore, at least in some embodiments, the presence of an active pharmaceutical ingredient, for example iodine, lowers the viscosity of the starch:API microparticles, allowing them to be sprayed. Also, it increasesmucoadhesion of the starch:API microparticles, making them even more suitable for mucosal administration.

[0063] In embodiments, the microparticles are between about 1 pm and about 1000 pm in size. Preferably, the microparticles are up to about 500 pm, up to about 250 pm, preferably up to about 150, preferably up to about 100 pm in size. Preferably, the microparticles are at least 5 pm, preferably at least 10 pm, preferably at least 25 pm, and preferably at least 50 pm in size. Most preferably, the microparticles are about 75 pm in size.

[0064] In embodiments, the microparticles are spheroidal in shape.

[0065] In embodiments, the carboxyalkyl starch in the starch-API microparticles is free of another polysaccharide (for example free of alginate and / or chitosan). In embodiments, it is free of a lipid, such as a phospholipid, such as lecithin.Method of manufacture

[0066] There is also provided a method of manufacture of the above pharmaceutical composition. This method comprises the steps of: a) providing precursor microparticles, wherein said precursor microparticles comprises a carboxyalkyl starch, wherein the carboxyalkyl starch is either:• uncrosslinked and with a degree of substitution with carboxyalkyl groups of less than about 0.25, or• crosslinked and having crosslinking degree of at least about 25, and wherein the carboxyalkyl starch adopts a V-type helix secondary structure defining an internal cavity within said helix, and b) loading the precursor microparticles with an active pharmaceutical ingredient, thus allowing at least partial insertion of the molecules of the active pharmaceutical ingredient within said internal cavity, thus yielding said starch:API microparticles, c) formulating said pharmaceutical composition.

[0067] In this method of manufacture, the pharmaceutical composition, the active pharmaceutical ingredient, the carboxyalkyl starch, degree of substitution with carboxyalkyl groups, crosslinking degree, etc. are as described in the previous section.Step a)

[0068] In this step, precursor microparticles comprising a carboxyalkyl starch. This step will vary depending on whether crosslinked or uncrosslinked carboxyalkyl starch is desired.

[0069] When using uncrosslinked starch, an uncrosslinked starch having with a degree of substitution with carboxyalkyl groups of less than about 0.25 or more than about 0.35 can be procured commercially. In preferred embodiments, such a starch can be prepared by carboxyalkylating a starch. This can be achieved by reacting thestarch with a carboxyalkylating agent, such as sodium monochloroacetate or monochloroacetic acid for carboxymethylation and sodium chloropropanoate or chloropropanoic acid for carboxyethylation. Preferably, as noted above, the starch is carboxymethylated. The amount of reactant used can be adjusted so that a carboxyalkylated starch with the desired degree of carboxyalkyl substitution is obtained.

[0070] In preferred embodiments, the starch is first gelatinized before being carboxyalkylated. Starch gelatinization is a process of breaking down of intermolecular hydrogen bonds of starch molecules in the presence of water and heat, allowing the hydrogen bonding sites (the hydroxyl hydrogen and oxygen) to engage more water. This irreversibly dissolves the starch granule in water. Water acts as a plasticizer. In embodiments, an alkaline agent, such as NaOH or KOH, is used in addition to water and heat to gelatinize the starch. In preferred embodiments, the alkaline agent is NaOH. After carboxyalkylation, the carboxyalkylated starch can be isolated from the reaction mixture and dried to form the precursor microparticles. This isolation can be achieved by any means commonly used by skilled persons to do such things.

[0071] In a specific embodiment, high amylose corn starch is suspended in water at approximately 55°C. An equal volume of 1.5 M NaOH is added with continued stirring for approximately 1 hour to gelatinize the high amylose corn starch into a gelatinized starch. The gelatinized starch is then carboxy methylated by adding sodium monochloroacetate (SMCA) in a quantity selected to achieve a desired degree of substitution with carboxyalkyl groups (DS). The carboxymethylated starch is then cooled, neutralized, and washed with methanol and acetone. The carboxymethylated starch is then dried to obtain the precursor microparticles.

[0072] When using crosslinked starch, it can be prepared by first providing a carboxyalkylated starch following the steps set out above. Then, the carboxyalkylated starch is crosslinked. In embodiments, the crosslinking can be achieved by emulsion crosslinking. In emulsion crosslinking, an emulsion of droplets of a first phase in a continuous second phase is prepared. The first phase is a liquid phase in which the carboxyalkylated starch is solubilized, the second phase is a liquid phase that does not comprise carboxyalkylated starch. In embodiments, the emulsion is a water-in-water emulsion, wherein the first phase is a reaction mixture obtained by gelatinizing starch as described above and the second phase is polyethylene glycol in water. Then, a crosslinking agent is added to the emulsion to crosslink the carboxyalkylated starch and form the precursor microparticles. In embodiments, the crosslinking agent is sodium trimetaphosphate (STMP) or epichlorohydrin, preferably STMP.

[0073] In a specific embodiment, a continuous phase is prepared by dissolving polyethylene glycol in water and maintaining under constant agitation at 55°C. A dispersed phase is prepared by dissolving carboxymethyl starch in 1 M NaOH. A water-in-water emulsion is formed by adding the dispersed phase to the continuous phase under constant stirring. Then, a sodium trimetaphosphate (STMP) solution is added to the water-in-water emulsion to obtain the crosslinked carboxymethyl starch microspheres. The pH of the reaction mixture is then neutralized, the crosslinked carboxymethyl starch microspheres are isolated from the reaction mixture and washed with methanol and then with acetone. Finally, the cross-linked carboxymethyl starch microspheres are dried.

[0074] In all of the above, a high amylose starch is preferably used, as described in the previous section.Step b)

[0075] Step b) involves loading the microparticles of the carboxyalkyl starch with an active pharmaceutical ingredient.

[0076] In embodiments, said loading is achieved by exposing the microparticles of the carboxyalkyl starch to a vapor, an aerosol or a spray of the active pharmaceutical ingredient, such as iodine. It is an advantage of the invention that such exposition results in the spontaneous formation of a carboxyalkyl starch: active pharmaceutical ingredient complex. In preferred such embodiment, the vapor of the active pharmaceutical ingredient is iodine vapor. Preferably, this exposition is carried out in a desiccator for a specified duration, preferably for 1 to 7 days, more preferably 7 days.

[0077] In alternative embodiments, said loading is achieved by impregnating the microparticles of the carboxyalkyl starch with a solution of the active pharmaceutical ingredient. Typically, the solution of the active pharmaceutical ingredient is a solution in a liquid that is the non-solvent for the carboxyalkyl starch so as to not dissolve the microparticles of the carboxyalkyl starch.

[0078] In yet other alternative embodiments, said loading is achieved by adding to the active pharmaceutical ingredient during the manufacture of the precursor microparticles so the active pharmaceutical ingredient is integrated within the microparticles as they are formed. In other words, in such embodiments, steps a) and b) are carried out simultaneously, yielding the starch:API microparticles in one step. This typically requires that the API does not adversely react with the reactant or affect the reactions occurring during the manufacture of the precursor microparticles.

[0079] Herein, a solvent is a liquid that dissolves a particular solute, resulting in a solution. In contrast, a nonsolvent is a liquid that does not dissolve a particular solute. In other words, when a solute is added to a non-solvent, it does not form a solution; it may form for example, a suspension.Step c)

[0080] The pharmaceutical composition of the invention will be formulated in a manner suitable for a chosen route of administration in manners well known to the skilled person. Typically, this involves the use of one or more pharmaceutically acceptable excipients as taught by Remington: The Science and Practice of Pharmacy by Alfonso R. Gennaro, 2003, 21thedition, Mack Publishing Company.

[0081] The pharmaceutical composition for mucosal administration of the invention typically comprise, in addition to the starch:API microparticles, one or more pharmaceutically acceptable excipient. As used herein, a “pharmaceutically acceptable excipient” refers to substances that are used in the formulation of a pharmaceutical product and are generally recognized as safe, non-toxic, and suitable for use in humans or animals. These excipients are used to aid the manufacturing process, protect, support, or enhance stability, bioavailability, or patient acceptability, assist in product identification, or enhance any other attribute of the overall safety and effectiveness ofthe drug during storage or use. Non-limiting examples of pharmaceutically acceptable excipients include absorption enhancers, adjuvants, antioxidants, binders, buffers and pH modifiers, carriers, chelating agents, coating agents, coloring agents, diluents, disintegrants, dispersion media, emollients, foaming agents and anti-foaming agents, fillers, gelling agents, glidants, humectants, lubricants, mucoadhesive agents, osmolarity adjusters, osmotic agents, permeation enhancers, plasticizers, preservatives (including antimicrobial agents), propellants, solvents, stabilizers, surfactants and emulsifying agents, suspending agents, sweeteners and flavoring agents, thickeners, vehicles, wetting agents and the like, compatible with pharmaceutical administration.

