Topical oral compositions for scavenging drugs / toxins from saliva and methods of making and using the same

Abstract

The present disclosure is directed to oral compositions and methods of use thereof. The oral composition comprises one or more comprising absorbent or absorbing complex, such as charcoal, silica, diatomaceous earth, bentonite, kaolin, sodium aluminosilicate, synthetic, surface modified or coated absorbent / adsorbent, providing scavenging for drugs / metabolites / toxins / bioagents. The composition, such as a gum, will be taken orally by a user and transfer a drug / metabolite / toxin / bioagent from saliva of said user to the composition and then removed.

Description

[0001] DESCRIPTION

[0002] TOPICAL ORAL COMPOSITIONS FOR SCAVENGING DRUGS / TOXINS FROM SALIVA AND METHODS OF MAKING AND USING THE SAME

[0003] PRIORITY CLAIM

[0004] This application claims benefit of priority to U.S. Provisional Application Serial No. 63 / 626,748, filed January 30, 2024, the entire contents of which are hereby incorporated by reference.

[0005] BACKGROUND

[0006] 1. Field of the Disclosure

[0007] The present disclosure relates generally to the fields of medicine, opioids and oral biology. More particular, the disclosure relates to oral scavenging formulations to remove toxins or drugs from the oral cavity of a subject.

[0008] 2. Background

[0009] About 43.6 million Americans currently suffer from substance use disorder (SUD) (ref. 1), and an estimated 1.7 million people use buprenorphine (BUP) as part of Medication- Assisted Treatment (ref. 2). Sublingual buprenorphine is the newest, safest, and preferred first- line treatment option for patients with SUD (refs. 3-6). However, patient adherence to buprenorphine therapy is critical due to socio-economic, psychological, and other accompanied health issues. The FDA recently issued a warning of increased risk of teeth decay in SUD patients on dissolvable sublingual tablets and films of buprenorphine, which may cause patients to quit the treatment. Six-month (or longer term) use of SUBOXONE® (BUP and naloxone) sublingual film can cause severe dental problems (refs. 7-9). Thus, there remains a significant need to address this particular side effect of buprenorphine (refs. 22,23).

[0010] SUMMARY

[0011] Thus, in accordance with the present disclosure, there is provided an oral composition comprising an absorbent and / or adsorbent. The composition may comprise a gum, such as at up to 50% wt / wt of the composition. The absorbent / adsorbent may be Fullers Earth, diatomaceous earth, bentonite zeolite, kaolin, charcoal, silica, diatomaceous earth, kaolin, starch, sodium aluminosilicate, or any synthetic, surface modified or coated absorbent / adsorbent. The composition may further comprise one or more of a saliva stimulator, a flavoring agent, an anti-microbial, an anti-fungal, topical anesthetic, and antibiofilm material. The composition may be in the form of an oral patch, a film, a wafer, a periodontal chip, or a chewable pellet.

[0012] Also provided is method of removing a substance from the oral cavity of a subject comprising delivering the composition as described herein for a set period of time and removing said composition after the end of said set period of time. The period of time may be up to 60 mins or up to 15-20 mins, or up to 15, 16, 17, 18, 19 or 20 mins. The substance may be a drug, metabolite, toxin or bioagent, such as an opioid. The subject may be an opioid (ab)user, such as an opioid abuser undergoing medication-assisted treatment, such as wherein medication-assisted treatment is in the form of sublingual buprenorphine.

[0013] Absorbents are defined herein to agents that soak up materials into their structure, while adsorbents are defined herein as agents collect materials on their surface

[0014] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The word “about” means plus or minus 5% of the stated number.

[0015] It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein. Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0017] FIGS. 1A-D. Adsorption of 5-FU (FIG. 1A), SN-38 (FIG. IB) and buprenorphine (FIG. 1C), (FIG. ID) on adsorbents.

[0018] FIGS. 2A-C. Chemical structures of 5-FU (FIG. 1A), SN-38 (FIG. IB) and buprenorphine (FIG. 1C).

[0019] FIG. 3. Langmuir isotherm model for adsorption of buprenorphine on bentonite.