[0082] As noted above, the pharmaceutical composition of the invention may be in powder, semi-liquid, or liquid form. In powder form, the pharmaceutical composition may consist of the starch:API microparticles only or comprise the starch:API microparticles together with one or more pharmaceutically acceptable excipients in powder form. In semi-liquid or liquid form, the starch:API microparticles can be suspended in a semi-liquid or liquid pharmaceutically acceptable excipients. Non-limiting examples of semi-liquid formulations include ointments, creams, gels, pastes, and foams. Non-limiting examples of liquid formulations include solutions, suspensions, emulsions, syrups, elixirs, oral and nasal liquid sprays.

[0083] Hereinbelow specific exemplary excipients for categories of excipients (e.g., binders, lubricants, sweeteners, etc.) are given once and generally not repeated. They are however intended to apply everywhere the same category of excipient is mentioned. Selection of appropriate excipients is well within the skills of the person of skill in the art.

[0084] In embodiments in which the pharmaceutical composition is for nasal administration, the pharmaceutical composition can be formulated as:• A nasal powder - a dry powder formulation comprising the carboxyalkyl starch microparticles, administered through the nose. Nasal powders may be formulated using bulking agents to increase the volume of the powder and improve handling (e.g., lactose, mannitol, and microcrystalline cellulose), stabilizers to help maintain the stability of the active pharmaceutical ingredient (e.g., trehalose and sucrose), a mucoadhesive agents to enhance the residence time of the powder on the nasal mucosa (e.g., chitosan and carbomers), an absorption enhancers to improve the permeability of the nasal mucosa to the active pharmaceutical ingredient (e.g., bile salts and surfactants like polysorbates), and lubricants to improve the flow properties of the powder (e.g., magnesium stearate and talc). Nasal powders can be administered using spray devices: these devices are designed to disperse the powder into fine particles (aerosol) administered nasally. They often use a mechanical pump or pressurized aerosol to achieve this.• A nasal liquid spray - a liquid formulation, sometimes an emulsion, in which the carboxyalkyl starch microparticles are suspended, delivered into the nostrils using a pump or aerosol device. Nasal liquid sprays may be formulated using a liquid or an emulsion to suspend the carboxyalkyl starch microparticles (e.g., water, ethanol, and propylene glycol, glycerin and polyethylene glycol), emulsifying agents to stabilize the emulsion (e.g., polysorbates and lecithin), preservatives to prevent microbial growth (e.g., benzalkoniumchloride and parabens), buffering agents to maintain the pH (e.g., sodium phosphate and citric acid), and viscosity enhancers to improve the residence time on the nasal mucosa (e.g., hydroxypropyl methylcellulose and carbomers). Nasal liquid sprays can be administered using spray devices: these devices are designed to deliver a fine mist of the liquid formulation into the nostrils. They also often use a mechanical pump or pressurized aerosol to achieve this.• Nasal drops - a liquid formulation, in which the carboxyalkyl starch microparticles are suspended, administered drop by drop into the nostrils. Nasal drops may be formulated using a liquid to suspend the carboxyalkyl starch microparticles (e.g., water, ethanol, propylene glycol, glycerin and polyethylene glycol), preservatives, buffering agents, and viscosity enhancers to improve the residence time on the nasal mucosa (e.g., hydroxypropyl methylcellulose and carbomers). Nasal drops can be administered using dropper bottles: these bottles are designed to deliver the liquid formulation drop by drop into the nostrils. They often use a squeeze mechanism to achieve this.• A nasal gel - a semi-solid formulation, in which the carboxyalkyl starch microparticles are suspended, applied inside the nostrils. Nasal gels may be formulated using liquids to suspend the active pharmaceutical ingredient (e.g., water, ethanol, and propylene glycol), gelling agents to create the semi-solid consistency (e.g., carbomers and hydroxypropyl methylcellulose), preservatives, buffering agents, and humectants to keep the nasal mucosa moist (e.g., glycerin and sorbitol). Nasal gels can be administered using applicators: these devices are designed to deliver the gel formulation into the nostrils. They often use a squeeze mechanism or a pre-filled syringe to achieve this.• A nasal foam - a foam formulation, in which the carboxyalkyl starch microparticles are suspended, that expand upon administration to cover a larger surface area of the nasal mucosa. Nasal foams may be formulated using liquids to suspend the carboxyalkyl starch microparticles (e.g., water, ethanol, and propylene glycol), foaming agents to create the foam structure (e.g., sodium lauryl sulfate and polysorbates), stabilizers (e.g., trehalose and sucrose), preservatives, and viscosity enhancers. Nasal foams can be administered using foam dispensers: these devices are designed to deliver the foam formulation into the nostrils. They often use a mechanical pump to achieve this.

[0085] In preferred embodiments, the pharmaceutical composition of the invention is formulated as a nasal powder, preferably formulated as a nasal spray.

[0086] In embodiments in which the pharmaceutical composition is for buccal administration, the pharmaceutical composition can be formulated as:• A buccal gel: a semi-solid formulation, in which the carboxyalkyl starch microparticles are suspended, that is applied to the buccal mucosa. It can provide rapid dispersion and absorption of the active pharmaceutical ingredient. Buccal gels may be formulated using liquids to suspend the carboxyalkyl starch microparticles (e.g., water, ethanol, and propylene glycol), gelling agents, preservatives, stabilizers (e.g., trehalose and sucrose), and permeation enhancers. Buccal gels can be administered using applicators: these devices aredesigned to deliver the gel formulation onto the buccal mucosa. They often use a squeeze mechanism or a pre-filled syringe to achieve this.• An oral spray - a liquid formulation, in which the carboxyalkyl starch microparticles are suspended, that is sprayed onto the buccal mucosa for rapid absorption. Oral sprays may be formulated using liquids to suspend the carboxyalkyl starch microparticles (e.g., water, ethanol, propylene glycol, glycerin and polyethylene glycol), preservatives, stabilizers (e.g., trehalose and sucrose), and permeation enhancers. Oral sprays can be administered using spray devices: these devices are designed to deliver a fine mist of the liquid formulation onto the buccal mucosa. They often use a mechanical pump or pressurized aerosol to achieve this

[0087] In embodiments in which the pharmaceutical composition is for vaginal administration, the pharmaceutical composition can be formulated as:• Vaginal creams - semi-solid formulations, in which the carboxyalkyl starch microparticles are suspended, applied inside the vagina using an applicator allowing the active pharmaceutical ingredient to be absorbed through the vaginal mucosa for local or systemic effects. Vaginal creams may be formulated using emulsifiers to create a stable emulsion (e.g., cetyl alcohol and stearyl alcohol), thickeners to provide the desired consistency (e.g., carbomers and xanthan gum), humectants to retain moisture (e.g., glycerin and propylene glycol), and preservatives.• Vaginal gels - semi-solid formulations, in which the carboxyalkyl starch microparticles are suspended, that provide a smooth consistency for easy application. Vaginal gels may be formulated using gelling agents to provide the desired consistency (e.g., carbomers and hydroxyethyl cellulose), humectant, preservatives, and stabilizers (e.g., citric acid and sodium citrate).• Vaginal foams - aerosolized formulations comprising the carboxyalkyl starch microparticles, that expand upon application to cover a larger surface area inside the vagina, allowing the active pharmaceutical ingredient to be absorbed through the vaginal mucosa for local or systemic effects. Vaginal foams may be formulated using foaming, emulsifiers, humectants, and preservatives.• Vaginal ointments - semi-solid formulations, in which the carboxyalkyl starch microparticles are suspended, that provide a protective barrier and release medication over time for local or systemic absorption through the vaginal mucosa. Vaginal ointments may be formulated using emollients to provide a protective barrier and enhance skin hydration (e.g., petrolatum and lanolin), emulsifiers, preservatives, and stabilizers (e.g., citric acid and sodium citrate).• Vaginal inserts - solid dosage forms comprising the carboxyalkyl starch microparticles, designed to be inserted into the vagina, where they release medication slowly over time, allowing the active pharmaceutical ingredient to be absorbed through the vaginal mucosa for local or systemic effects. Vaginal inserts may be formulated using bioadhesive agents to ensure prolonged contact with the vaginal mucosa (e.g., hydroxypropyl methylcellulose and polycarbophil), disintegrants (e.g., croscarmellose sodium and sodiumstarch glycolate), lubricants, and stabilizers (e.g., citric acid and sodium citrate).• Vaginal tampons: absorbent materials impregnated with the carboxyalkyl starch microparticles for local treatment. They are designed to be inserted into the vagina, where they release medication for local treatment, allowing the active pharmaceutical ingredient to be absorbed through the vaginal mucosa. Vaginal tampons may be formulated using absorbent materials to provide structural integrity and ensure effective absorption (e.g., cotton and rayon), bioadhesive agents to enhance contact with the vaginal mucosa (e.g., hydroxypropyl methylcellulose and polycarbophil), and preservatives.Method of use

[0088] There is also provided the use of the pharmaceutical composition of the invention for delivering the active pharmaceutical ingredient to a mucosa of a patient in need thereof. There is also provided a method of delivering the active pharmaceutical ingredient to a mucosa of a patient in need thereof, the method comprising administering the pharmaceutical composition of the invention to said mucosa of said patient. There is also provided a method for mucosal administration of an active pharmaceutical ingredient to a patient in need thereof, the method comprising administering the pharmaceutical composition of the invention to said mucosa of said patient.

[0089] In embodiments, the mucosa is:• the oropharyngeal mucosa, which lines the back of the mouth and the upper part of the throat,• the nasal mucosa, which lines the nasal cavity,• the olfactory mucosa, which lines the upper part of the nasal cavity,• the oral mucosa, which lines the inside of the mouth,• the esophageal mucosa, which lines the esophagus, or• the vaginal mucosa, which lines the vagina.

[0090] Indeed, these mucosa contain a-amylase. Alpha-amylase is an enzyme that breaks down starches into simpler sugars. It can therefore break down the carboxyalkyl starch microparticles in the pharmaceutical composition of the invention and release the active pharmaceutical ingredient.

[0091] As noted above, in embodiments, the pharmaceutical composition is for nasal, buccal, or vaginal administration. Thus, the pharmaceutical composition is administered nasally, buccally, or vaginally.

[0092] In embodiments, the pharmaceutical composition is formulated as a spray. Preferably, then, the pharmaceutical composition is preferably for oral, nasal and for oropharyngeal administration. Indeed, it is an advantage of the invention that the carboxyalkyl starch microparticles of the invention are sprayable.

[0093] In embodiments, the active pharmaceutical ingredient is an anti-infective agent.

[0094] There is also provided the use of the pharmaceutical composition of the invention as anti-infective agent forpreventing and / or treating an infection. There is further provided a method of preventing and / or treating an infection in a patient in need thereof, the method comprising administering the pharmaceutical composition of the invention to a mucosa of said patient.

[0095] In embodiments, the anti-infective is an antiviral agent. In embodiments, the infection is a viral infection. In embodiments, the viral infection is COVID-19, or an infection caused by SARS-CoV-2 virus or hCoV-OC43 virus.

[0096] There is also provided the use of the pharmaceutical composition of the invention as antiviral agent for preventing viral replication. There is further provided a method of preventing viral replication in a patient in need thereof, the method comprising administering the pharmaceutical composition of the invention to a mucosa of said patient. In embodiments, the viral replication is replication of SARS-CoV-2 virus or hCoV-OC43 virus.

[0097] In embodiments, the anti-infective is an antifungal agent. In embodiments, the infection is a fungal infection. In embodiments, the fungal infection is an infection caused by Candida albicans. In embodiments, the fungal infection is vaginal or buccal candidiasis.

[0098] In embodiments, the anti-infective is an antibacterial agent. In embodiments, the infection is a bacterial infection. In embodiments, the bacterial infection is an Escherichia coli. infection, preferably a vaginal Escherichia coli. infection.

[0099] In one embodiment, the patient is an animal. In preferred embodiments, the patient is a mammal, and preferably a human.

[0100] The pharmaceutical composition of the invention should contain the active pharmaceutical ingredient in an amount effective to achieve the desired therapeutic effect while avoiding adverse side effects. The amount of the pharmaceutical composition which is effective in the treatment of a particular disease, disorder or condition will depend on the nature and severity of the disease, the target site of action, the patient’s weight, special diets being followed by the patient, concurrent medications being used, the administration route and other factors that will be recognized by those skilled in the art. The dosage will be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters from the patient. Typically, 0.001 to 100 mg / kg / day will be administered to the subject. Effective doses may be extrapolated from dose response curves derived from in vitro or animal model test systems. For example, in order to obtain an effective mg / kg dose for humans based on data generated from rat studies, the effective mg / kg dosage in rat is divided by six.Definitions

[0101] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0102] The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. In contrast, the phrase “consisting of’ excludesany unspecified element, step, ingredient, or the like. The phrase “consisting essentially of” limits the scope to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the invention.

[0103] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All subsets of values within the ranges are also incorporated into the specification as if they were individually recited herein.

[0104] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0105] The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

[0106] No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0107] Herein, the term "about" has its ordinary meaning. In embodiments, it may mean plus or minus 10% or plus or minus 5% of the numerical value qualified.

[0108] 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.

[0109] Herein, the term alkyl” refers to a monovalent alkane radical of general formula -CnH2n+i. It is to be noted that, unless otherwise specified, the hydrocarbon chains of the above groups can be linear or branched. Further, unless otherwise specified, these groups can contain between 1 and 18 carbon atoms, more specifically between 1 and 12 carbon atoms, between 1 and 6 carbon atoms, between 1 and 3 carbon atoms, or contain 1 or 2, preferably 1 , or preferably 2 carbon atoms.

[0110] The term “amylolysis” means starch hydrolysis catalysed by an amylase (amylolytic enzyme), in this disclosure alpha-amylase (salivary amylase).

[0111] Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0112] The present invention is illustrated in further details by the following non-limiting examples.Example 1 - Carboxymethyl Starch:lodine anti-infective complexes: Expanded V-helix, spontaneous Iodine loading, increased mucoadhesion and sprayability, higher amylolysis rateAbbreviations

[0113] CL: Cross-Linked; Cid: Cross-linking degree; CM: Carboxymethyl; CMS: Carboxymethylstarch; CMS:l2 (CMS complex with iodine); DS : Degree of Substitution; CMS (DS 0.15): CMS powder with DS 0.15; CMS (DS 0.30): CMS powder with DS 0.30; CMS-CL20(MS), CMS-CL30(MS) and CMS-CL40(MS): CMS-Cross-Linked at various cross-linking degrees, where the numbers (cld) represent the percentage of STMP cross-linker reported to the initial amount of CMS, under microsphere(MS) form; G (Gelatinized); HAS (High Amylose Starch); Hylon® VII (Brand name Hylon VII of native HAS); HAS(G): High Amylose Starch Gelatinized; HAS-CL5 (HAS cross-linked with 5 / 100 epichlorohydrin / HAS (cld 5); HAS-CL10 (HAS cross-linked with 10 / 100 epichlorohydrin / HAS (cld 10); KeV (Kiloelectronvolts); MS (Microspheres); SMCA (Sodium Monochloroacetate); STMP (Sodium Tri-Meta-Phosphate).

[0114] Worth to note: Starch materials are generally recognized as safe (GRAS) and products containing starch are nontoxic, biocompatible, quite stable and slowly biodegradable in the biological environment (Gill et al., 1998).Reagents

[0115] Hylon® VII, a high amylose corn starch (HAS, 70% of amylose), was from Ingredion (Westchester, IL, USA). Sodium monochloroacetate (SMCA), sodium trimetaphosphate (STMP), epichlorohydrin, mucin, gelatin, bacterial a- amylase and human salivary a-amylase were from MilliporeSigma (Darmstadt, Germany). Iodine l2), KI, NaOH, and HCI were from Fisher (Hampton, New Hampshire, USA).1 . Starch derivatization1. 1. Preparation of carboxymethyl starch (CMS) powder

[0116] To allow chemical modification, starch needs to be first gelatinized as previously reported (Le Tien et Mateescu, 2017). An amount of 140 g of Hylon VII (corn starch with a 70% amylose content), was first suspended in approximatively 340 mL of water at 55 "C for 20 min under stirring and then an equal volume of 360 mL of 1 .5 M NaOH was added with continued stirring for 1 h. Carboxymethylation was carried out by adding 50 g sodium monochloroacetate (SMCA) continuing the reaction for 2h in the same conditions of stirring and 55 °C.

[0117] The mixture was then cooled down, neutralized, and washed first with 60%, 80%, and then 100% of methanol. The precipitate was then washed with acetone by filtration and oven-dried at 40 °C before being sieved to obtain CMS powders with particles size < 300 pm.