[0020] FIG. 4. Buprenorphine scavenging capacity from saliva fluid by adsorbents / absorbents. Statistical analysis was performed with One-way ANOVA. * Means p <0.05, ** means p<0.01, *** means p<0.001.

[0021] FIG. 5. Time and concentration-dependent reduction in saliva buprenorphine concentration by control (CTRL) vs DE chewing gum compositions. Statistical analysis was performed with One-way ANOVA. * Means p <0.05, ** means p<0.01 , *** means p<0.001, **** means p<0.0001.

[0022] FIG. 6. Chewing gum Formulation 1.

[0023] FIG. 7. Chewing gum Formulation 2.

[0024] DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0025] As discussed above, opioid misuse and / or abuse in is worldwide public health concern reaching epidemic dimensions. According to WHO statistics, in 2021 about 296 million people worldwide (or 5.8% of the global population aged 15-64 years) used drugs at least once, out of which 60 million of them used opioids, with 39.5 million people having substance use disorder (SUD). In 2019, around 600,000 deaths worldwide were attributed to drug use, 80% of them related to opioids and 25% caused by opioid overdose. The only effective treatment that can decrease the risk of overdose, if administered in time, is buprenorphine, yet less than 10% of people who need it are actually receiving it1. Furthermore, the effectiveness of this drug is dependent on patient compliance, which is a major challenge for this patient population.

[0026] Recently, the FDA raised concerns over the negative impact of sublingual buprenorphine use on oral health (including increased incidences of dental caries, tooth decay and even loss of teeth) in patients undergoing treatment for opioid use disorder2. So far, this problem has not been addressed adequately by any existing device, process, or methods, increasing the risk of treatment discontinuation in patients with opioid use disorder prescribed with sublingual buprenorphine treatment.

[0027] In the in vivo studies reported here, the inventors established a positive association between the occurrence of dental caries and sublingual buprenorphine and high accumulation of buprenorphine in salivary glands, resulting in high long-term exposure of oral tissue to the buprenorphine. The inventors showed higher preferential accumulation of buprenorphine in rat salivary gland upon sublingual administration (>100 times higher concentration in salivary glands than in plasma) as compared to i.v. dosing (only >10 times higher concentration in salivary glands than in plasma) using a validated and sensitive LC-MS / MS method for quantification of buprenorphine (Lower Limit of Quantitation or LLOQ=0.488 nM and lower limit of detection or LLOD=0.122 nM), and its metabolites (norbuprenorphine, buprenorphine glucuronide, and norbuprenorphine glucuronides).

[0028] Prolonged exposure of oral cavity to high concentrations of drug (buprenorphine), can result in the reduction of salivary production due to anticholinergic activity of opioids which further disturbs the microbiota balance in mouth, e.g., rising growth of Streptococci mutans, and altering of normal pH, which together significantly increase the risk of teeth erosion.

[0029] Knowing this, and considering other toxins, drug or food related, residing in the oral cavity, the inventors were searching for the solution that employed scavenging as a part of oral hygiene process. Topical oral compositions used in dentistry such as oral patches, wafers and films, periodontal chips, and chewing gums, have the capacity to deliver substances (antimicrobials, fluoride, etc.) for protection of oral health in a more convenient way than usual toothbrushing or mouth washing (rinsing). These compositions have been used as a vehicle for administration of drugs to oral tissue and systemic delivery. Examples include lidocaine and insulin release, canker sore buccal patches, nicotine chewing gum, periodontal chips with chlorhexidine gluconate (PerioChip), all of which are used. However, the utilization of these compositions for removing substances from the oral cavity has not been reported to the inventors’ knowledge. There are solutions for stain removal (W02005 / 013712), teeth whitening (KR20040104108A), and lysis and killing of microbes (U.S. Patent 6,365,130 Bl, ref. 17). Here, the inventors suggest incorporation of adsorbents, absorbents, and / or saliva stimulators to such topical compositions to enable their capacity to remove toxins from the salivary glands by increasing saliva production, and subsequent scavenging of toxin from saliva.