[0118] The obtained CMS derivative presented a degree of substitution (DS = 0.15 + 0.030) and was hereto called CMS(DS 0.15). Another CMS derivative was obtained exactly in the same conditions, but doubling the amount of SMCA from 50 g to 100 g and obtaining a CMS product with DS = 0.30 + 0.080, hereto called CMS(DS 0.30).1.2. Preparation of microspheres CMS(MS)

[0119] CMS(MS) were prepared by a water-in-water (W / W) emulsion method in three steps: a) preparation of the continuous phase, b) addition of the dispersed phase, and c) cross-linking of the beads (Li et al., 2012). a) The initial continuous phase (40 g of polyethylene glycol 20 000 in 100 mL of water) was maintained under constant mechanical agitation (500 rpm) in a water bath maintained at 55 °C. b) The emulsion was formed by adding a solution of 5 g CMS (DS 0.15) in 25 mL of 1 M NaOH) under stirring, c) For CMS (DS 0.15) crosslinking, 1.0 g, 1.5 g, or 2.0 g STMP were added to the emulsion under continued stirring for 30 min, to obtain respectively different crosslinking degrees conventionally expressed as percentages of crosslinker (20%, 30% and 40%) used to cross-link the CMS (DS 015) materials. The cross-linked CMS derivatives are hereto called CMS-CL20, CMS-CL30 and CMS- CL40, where the numbers represent the percentage of STMP cross-linker reported to the initial amount of CMS to cross-link. After neutralizing the pH to 7 with acetic acid, the emulsion was left under agitation for 2 h at room temperature and then kept in the fridge overnight to promote sedimentation of the microspheres (CMS-CL(MS). The collected CMS-CL(MS) were then washed, successively with 60%, 80%, and 100% methanol. Finally, the microspheres were dried with acetone under vacuum, left overnight at 37 °C, and stored in sealed containers until use. The obtained dry CMS-CL20(MS), CMS-CL30(MS) and CMS-CL40(MS) were then sieved to retain particles smaller than 300 pm.1.3. Cross-linked starch with epichlorohydrin (HAS-CL5 and HAS-CL 10)

[0120] An amount of 100 g of high amylose starch was dissolved in 300 mL of 5 M sodium hydroxide (cooled on an ice bath for at least 30 min before adding starch) and homogenized (still in the cold) for another 30 min. Then 5 or 10 g of epichlorohydrin was gradually added to obtain a cross-linking of 5 % or 10 %, respectively. Each HAS-CL was finally dried with acetone (at increasing concentrations). The dried powders were sieved, retaining particles between 75 and 300 pm in size.1.4. Iodine loading

[0121] Two methods were used for the inclusion of iodine in starch: i) with a Lugol's reagent (solution) and ii) by iodine vapor (spontaneous loading). i) Inclusion of iodine using Lugol’s reagent: iodo-iodide solution (h+KI) was prepared in the laboratory (10 g KI and 5g l2in 100 mL water), allowing the inclusion of iodine molecules in the helix structures formed by the starch (iodine retained by Van der Waals bonds).ii) Iodine vapor: 1 g powders of starch derivatives were placed in a beaker also containing 2 g of solid molecular iodine l2and the system was maintained closed in a desiccator for one week, checking the mass of each sample at the end.

[0122] The CMS (DS 0.15) exhibited the best iodine l2retention. This was a spontaneous inclusion of iodine by vapor exposure, a surprisingly simple Gas:Solid self-loading process.Iodine content determination

[0123] Sodium thiosulfate (Na2S2O3) was used in titrimetric analysis of l2based on reduction of iodine l2to Ij (Asakai et Hioki, 2011; Assoumanou et a / ., 2011).2Na2S2O3 + 12— * 2Nal + Na2S40e

[0124] During titration, a solution of starch was added as indicator and the titration was continued until the equivalence: the disappearance of the blue color corresponded to the consumption of l2(iodine). Practically, 0.3 g powder of starch complexes with iodine suspended in 10 mL distilled H2O were titrated with 0.0025 M standardized thiosulfate solution.

[0125] The highest iodine contents (mg / g of starch derivative powder) were for cross-linked High Amylose Starch (HAS-CL10): 95 mg / g powder, for CMS (DS 0.15): 90 mg / g powder and for CMS-MS (CL40%): 108 mg / g (Fig. 2).

[0126] This was a spontaneous inclusion of iodine by vapor exposure, an advantageous procedure of loading related to the ability of l2to sublimate.

[0127] The CMS (DS 0.15) exhibited a high iodine (l2) retention. Concerning the CMS microspheres cross-linked with STMP, the iodine loading increased linearly with the cross-linking degree. The high iodine retention CMS- CL40: l2(MS) of about 108 mg l2 / g at elevated crosslinking degree (40 %) with STMP could be explained by: i) more polar anionic metaphosphate groups (one per each phosphate bridge) favoring the hydration and ii) more expanded matrices due to polar metaphosphate groups grafted by the reaction with STMP and consequently producing an expanded diameter of the V-helices (when compared with the unsubstituted starch) favoring iodine retention.

[0128] The iodine loading (90.45 mgl2 / g) of carboxy methylated CMS (DS 0.15) material with a low degree of substitution (DS 0.15) was higher than that of 18 mg / g of CMS (DS 0.30) with a higher DS. As an explanation, a better fitting of hydrophobic iodine size with the size of the hydrophobic channel of V-type helix cannot be excluded. Furthermore, the lower iodine loading by CMS (DS 0.30) can be explained by the higher polar character of CMS (DS 0.30) with more carboxylic polar groups that may prevent the access of hydrophobic iodine (Wang et al., 2017) by repulsive interactions.

[0129] Major differences in iodine loading were found for CMS-CL(MS) at various cross-linking degrees (Fig. 2). For instance, the loading of CMS-CL20):l2(MS) was only 8 mg / g powder (whitish in Fig.2) whereas for CMSCL30:l2(MS) the loading was about 50 mg / g (moderately brown), and for the highly loaded CMS-CL40:l2(MS) the loading was 108 mg / g (dark brown in Fig. 3).

[0130] Our starch-based complexes with iodine have been compared with povidone-based commercial products BETADINE® 1 % and BETADINE®5%, where the percentages represent the concentration of the compound Povidone:lodine (PVI) and whose concentration of iodine were 0.89 mg l2 / ml_ and 5.21 mg 12 / mL, respectively, as inhouse determined by titration with thiosulfate.

[0131] The CMS (DS 0.15):l2at various concentrations gave similar values to BETADINE® at the same concentrations: ex at 5% the iodine content was about 5.21 mg l2 / ml_ for Betadine® and 4.52 mg l2 / ml_ for CMS (DS 0.15):l2materials. The CMS (DS 0.15) exhibited various properties (mucoadhesion, sprayability, amylolysis) favoring its use as microbicidal agentTable 1 - Iodine content of commercial Betadine® and of CMS(DS0.15):l2materials, at various concentrations

[0132] Although the almost similar iodine content of Betadine® and of CMS(DS 0.15): l2, there are some advantages for CMS(DS 0.15):l2complex, as follows: There are several major differences, as follows : i) CMS:I2- is an iodine complex based on a starch derivative (CMS) a material of natural (vegetable) sourcing, rather than a synthetic one. ii) As an inclusion complex (clathrate) CMS:I2- is easy to obtain (spontaneous reaction) while PVP-I is rather an electrostatic binding. Hi) The CMS:I2- is susceptible to amylolysis (hydrolysis with salivary amylase).

[0133] Only modified starch with expanded V-type helices allowed a good iodine inclusion and this was not related to gelatinization. This consideration is supported by the fact that gelatinized starch presented the lowest starch loading (32 mg l2 / g) and native Hylon VII

[0134] The CMS (DS 0.15): 90 mg / g was preferred for further uses as anti-infective because its excellent mucoadhesion, low viscosity, best sprayability and highest susceptibility to amylolysis with salivary amylase.1.5. Physico-chemical characterization of modified starch1.5.1. Determination of the DS by back titration

[0135] CMS was protonated for 20 min in 0.1 M HCI and washed to a conductivity below 50 piS / cm, then dried and used to determine DS (the amount of -COOH groups / glucose monomer unit), by reverse titration. A quantity of100 mg of CMS (in triplicate) was solubilized in 20 mL of 0.05 M NaOH. Subsequently, the excess NaOH was determined by titration with 0.05 M HCI using phenolphthalein as an indicator. The Blank consisting of 20 mL of 0.05 M NaOH was also titrated (Stojanovic et al., 2000; Stojanovic et al., 2005).