[0030] Thus, the disclosure relates to compositions and methods of use for removing drugs or toxins, such as buprenorphine (and / or its metabolites), from oral cavity comprising the steps of providing at least one topical oral composition comprising adsorbing or absorbing complex, such as charcoal, silica, diatomaceous earth, kaolin, sodium aluminosilicate, providing scavenging of drug / toxin to said user by transferring of drug from saliva of said user to the topical oral composition by residing in oral cavity, said topical oral composition involving a transfer of drug / toxin from salivary gland to saliva of said user in a customary period during topical oral composition residence in oral cavity.

[0031] These and other aspects of the disclosure are described in detail below.

[0032] I. Buprenorphine

[0033] Buprenorphine, sold under the brand name Subutex among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous and subcutaneous), as a skin patch (transdermal), or as an implant. For opioid use disorder, it is typically started when withdrawal symptoms have begun and for the first two days of treatment under direct observation of a health-care provider.

[0034] In the United States, the combination formulation of buprenorphine / naloxone (Suboxone) is usually prescribed to discourage misuse by injection. However, more recently the efficacy of naloxone in preventing misuse has been brought into question, and preparations of buprenorphine combined with naloxone could potentially be less safe than buprenorphine alone. Maximum pain relief is generally within an hour with effects up to 24 hours. Buprenorphine affects different types of opioid receptors in different ways. Depending on the type of opioid receptor, it may be an agonist, partial agonist, or antagonist. Buprenorphine's activity as an agonist / antagonist is important in the treatment of opioid use disorder: it relieves withdrawal symptoms from other opioids and induces some euphoria, but also blocks the ability for many other opioids, including heroin, to cause an effect. Unlike full agonists like heroin or methadone, buprenorphine has a ceiling effect, such that taking more medicine past a certain point will not increase the effects of the drug.

[0035] Side effects may include respiratory depression (decreased breathing), sleepiness, adrenal insufficiency, QT prolongation, low blood pressure, allergic reactions, constipation, and opioid addiction. Among those with a history of seizures, a risk exists of further seizures. Opioid withdrawal following stoppage of buprenorphine is generally less severe than with other opioids. Whether use during pregnancy is safe is unclear, but use while breastfeeding is probably safe, since the dose the infant receives is 1 -2% that of the maternal dose, on a weight basis.

[0036] In addition to prescription as an analgesic it is a common medication used to treat opioid use disorders, such as addiction to heroin. In 2020, it was the 186thmost commonly prescribed medication in the United States, with more than 2.8 million prescriptions. In the United States, buprenorphine is a schedule III controlled substance. In the U.S., the combination formulation of buprenorphine / naloxone is generally prescribed to deter injection, since naloxone, an opioid antagonist, is believed to cause acute withdrawal if the formulation is crushed and injected. Taken orally, the naloxone has virtually no effect, due to the drug's extremely high first-pass metabolism and low bioavailability (2%). However, the efficacy of naloxone in preventing misuse by injection has more recently been brought into question and preparations including naloxone could even be less safe than preparations containing solely buprenorphine. Anecdotally, posters on drug-related online forums have stated that they were able to attain a high by injecting preparations of buprenorphine despite being combined with naloxone.

[0037] Before starting buprenorphine, individuals are generally advised to wait long enough after their last dose of opioid until they have some withdrawal symptoms to allow for the medication to bind the receptors, since if taken too soon, buprenorphine can displace other opioids bound to the receptors and precipitate an acute withdrawal. The dose of buprenorphine is then adjusted until symptoms improve, and individuals remain on a maintenance dose of 8- 16 mg. Because withdrawal is uncomfortable and a deterrent for many patients, many have begun to call for different means of treatment initiation. Some providers have begun to use the Bernese method, also known as microdosing, in which very small doses of buprenorphine are given while patients are still using street opioids, and without precipitating withdrawal, with medicine levels slowly titrated upward.

[0038] Common adverse drug reactions associated with the use of buprenorphine, similar to those of other opioids, include nausea and vomiting, drowsiness, dizziness, headache, memory loss, cognitive and neural inhibition, perspiration, itchiness, dry mouth, shrinking of the pupils of the eyes (miosis), orthostatic hypotension, male ejaculatory difficulty, decreased libido, and urinary retention. Constipation and central nervous system (CNS) effects are seen less frequently than with morphine. Central sleep apnea has also been reported as a side effect of long-term buprenorphine use. Buprenorphine treatment carries the risk of causing psychological or physiological (physical) dependencies. It has a slow onset of activity, with a long duration of action, and a long half-life of 24 to 60 hours. Once a patient has stabilized on the (buprenorphine) medication and program, three options remain: continual use (buprenorphine-only medication), switching to a buprenorphine / naloxone combination, or a medically supervised withdrawal.

[0039] IL Compositions

[0040] Topical oral compositions are designed to perform a function in oral cavity, but traditionally mostly referred to dental health protection as well as drug delivery. Due to anatomic composition and high vascularization oral cavity is a promising organ for the local and systemic application of drug substances. Formulations can take solid forms (e.g., tablets, wafers, films, fibers, and patches), liquid forms (e.g., sprays and drops), and semi-solid forms (e.g., gels, ointments). Antimicrobial formulations were the first topical oral compositions on the market. Due to the elution with saliva, the residence time of the mouth-dissolvable formulation in oral cavity is relatively short. Medical devices placed in the oral cavity that can reside for an extended period of time without disintegration and can be expectorated to play an important role in solving this problem. These include oral patches, films, wafers, periodontal chips and chewing gums.

[0041] Natural adsorbents and absorbents include charcoal, silica, diatomaceous earth, bentonite, kaolin, starch, sodium aluminosilicate, etc., have large outer and inner pore surface area available for adsorbing (binding) or absorbing (trapping) small molecular weight ingredients. These are used in water treatment, wine and water purification, chemicals refining, air cleaning etc. as well as cosmetic and pharmaceutical products, such as for topical delivery for pharmaceutical compositions, UV absorbents in sunscreen, deodorants, cation releasing and self-warming cosmetic products and many others. Therefore, the inventors are proposing the incorporation of absorbents and / or adsorbents to topical compositions that reside in oral cavity for certain amount of time allowing its detoxifying performance for improved oral health care and lower risk of dental diseases coming from extended toxin residence in mouth. They are also proposing the incorporation of saliva stimulants, including but not limited to natural essential oils, such as peppermint oil etc. containing volatile and / or pungent ingredients which can increase saliva production, to improve the scavenging of toxins accumulated in the salivary glands.

[0042] Other examples of compositions that can be employed include those in and references 10-18 listed below, all of which are incorporated herein by reference.

[0043] III. Formulation

[0044] The present disclosure provides pharmaceutical compositions. In a specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a particular carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Other suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0045] The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical agents are described in “Remington's Pharmaceutical Sciences.”

[0046] IV. Uses

[0047] Increasing residence time in contact with the oral mucosa of topical oral compositions comprising adsorbents / absorbents could provide removal of unwanted substances in the oral cavity, either accumulated in salivary glands or excreted in saliva. Oral cavity is a pool of enzymes, hormones, many low molecular weight organic substances as well as bacteria and metabolites. Some of them may have a negative effect on oral health, and even toxic. Inventors are proposing application of topical oral compositions with safe and effective capacity to scavenge drugs and toxins from saliva.

[0048] For therapeutic uses, this topical oral composition (possibly characterized as a Class I Medical device) could comprises at least one “generally recognized as safe” adsorbent or absorbent for use in scavenging drugs / metabolites / toxins / bioagents from oral cavity. It could more specifically comprise “generally recognized as safe” adsorbents or absorbents in the range of from about 5 to 50 wt % of medical devices. The composition can comprise at least one natural or synthetic saliva stimulant, wherein said topical oral composition is applied in oral cavity; for use in stimulating saliva production for aiding in scavenging of drugs / metabolites / toxins / bioagents accumulated in salivary glands, such as in the range of from about 0.1 to 5 wt % of topical oral composition.