[0136] It was calculated as: nC00H= vi> ~ v) x cHCtwhere: Vb (in mL) is the volume of HCI used for the titration of the blank; v (in mL) is the volume of HCI used for titration of the sample; CHCI (in mol / L) is the HCI concentration.1.5.2. Morphology

[0137] The morphology of loaded and unloaded Hylon VII, CMS, CMS-CL(20; 30; 40) (MS) and of HAS-CL(5,10) powders was examined by scanning electron microscopy (SEM). The powders were mounted on SEM sample holders with double-stick carbon tape. The images of the samples were obtained in a high-vacuum SEM mode with a 10 keV.

[0138] Native High-Amylose Starch, (HAS) appeared in SEM micrographs (Fig. 4) as compact powder-shaped granules. This compactness, smooth and regular size (about 50-80 pm). The SEM image analysis showed a roughly aspect for Carboxymethyl starch: CMS (DS 0.15) and CMS (DS 0.30), conferring high specific surfaces and even a porous structure which are advantageous for iodine adsorption. (Fig.4).

[0139] The HAS cross-linked at various epichlorohydrin / HAS ratios: HAS-CL5 and HAS-CL10 presented, both, a roughness suggesting a higher specific surface, explaining better iodine inclusion (62 mg / g and 95 mg / g, respectively) than that of the gelatinized HAS-G which appeared with a lower roughness and consequently with lesser iodine retention (32 mg / g).1.6. Structural characteristics1.6.1. Fourier Transformed Infrared (FTIR)

[0140] When compared with Hylon VII, the FTIR spectra of CMS powder (Fig.5) showed a new band around 1590 cm1(ascribed to carboxyl groups). The intensity of band in the region 3000-3700 cm1, characteristic of hydroxyl groups, was slightly decreased for the CMS:l2 complex in comparison to the non-complexed CMS. This can be explained by the intercalation of iodine in the V-type starch helix, with a possible limitation of the hydroxyl stretching bands. This decrease was found only for CMS and not for native Hylon VII starch, because of much lower amount of iodine loaded into this material, when compared to CMS.1.6.2. X-Ray Diffraction for characterisation of CMS and CMS:I2 materials

[0141] X-ray patterns showed a well-organized semicrystalline structure for native corn starch (Hylon vll) with peaks at about 5°, 14°, 16°, 19°, 21 °, 23° and 30° (Fig. 6) suggesting a crystalline structure typical of corn starches with double helices in a dense packing. This structure restrains solubility, prevents chemical reactions (such asenzymatic hydrolysis) and limits inclusion complexation) explaining the low iodine loading (Fig. 2, Fig. 3).

[0142] For CMS (DS 0.15 and DS 0.30), the peaks at 5°, 14°, 16° and 23° characteristic of B-type helices vanished whereas the peaks at 20° and 22° characteristic of the V-type (simple helix structure) have been strengthened, but in the context of a more amorphous pattern.

[0143] As a general feature, it has been observed that the iodine inclusion into the helices of HAS starch and of its derivatives, in addition to the change in chemical structure, induces even more decreases in crystallinity. This behavior could be ascribed to a more pronounced destabilization of hydrogen bonding mainly inter- but also intrachain of starch derivatives. As a result, after iodine vapor loading, the crystallinity was even more reduced. This aspect is important suggesting more hydratability of the network, lower viscosity, higher sprayability and better susceptibility to amylolysis of starch granules. This behavior could be attributed to the treatment-induced destabilization of the network of starch materials.1. 7. Mucoadhesion assays

[0144] It was of interest to evaluate the mucoadhesive characteristics of CMS:l2 complexes in view of further utilization for buccal, oropharyngeal or vaginal administration.

[0145] Mucin-gelatin adhesive supports were prepared by casting from a warm filmogenic solution containing 10 % gelatin and 5 % mucin. The supports for mucoadhesion were obtained by gently pouring 2.5 g of the mucin-gelatin filmogenic mixture into hexagonal weighing dishes (diameter 85 mm) and left to solidify for 2h before testing. The assays were carried out at an inclination of 45° (Robinson et al., 2021).

[0146] The adhesion of suspended particles was tested by pipetting 100 pL of the suspensions of samples onto the mucin or mucin-gelatin plate at the hexagonal weighing dishes containing mucin-gelatin support. For each material, three samples were applied for different times of contact (t= 0 s; 120 s and 300 s) to the same support at a distance of 10 mm each other. At the end of the interval, the adhesive backing was immediately inclined at 45° inclination (time zero) and the time taken for droplets to run 20 mm down onto the mucin-gelatin surface was recorded and considered to evaluate the relative mucoadhesion of various formulations (Fig. 7A). A much stronger mucoadhesion measured as a longest runtime (480 seconds) was found for CMS (DS O.15):I2 formulations (Fig. 7B) when compared unloaded CMS (DS 0.15). A possible explanation of higher mucoadhesion for CMS(DS O.15):I2 can be related to the nonpolar iodine hosted by the V-helix, that would trigger a repulsion of outer carboxylic groups, enhancing thus the adhesion. Also, a better mucoadhesion of the loaded CMS(DS 0.15): I2 was found when compared with the commercial product Betadine® (Fig. 7B).1.8. Viscosity and Sprayability assays

[0147] To test the sprayability of CMSJ2, and of Betadine (suspensions 1% and 5%) each formulation was first homogenized and then loaded into a manual spray bottle. The assay was realized on a white paper placed on a flat surface to assess the spray distribution. The spray bottle was held approximately 15 to 30 cm from the surface, and an equal number of intermittent spray pushes was applied for each sample. The distribution of the spray wasobserved Fig.8), noting whether the liquid formed a uniform layer, concentrated in certain areas, or unevenly dispersed. For each sample (CMSJ2, and PVP-I) at various concentrations, it was estimated the spray pattern's consistency when splashed on a white paper screen and analyzed for comparison.

[0148] The CMS(DS 0.15): l2, presented an excellent sprayability and this was correlated with the low viscosity of this material, when complexed with the iodine.

[0149] The unloaded CMS material, presented a viscosity so high that sprayability was not measurable.

[0150] Surprisingly, it was found that the viscosity of starch-based products is drastically reduced following iodine loading (Fig 8 - Inset Table). This Inset Table (Fig 8) shows the effect of iodine on viscosity and sprayability of each formulation . The lowered viscosity by iodine inclusion was an unexpected and an important result, allowing the sprayability of the iodine-loaded material (Fig 8).1.9. Hydrolysis of Iodine complexes by different a-amylase preparations

[0151] Commercial human salivary a-amylase, bacterial a-amylase, or crude saliva were assayed by adding 1 mL of each enzyme stock solution (the enzyme concentration were chosen such as to obtain 0, 20, 40 and 60 enzyme units) to 1 mL of 1 % (w / v) Hylon VII, CMS, or CMS:l2 suspension. To facilitate the solubility of Hylon VII, it was heated under stirring, brought to a boil, and cooled down after solubilization. The amylolysis with liberation of reducing sugars was carried out by incubating of the mixture at 37 °C for 3 min. The reaction was stopped by adding 1 mL of 3,5-dinitrosalicylic acid and heating it at 100 °C for 5 min for determination of reducing sugars. The volume of the reaction mixture was rapidly adjusted to 10 mL with distilled water and cooled down on an ice bath before reading the absorbance at A540 nm. A standard curve was drawn upon measuring the absorbance at A540 nm of known concentrations of glucose solutions following the same mentioned procedure. At least four measurements were made for each condition and the data given are an average of these results. One enzyme unit (EU) of enzyme) is defined as the amount of enzyme that releases 1 imol of reducing sugar (r.e. maltose equivalent) per minute under the standard assay conditions.

[0152] The substrate specificity of the amylolytic enzymes was determined against 1 % Hylon VII, CMS or CMS:l2.

[0153] The amylolysis of starch derivatives was assayed with various enzyme concentrations: 20-60 U / mL for both salivary and bacterial commercial alpha-amylases - Figs. 9 A and B and with 0.2-1 mL for crude saliva - Fig. 9C. These figures show reducing sugar production from hydrolysis of the various starches at 37 °C.

[0154] Unexpectedly, The highest amount of reducing groups was liberated from CMS: l2, followed by CMS and Hylon VII, respectively. A similar behaviour was observed with these starches treated with crude saliva.

[0155] The hydrolysis rate of cross-linked starch microspheres CMS-CL(20, 30, and 40)(MS) was higher than the hydrolysis rate of the other cross-linked starch derivatives. This suggested that the carboxymethyl starch CMS (DS 0.15) could be a matrix with a good susceptibility at amylolysis with alpha-amylase.

[0156] The behavior of CMS:l2 as virucidal agent, particularly as an anti-infective approach against the respiratory viruses, including SARS-CoV-2 is described in the subsequent example 2. (Tajer et al, 2025) in this journal.

[0157] An advantage of CMS:l2 is the natural (vegetable) sourcing to obtain CMS matrix whereas PVP-I is based on synthetic polyvinylpyrrolidone material. Another advantage is the simple (spontaneous) reaction to obtain the CMS:l2 product that is very stable (more than 12 months) as a clathrate. Finaly, another advantage of CMS:l2 seems to be its susceptibility to amylolysis (hydrolysis) with salivary amylase) on site, facilitated by its mucoadhesion. Thus, eventual dissipation of iodine through esophagus, is prevented.Example 2 - Carboxymethyl Starch:lodine Complexes as Virucidal Agents: Salivary Amylase Triggers On-Site Iodine Release, Preventing Human Coronavirus OC43 ReplicationAbbreviationsAMEM Alpha Minimum Essential Medium EagleDS Degree of substitutionDTT DithiothreitolEDTA Ethylenediaminetetraacetic acidEGTA Ethylene glycol-bis(2-aminoethylether)-N, N, N', N'-tetraacetic acidFBS Fetal Bovine SerumMgSCU Magnesium sulfateNS2 Noonan Syndrome 2 genePBS Phosphate-Buffered SalineXTT 2,3-Bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilideMaterials

[0158] Hylon VII®, a commercial high amylose corn starch (HAS 70% of amylose), was from Ingredion (Westchester, IL, USA). Sodium monochloroacetate, commercial bacterial alpha-amylase and human salivary amylase were purchased from Millipore Sigma (Darmstadt, Germany). “Home-made” a-amylase (crude saliva centrifuged and filtered), has been used for comparison. XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfo-phenyl)], AMEM (Alpha Minimum Essential Medium Eagle) and FBS (Fetal Bovine Serum) were also purchased from Sigma. The other chemicals were reagent-grade and used without further purification.Cell lines

[0159] HRT-18, an epithelial cell line derived from a colorectal adenocarcinoma, was a generous gift from Dr.Pierre Talbot (INRS-Armand-Frappier, Canada). Cells were maintained in AMEM medium supplemented with 10% fetal bovine serum (FBS) and antibiotics (1 % penicillin-streptomycin) in 5% CO2 at 37 °C.Human coronavirus hCoV-OC43 amplification

[0160] A modified version of hCoV-OC43 called hCoV-OC43RLuc was used.

[0161] The Renilla luciferase reporter gene was inserted in the NS2 gene of the hCoV-OC43 genome, thereby allowing the monitoring of infection through the measurement of luciferase activity. Viral stocks were refreshed by infection of HRT18 (2 x 106cells) for 48 hours at 33 °C. The supernatant was then harvested, ultracentrifuged at 27000 rpm / min for 1 h and filtered through a 0.22 pm filter.Cell viability and in vitro infection assay

[0162] Luciferase activity (RLU) was measured to evaluate viral replication, while the 2,3-bis-(2-methoxy-4-nitro-5- sulfo-phenyl) assay (XTT) was run in parallel to confirm the absence of a significant effect on cell viability and metabolism. We thus initially examined whether CMS:l2 affected viability of HRT-18 cells. The cells were incubated with CMS: l2, Betadine, or Lugol at different concentrations. Control samples included virus-free cells (Mock control set at 100% viability), and cells infected with non-treated viruses (Virus [NT]).

[0163] The CMS (DS 0.15): l2(hereto called CMS:I2), Betadine®, Lugol (from 0.001 to 1 %) and alpha-amylases (60 Units / mL of commercial or home-made human saliva) were added alone or together with other treatments to 10 p.L of hCoV-OC43RLuc (TCID50x105 / mL) for 30 min at room temperature. The TCID50 (Tissue Culture Infectious Dose 50%) is a quantitative measure used in virology to estimate the amount of virus required to infect 50% of a given cell culture (particularly used for viruses that do not form plaques).

[0164] Virus-containing mixtures were subsequently added to 3x105HRT-18 cells in AMEM medium supplemented with 1 % FBS, antibiotics and 100 nM non-essential amino acids, at 33 °C. After 2 days, cell viability was assessed using the XTT assay. The absorbance was determined at 450 nm. For measurement of infectivity, HRT-18 cells were next detached from each well with 0.25 % trypsin and washed with 1X PBS. Cells were lysed in 100 pL Renilla lysis buffer for 10 min on ice, and centrifuged at 15000 rpm. Supernatants (100 pL) were then quantified for luciferase activity using a luminescence 96 well plate reader (Biotek, Montreal, Canada).

[0165] The virucidal activity of CMS:I2and of other iodine compounds was quantitatively assessed against the luciferase-expressing hCoV-OC43RLuc virus, using the luciferase-based infectivity assay and cell target HRT-18. The cell viability assay confirmed that CMS:I2did not affect cell viability / metabolism compared to nontreated virus- infected cells (Fig. 10A).

[0166] Similarly, Betadine® and Lugol did not show variations in the viability (XTT) results. The infection of HRT-18 cells was monitored next by measuring luciferase activity. As expected, both Betadine and Lugol reduced viral replication, particularly at high concentrations (Fig. 10 B-C). Importantly, CMS:l2had a comparable virucidal effect, and was more efficient at high concentrations (even in the absence of salivary amylase).

[0167] HRT18 cells were next exposed to hCoV-OC43RLuc, untreated or treated with CMS:I2at various concentrations, in the presence and absence of the two amylolytic enzymes: salivary a-amylase and home-madesaliva preparations. The effect of CMS:l2 with saliva on virus infectivity is shown in Fig. 11 . With the CMS:h at concentrations of 1 % and 5%, in the presence of saliva, the hCoV-OC43 replication was markedly reduced to 0.03% and 0.006% respectively, compared to untreated infected control cells (set at 100%). At the lowest iodine concentrations (0.01 % and 0.05%), the reduction in infectivity was closer to 50% in the presence of human saliva, compared to infectivity of 100 % of control untreated virus. All tested conditions, again, had practically no impact on cell viability (Fig. 11A).

[0168] As human saliva is known to contain multiple components and showed an effect on viral replication on its own, the infectivity experiments were repeated with the CMS:l2-treated hCoV-OC43 virus concomitantly exposed to commercial salivary a-amylase (Fig. 12). Virucidal activity was markedly increased (low infectivity) in CMS:l2 upon incubation with salivary a-amylase (Fig 12B). Similarly, no change in cell viability (Fig. 12A) was observed in cells incubated with different treatments of hCoVOC43 virus.

[0169] The virucidal activity of various a-amylases alone (in the absence of CMS:l2) toward hCoV-OC43, have been compared (Fig. 13). Upon incubation of hCoV-OC43RLuc with bacterial or human a-amylases or crude saliva, practically no reduction in luciferase activity was measured in treated samples showing the same infectivity as the non-treated (NT) virus and, consequently, the CMS:l2 virucidal agent is essential. As expected, cell viability was not impacted.

[0170] Overall, these results showed a strong virucidal activity of CMS:l2 toward the human coronavirus hCoV- OC43 and that human saliva, most likely via its a-amylase enzymatic activity, significantly augmented this viricidal property. This raises the possibility of using CMS:I2as a sprayable solution for decontaminating the naso / oropharyngeal area. This appears to be a possible general mechanism underlying the inhibitory effect of iodine on other viruses, including human and avian influenza viruses (Sharma et a / ., 2021).

[0171] The putative impact of the new approach with CMS:I2as a virucidal agent is supported by the enhanced mucoadhesive properties of CMS when complexed with iodine (CMS:h). This main virucidal role of CMS:l2 is confirmed by the fact that no antiviral activity was found for the three amylases (including crude saliva) tested separately (Fig. 13) in the absence of CMSJ2, despite some known antimicrobial (almost bactericidal) effects of saliva.