[0049] Methods of use for scavenging drugs / metabolites / toxins / bioagents from saliva can generally include administering to the subject an topical oral composition comprising at least one adsorbent or absorbent and at least one saliva stimulant, such as wherein said topical oral composition is applied in oral cavity for up to 60 mins, depending on the adsorption / absorption behavior of the drug / metabolite / toxin / bioagent, without swallowing the said topical oral composition. Alternatively, the topical oral composition is applied in oral cavity and chewed or masticated in the oral cavity for up to about 15 mins, and spit out / removed from the oral cavity.

[0050] V. Examples

[0051] The following examples are included to demonstrate preferred embodiments. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of embodiments, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Example 1

[0052] The inventors studied how the route of administration impacts salivary gland distribution and oral fluid exposure of buprenorphine, the disposition mechanisms involved, and the effects of buprenorphine on biofilm formation of S. mutans, which is one of the primary causative agents for dental caries development. They developed validated, sensitive LC- MS / MS methods for measuring buprenorphine and its metabolites (norbuprenorphine, buprenorphine glucuronide, norbuprenorphine glucuronide) concentrations in rat blood, saliva, and salivary gland samples. Results showed that salivary gland concentrations of buprenorphine were > 100-fold higher than plasma concentrations 5 hrs after sublingual administration, whereas only 10-fold higher than plasma concentrations 5 hrs after i.v. dosing. In addition, others have found that buprenorphine increased the 5. mutans biofilm formation in an in vitro experiment.

[0053] Therefore, they propose using topical oral compositions, including, but not limited to oral patches, films and wafers, periodontal chips, chewing gums, possibly characterized as a Class I Medical device, firstly to stimulate the saliva production, and then to scavenge drugs / toxins from excreted saliva. For example, it has been reported that saliva production increases 3 times, even up to 7 times, upon chewing, primarily depending on the chewing gum taste (ref. 21 ). This could allow more drug (buprenorphine) to be excreted from the salivary gland, reducing the concentrations in salivary glands. Also, oral patches, films, wafers, and periodontal chips can serve as good delivery systems for saliva stimulants such as cholinergic agents. Additionally, the inventors have incorporated adsorbent / absorbent in topical oral composition matrix to scavenge toxic drugs (such as buprenorphine) from saliva to prevent the drug from being bioavailable again to the oral tissue.

[0054] Moreover, the inventors showed that their formulated topical oral compositions could be further fortified by adding a natural-occurring antimicrobial ingredient with flavoring properties (such as clove oil) to aid in reduction of microbial load in oral cavity and increase the organoleptic acceptance and saliva production. Topical oral compositions have been used as a vehicle for delivering drugs, but so far they have do not appear to have been employed in the safe removal of unwanted drugs or toxins from saliva (oral cavity), especially drugs that are accumulated in salivary gland that adversely affects oral health. Also, this approach can be used for removing other dietary and environmental toxins from saliva, delivering oral health benefit through cleaning oral cavity, and reducing the risk of tooth decay, cavities, infections, periodontal diseases, and loss of teeth. Topical oral compositions such as, but not limited to oral patches, films, wafers, periodontal chips or chewing gums, would be an affordable and convenient composition for oral healthcare, an alternative method for oral diseases control.

[0055] A preliminary formulation of one topical oral composition such as chewing gum has been tested on lab scale, where the adsorbent / absorbent loading capacity of chewing gum was tested and found to be 30% of the chewing gum weight. Preliminary experiments on adsorbents / absorbents buprenorphine scavenging capacity included four different materials (Fullers Earth, diatomaceous earth, zeolite and kaolin). The scavenging capacities of these adsorbents / absorbents were tested in vitro, exposing them for 4 hours to saliva containing physiologically relevant buprenorphine concentration (5 pM). The best performing adsorbent / absorbent was diatomaceous earth, showing the scavenging capacity of 88.60%, and was chosen for testing in chewing gum matrix. Preformulated chewing gum was loaded with 10% of diatomaceous earth, frozen, crushed and mixed with saliva with buprenorphine (5 pM) containing saliva (to obtain final adsorbent / absorbent concentration 10 and 30 mg / ml). After 15, 30 and 60 minutes of mixing, the content of buprenorphine in saliva was found to be lower by 36.70-62.21% (10 mg / ml adsorbent / absorbent) and 55.54-79.15% (30 mg / ml adsorbent / absorbent) compared to the control chewing gum composition.