[0172] In conclusion, considering the data of this report, it is possible to consider that CMS:l2-based formulations could act and prevent the initial phases of SARS-CoV-2 infection, such as viral attachment and replication, reducing the risk of the downstream infection process.Example 3 - Application of Carboxymethyl Starch:lodine Complexes as Antimicrobial Agents. Toxicity Induced Against Candida albicans and Escherichia coll

[0173] This study explored the use of carboxymethyl starch (CMS) as a replacement for commonly used polymersin iodopovidone complex production, focusing on iodine’s antimicrobial effects against Candida albicans and Escherichia coli. Results demonstrated CMS: h's inhibition of C. albicans growth via disc diffusion assays and highlighted viability reduction via MTT assay. The suspension 5% of iodine complex showed a high inhibition of E. coli growth after 24 h of contact. In conclusion, the iodine offered insights into CMS:l2 complex's potential as an antimicrobial agent.Materials and Methods

[0174] Hylon VII®, a commercial high amylose corn starch (HAS 70% of amylose), was from Ingredion (Westchester, IL, USA), Potato dextrose agar and Potato Dextrose Broth, the growing mediums were purchased from Sigma Aldrich (Darmstadt, Germany), as well as MTT was also purchased from Millipore Sigma. Lysogeny Broth medium and agar were supplied by Biobasic (Markham, ON, Canada). The Candida albicans strain supplied by Innofibre - Innovation center and Escherichia coli DH5a strain was purchased from American Type Culture Collection (ATCC, Manassas, VA, USA).Suspensions of anti-infective agents

[0175] Different concentrations of CMS:l2 (1% and 5% stock solution) were prepared. Serial dilutions were then made from the stock solution. The two tested controls, Lugol, Betadine 1% and 5%, were diluted to the same concentrations.Antimicrobial activity of CMS:l2 samplesDiffusion and growth assay

[0176] The behavior of the prepared antimicrobial agents was evaluated by the diffusion and inhibition zone tests toward Candida albicans and Escherichia coli DH5a strains. Approximatively 74 x 106CFU / mL of each strain (E. coli and C. albicans) with an optical density at 600 nm (ODeoo). CFU stands for Colony Forming Units. The test was performed by seeding 10 mg powder compressed as a tablet of two diameters (9 mm and 12 mm) of CMS:l2 directly into the middle of the prepared Petri dishes. After 24 h of incubation at 37 °C for E. coli and at 30 °C for C. albicans, the diffusion zone where both strains proliferation was inhibited was measured.Viability test

[0177] The CMS:l2 cytotoxicity effect was determined by MTT assay with Candida albicans as a model for eukaryotic cells. Aliquots of 1.0 mL with 1 *106CFUs / mL of C. albicans were pipetted into Eppendorf tubes with 1-5 mg / mL of iodine agent (CMS:l2 or commercial Betadine® product) or Lugol.. The suspensions were incubated at 30°C for 48 h. After incubation, 50 pL of MTT solution (5mg / mL) was added and incubated at 30°C for 2 h. The reaction was stopped with 100 pL of DMSO and then, the absorbance was measured at 570 nm against yeast-free control.

[0178] Additional evaluation of the antibacterial capacity was performed by using CMS:l2 agent. It was compared tothat of the commercial product Betadine® with E. coli as a bacterial model in LB broth with an OD 600 nm. The antimicrobial samples were added to the E. coli suspension at two different concentrations (1% and 5%) and incubated at 37 °C, with agitation at 180 rpm for 48 h. During this period, sampling was withdrawn at 24 h and 48 h.Then dilution series were carried out, and 0.1 mL was spread on LBA Petri dishes. The plates were then incubated at 37 °C for 24 h, and CFUs were counted after treatment.Diffusion and growth assays

[0179] An ideal antifungal agent should be active against fungal species but also against bacteria. The antifungal activity of CMS:l2 was exhibited by disk diffusion assay. CMS:l2 formed inhibition zones with C. albicans.

[0180] The average of the inhibition zone diameter (IZD) of iodine complex against these isolates was 9 mm (range 19 - 25 mm) and 12 mm (range=40 - 43 mm). The growth inhibition zones of CMS:l2 against C. albicans i are shown in (Fig. 14 and Table below). The drop was recorded from 4.3-4.0 for 9 mm disc of CMS:l2 to 2.5-1 .9 mm for 12 mm discs, which reveals stronger antibacterial activity for a larger contact area.

[0181] Table 2 : Inhibition zone diameter for C. albicans after exposure to CMS^discs in cm (9 mm, 12 mm)Sample C. albicansCMS: 12 (9 mm discs) 2.3 _CM S: (9 mm discs) 2.5 _CMS: 12 (9 mm discs) 1.9 _CMS: 12 (12 mm discs) 4.3 _CMS: 1 (12 mm discs) 4.1 _CMS: 12 (12 mm discs) 4.0Viability test

[0182] MTT test was used to determine the chronic effect of CMS:l2 suspension exposure (long-term) on C. albicans growth. Candida strain was subjected for 0 to 48 h to CMS:l2 concentrations ranging from 1% to 5%. After48 h of chronic iodine complex exposure (Fig. 15). MTT test revealed that C. albicans was substantially reduced in a dosage and time dependent manner, with 50 and 46% yeast viability in both concentrations 1 % and 5% of CMS:l2

[0183] The obtained data indicate that suspensions of CMS:l2 at concentrations of 1 % and 5% after incubation for24 and 48 h at 37°C significantly inhibited the E. coli population (Fig. 16). In addition, the highest concentration of CMS:l2 (5%) had a toxic effect (viability of 3.9%) after the first 24 hours of incubation. Response profiles similar to those of Betadine 5% treatment have been observed. The incubation of culture cells with CMS:l2 1 % had a weaker effect on their inhibition with a viability rate of 46.5% after 24 h of incubation and 33.7% after 48 h.Discussion

[0184] We used carboxymethyl starch with the aim to replace the polyvinylpyrrolidone as matrix the iodopovidone complex PVP-I, which are absorbed and excreted in the urine after exposure.

[0185] The scope of the disclosure should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.REFERENCES

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Claims

CLAIMS:

1. A pharmaceutical composition for mucosal administration comprising microparticles, said microparticles comprising carboxyalkyl starch and one or more active pharmaceutical ingredients (API), wherein the carboxyalkyl starch is either: uncrosslinked and having a degree of substitution with carboxyalkyl groups of less than about 0.25, or crosslinked and having crosslinking degree of at least about 25, wherein the carboxyalkyl starch adopts a V-type helix secondary structure defining an internal cavity within said helix, and wherein the molecules of the one or more active pharmaceutical ingredients are at least partially contained within said internal cavity of the carboxyalkyl starch.

2. The pharmaceutical composition of claim 1, wherein the mucosal administration is oropharyngeal, nasal, buccal, intraesophageal, or vaginal administration, preferably oropharyngeal, nasal, or buccal administration.

3. The pharmaceutical composition of claim 1 or 2, further comprising one or more pharmaceutically acceptable excipients.

4. The pharmaceutical composition of any one of claims 1 to 3, being formulated as an oral or nasal spray.

5. The pharmaceutical composition of any one of claims 1 to 4, being in powder form, semi-liquid form, or in liquid form.

6. The pharmaceutical composition of claim 5, being in powder form.

7. The pharmaceutical composition of claim 5, being in semi-liquid form or in liquid form.

8. The pharmaceutical composition of claim 7, wherein the microparticles are suspended in a semi-liquid or liquid pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 7 or 8, being an ointment, a cream, a gel, a paste, a foam, a solution, a suspension, an emulsion, a syrup, an elixir, or a nasal or oral liquid spray.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the one or more active pharmaceutical ingredients is one or more of:an anti-infective including amebicides, aminoglycosides, anthelmintics, antiviral agents (including adamantane antivirals such as amantadine and rimantadine, antiviral boosters such as ritonavir and cobicistat, antiviral combinations, antiviral interferons, antiviral monoclonal antibodies, and virucidal agents blocking the viral replication), antifungals (including azole antifungals, echinocandins, polyenes, and other antifungals), antibacterial agents (including sulfonamides, tetracyclines, and other antibiotics); a genitourinary tract agent; a topical agent including mouth and throat products, nasal preparations (including nasal antihistamines and decongestants; or an alternative medicine (including herbal products, and probiotics).11 . The pharmaceutical composition of claim 10, wherein the one or more active pharmaceutical ingredients is an anti-infective.

12. The pharmaceutical composition of embodiment 11, wherein the anti-infective is an antiviral agent, preferably one or more of an adamantane antiviral, such as amantadine, and rimantadine, an antiviral booster, such as ritonavir and cobicistat, an antiviral combination, iodine, or a virucidal agent blocking the viral replication.

13. The pharmaceutical composition of claim 11, wherein the anti-infective is an antifungal agent, preferably one or more of an azole antifungal, an echinocandin, such as nystatin, amphotericin b, amphotericin b liposomal, and amphotericin b lipid complex, an aminosalicylate or an aminosalicylic acid, or a nicotinic acid derivative.

14. The pharmaceutical composition of claim 11 , wherein the anti-infective is a sulfonamide, such as sulfamethoxazole / trimethoprim, and sulfadiazine.

15. The pharmaceutical composition of claim 11 , wherein the anti-infective is a vaginal anti-infective agent for treating a bacterial or fungal vaginal infection; preferably a vaginal antifungal (such as for treating vaginal thrush), or a vaginal antibacterial for treating a bacterial infection such as bacterial vaginosis or for managing irritation or soreness.

16. The pharmaceutical composition of claim 15, wherein the anti-infective is miconazole topical, tioconazole topical, metronidazole topical, clindamycin topical, terconazole topical, clotrimazole topical, iodine topical, butoconazole topical, hydroxyquinoline topical, sulfanilamide topical.

17. The pharmaceutical composition of any one of claims 1 to 10, wherein the one or more active pharmaceutical ingredients is a vaginal agent, preferably a female sex hormone (for example a combinationof estrogen and progestin or just estrogen) or a contraceptive agent, such as estradiol topical, citric acid / lactic acid / potassium bitartrate topical, conjugated estrogens topical.

18. The pharmaceutical composition of any one of claims 1 to 17, wherein the microparticles consist of the carboxyalkyl starch and the one or more active pharmaceutical ingredients.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the carboxyalkyl starch is carboxy methyl starch.

20. The pharmaceutical composition of any one of claims 1 to 19, wherein the carboxyalkyl starch is crosslinked.

21. The pharmaceutical composition of claim 20, wherein said crosslinking degree is at least about 25, preferably at least about 40.

22. The pharmaceutical composition of any one of claims 1 to 19, wherein the carboxyalkyl starch is uncrosslinked.

23. The pharmaceutical composition of claim 22, wherein said degree of substitution with carboxyalkyl groups is less than about 0.25, preferably less than about 0.20, and more preferably about 0.1524. The pharmaceutical composition of any one of claims 1 to 23, wherein the microparticles are between about 1 pm and about 1000 pm in size.

25. The pharmaceutical composition of any one of claims 1 to 24, wherein the microparticles up to about 500 pm, up to about 250 pm, preferably up to about 150, preferably up to about 100 pm in size.

26. The pharmaceutical composition of any one of claims 1 to 25, wherein the microparticles are at least 5 pm, preferably at least 10 pm, preferably at least 25 pm, and preferably at least 50 pm in size.

27. The pharmaceutical composition of any one of claims 1 to 26, wherein the microparticles are about 75 pm in size.

28. The pharmaceutical composition of any one of claims 1 to 27, being mucoadhesive.

29. The pharmaceutical composition of any one of claims 1 to 28, wherein the presence of iodine as an active pharmaceutical ingredient increases mucoadhesion, lowers viscosity, increases sprayability, and / or increases susceptibility to amylolysis.

30. The pharmaceutical composition of any one of claims 1 to 29, wherein, when the pharmaceutical composition is hydrolysed by alpha-amylase, the pharmaceutical composition releases in situ the one or more active pharmaceutical ingredients, such as iodine exerting the anti-infective action.31 . An oral or nasal spray comprising the pharmaceutical composition of any one of claims 1 to 30, wherein the spray comprises a canister containing the pharmaceutical composition, an atomizer for dispersing the pharmaceutical composition into an aerosol, and an outlet to disperse the aerosol into the nose or mouth of a patient.

32. A method of manufacture of the pharmaceutical composition of any one of claims 1 to 30, the method comprising the steps of: a) providing precursor microparticles, wherein said precursor microparticles comprises a carboxyalkyl starch, wherein the carboxyalkyl starch is either:• uncrosslinked and having a degree of substitution with carboxyalkyl groups of less than about 0.25, or• crosslinked and having crosslinking degree of at least about 25, and wherein the carboxyalkyl starch adopts a V-type helix secondary structure defining an internal cavity within said helix, and b) loading the precursor microparticles with one or more active pharmaceutical ingredients, thus allowing at least partial insertion of the molecules of the one or more active pharmaceutical ingredients within said internal cavity, thus yielding said microparticles comprising said one or more active pharmaceutical ingredients, c) formulating said microparticles comprising said one or more active pharmaceutical ingredients into said pharmaceutical composition.

33. The method of claim 32, wherein step a) comprises carboxyalkylating a starch, fore example by reacting the starch with a carboxyalkylating agent, such as sodium monochloroacetate or monochloroacetic acid for carboxymethylation and sodium chloropropanoate or chloropropanoic acid for carboxyethylation.

34. The method of claim 32 or 33, wherein step a) further comprises crosslinking the carboxy alkylated starch.

35. The method of claim 34, wherein the crosslinking is achieved by emulsion crosslinking wherein: an emulsion of droplets of a first phase in a continuous second phase is prepared, the first phase being a liquid phase in which the carboxyalkylated starch is solubilized, the second phase being a liquid phase that does not comprise carboxy alkylated starch and a crosslinking agent is added to the emulsion to crosslink the carboxyalkylated starch and form the precursor microparticles.

36. The method of claim 35, wherein the emulsion is a water-in-water emulsion, and wherein the first phase is a reaction mixture obtained by gelatinizing starch and the second phase is polyethylene glycol in water.

37. The method of claim 35 or 36, wherein the crosslinking agent is sodium trimetaphosphate (STMP) or epichlorohydrin, preferably STMP.

38. The method of any one of claims 32 to 37, wherein said loading at step b) is achieved by exposing the microparticles of the carboxyalkyl starch to a vapor, an aerosol or a spray of the active pharmaceutical ingredient, preferably iodine, preferably in a desiccator, preferably for 1 to 7 days, preferably for 7 days.

39. The method of any one of claims 32 to 37, wherein said loading at step b) is achieved by impregnating the microparticles of the carboxyalkyl starch with a solution of the active pharmaceutical ingredient.

40. Use of the pharmaceutical composition of any one of claims 1 to 30 for delivering said one or more active pharmaceutical ingredient to a mucosa of a patient in need thereof.

41. A method of delivering one or more active pharmaceutical ingredients to a mucosa of a patient in need thereof, the method comprising administering the pharmaceutical composition of any one of claims 1 to 30 to said mucosa of said patient.

42. A method for mucosal administration of an active pharmaceutical ingredient to a patient in need thereof, the method comprising administering the pharmaceutical composition of any one of claims 1 to 30 to said mucosa of said patient.

43. The use of claim 40 or the method of claim 41 or 42, wherein the mucosa is the oral mucosa, the nasal mucosal, the oropharyngeal mucosa, or the vaginal mucosa.

44. The use of claim 40 or 43, wherein the pharmaceutical composition is for nasal, oropharyngeal, buccal, or vaginal administration.

45. The method of any one of claims 41 to 43, wherein the pharmaceutical composition is administered nasally, oropharyngeally, buccally, or vaginally.

46. The use / method of any one of claims 40 to 45, wherein the pharmaceutical composition is formulated as a spray.

47. The use / method of any one of claims 40 to 46, wherein the active pharmaceutical ingredient is an anti- infective agent.

48. Use of the pharmaceutical composition of any one or claims 1 to 30 as anti-infective agent for preventing and / or treating an infection.

49. A method of preventing and / or treating an infection in a patient in need thereof, the method comprising administering the pharmaceutical composition of any one or claims 1 to 30 to a mucosa of said patient.

50. The use / method of claims 48 or 49, wherein the anti-infective is an antiviral agent.51 . The use / method of any one of claims 48 to 50, wherein the infection is a viral infection.

52. The use / method of claim 51, wherein the viral infection is COVID-19, or an infection caused by SARS-CoV- 2 virus or hCoV-OC43 virus.

53. The use / method of claims 48 or 50, wherein the anti-infective is an antifungal agent.

54. The use / method of any one of claims 48, 49, and 53, wherein, the infection is a fungal infection.

55. The use / method of claim 54, wherein the fungal infection is an infection caused by Candida albicans.

56. The use / method of claim 55, wherein the fungal infection is vaginal or buccal candidiasis.

57. The use / method of claims 48 or 49, wherein the anti-infective is an antibacterial agent.

58. The use / method of any one of claims 48, 49, and 57, wherein the infection is a bacterial infection.

59. The use / method of claim 58, wherein the bacterial infection is an Escherichia coli. infection.

60. Use of the pharmaceutical composition of any one of claims 1 to 30 as antiviral agent for preventing viral replication.61 . A method of preventing viral replication in a patient in need thereof, the method comprising administering the pharmaceutical composition of any one of claims 1 to 30 to a mucosa of said patient.

62. The use / method of claim 61 , wherein the viral replication is replication of SARS-CoV-2 virus or hCoV-OC43 virus.

63. The use / method of any one of claims 48 to 62, wherein the patient is an animal, preferably a mammal, and more preferably a human.

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