[0056] Example 2 - Trapping drugs in absorbents / adsorbents

[0057] For testing the ability of absorbents / adsorbents to trap drugs, the inventors used spectrofluorimetric method, characterized by its rapid and straightforward attributes, as published (refs. 19 and 20). As potential adsorbates, they tested SN-38 (an active metabolite of chemotherapy drug Irinotecan) and buprenorphine as two hydrophobic molecules, and 5- fluorouracil (5-FU, also a chemotherapy drug) as a hydrophilic molecule. Bentonite and / or diatomaceous earth were used as two different adsorbents. Experiments were executed using migration assay with 6-well plates with membrane inserts. The adsorbent was suspended in saline (pH 6) with 1% DMSO and 5% methanol (0.5 mg / ml) and poured into wells membrane insert, while the drug solution (70 pM for 5-FU and buprenorphine, and 2 pM for SN-38, in the same saline solvent) was poured onto the other side of the membrane, each in triplicate. The wells were incubated at 37° C on a shaker (100 rpm). The optimal contact time, i.e. when the saturation of adsorbent with drug was achieved, was determined by testing the concentration of free unabsorbed drug (Ce) transferred across the membrane at different time points (0-120 min), as presented in FIGS. 1A-D. The results showed that 5-FU was also quickly adsorbed on bentonite, reaching highest adsorption of 42.02% by 15 min, but did not desorb, keeping bentonite saturated with the drug at least till 120 min (FIG. 1 A). On the other hand, SN-38 was quickly and poorly trapped into bentonite, reaching maximum adsorption of 32.25% by 10 minutes, followed by gradual desorption (FIG. IB). On the other hand, buprenorphine saturated bentonite by 60 min with 62.25% of drug adsorbed, showing superior adsorption affinity to bentonite compared to 5-FU and SN-38 (FIG. 1C). The difference in adsorption of these nonpolar drugs can be explained by the difference in their structure (FIGS. 2A-C) causing different ionization of functional groups at experimental pH.

[0058] At pH 6, buprenorphine has a net positive charge due to the protonated tertiary amine (FIG. 2A). SN-38 is predominantly neutral, though there may be a very small fraction of molecules with a negative charge due to the hydrolyzed carboxylate form. 5-FU is predominantly neutral with no net charge because the experimental pH is below its pKa value (7.8). On the other hand, overall surface charge of bentonite at pH 6 is negative due to the silicate structure, which is not pH dependent and is permanent, while the edges contain hydroxyl groups (e.g., Al-OH or Si-OH) and are partially protonated giving a slight positive charge. Therefore, negatively charged bentonite has highest adsorption capacity for positively charged buprenorphine, compared to neutral 5-FU, or slightly negatively charged SN-38 showing quick desorption of poorly adsorbed molecule due to repulsion of the same (negative) charges. Therefore, buprenorphine was tested further for adsorption on diatomaceous earth (DE), a silica-based adsorbent originating from fossilized remains of diatoms, which is also negatively charged at pH 6 due to the deprotonation of silanol groups on its silica surface. However, the adsorption of buprenorphine on DE was slower and weaker, reaching saturation (42.51% adsorbed) by 90 min (FIG. ID).

[0059] Adsorption of buprenorphine on bentonite was further evaluated by testing adsorption of different drug concentrations (50-130 pM) at saturation contact time (60 min), using migration assay described above. Based on the obtained equilibrium drug concentration and calculated adsorption capacity (qe), Langmuir isotherm was generated (FIG. 3), and this isotherm model was confirmed as the best fit to the experimental data, with R2of 0.98, indicating an excellent agreement between the model and adsorption behavior. Example 3 - Comparing buprenorphine scavenging capabilities of different adsorbents / absorbents

[0060] The inventors’ LC-MS / MS method for evaluating buprenorphine levels (attached manuscript) is used for testing the absorption / adsorption efficiency of three natural adsorbents / absorbents: Fuller’s earth (FE), Diatomaceous earth (DE), Zeolite (ZE), and Kaolin (KA) to remove buprenorphine from saliva. First, in vitro experiments were executed using a Rapid Equilibrium Dialysis (RED, Thermo ScientificTM) assay. In the dialysis assay, the buprenorphine-saliva solution (5 pM) was tested against the suspension of adsorbent / absorbent (Fuller’s Earth (FE), Diatomaceous Earth (DE), Zeolite (ZE) and Kaolin (KA)) at the concentration of 25 mg / ml in PBS, each in triplicate, at 37° C on a shaker (200 rpm) and allowed to incubate for 4 hours. Post-incubation, a 150 pL sample was taken from each chamber of each well, vortexed for 1 minute, then 10 pL of each sample was taken to undergo liquid-liquid extraction with 190 pL of 3:1 Acetonitrile: Methanol, by vortexing for 1 minute, sonicating for 5 minutes, followed by centrifugation for 15 minutes at 14,000 rpm. 160 pL of the supernatant was then collected from each sample and injected for LC-MS analysis. The results showed that there was a significant difference between buprenorphine scavenging capacities of tested materials when applied at the same concentration (FIG. 4).

[0061] Example 4 - Addition of adsorbents / absorbents in Chewing Gum to improve buprenorphine scavenging capacity

[0062] Among tested adsorbents / absorbents DE stood out (84.17% buprenorphine scavenging capacity) (FIG. 4) and was chosen for further testing in composition matrix such as chewing gum. For this experiment, preformulated chewing gum was loaded with DE (10% w / w initial gum weight). Blank extrudable chewing gum sheets were carefully heated to melt without burning. DE was mixed with melted blank chewing gum reaching 10% concentration and shaped into films (21 x 6 x 4 mm) when cooled. Gum pieces were flash frozen and crushed. Buprenorphine scavenging capacities of chewing gum compositions with DE were evaluated in an experiment where 1 ml saliva containing 5 pM buprenorphine was mixed at 37°C (120 rpm) with crushed chewing gum composition. The amount of chewing gum was adapted to achieve 10 and 30 mg / ml of DE in saliva solution. Control chewing gum composition (CTRL) was also used to test the scavenging capacity of pure chewing gum. In vitro buprenorphine scavenging capacities of CTRL and DE gum compositions were evaluated by shaking (200 rpm) the chewing gum particles (n=3) in 1 ml of saliva containing BUP (5 pM). Aliquots of saliva were taken at 15, 30 and 60 min and saliva samples were analyzed by LC-MS / MS for buprenorphine content.

[0063] The results showed significantly lower concentrations of buprenorphine in saliva incubated with chewing gum compositions comprising DE (from 2.68 pM at 15 min (46.4% scavenged) to 0.46 pM at 60 min (90.8% scavenged) compared to CTRL chewing gum composition (from 3.78 pM at 15 min (24.4% scavenged) to 2.90 pM at 60 min (42% scavenged) (FIG. 5). Also, all compositions showed concentration and time dependent statistically significant reduction in buprenorphine concentration in saliva. Compared to CTRL composition, buprenorphine concentration after 15 min of incubation with composition comprising DE was up to 55.54% lower, while after 60 min the decrease was even more pronounced (up to 79.15%).

[0064] Example 5 - Oral composition embodiments

[0065] As an embodiment of the claimed compositions, chewing gum formulation 1 was produced at laboratory scale (formulation 1) and then upscaled to pilot plant manufacturing (formulation 2).

[0066] Handling procedure. Wet ingredients were homogenized with binding excipient 1 and added to the rest of dry ingredients to be mixed and homogenized in blender for 15 minutes. Mixture was then tableted with tablet press machine. Tableted gum pieces of 1.8 g were packed in airtight 3.5 oz white PET Plastic Packer Bottle (FIG. 6).

[0067] Sensorial evaluation. Trained panel (n=3) evaluated the gum and found it uniform in size, color, surface shine and shape, high crumbliness, freshness and intensity of notes, medium hardness, impact, hydration, sweetness, elasticity and string, and low smoothness, tack to teeth.

[0068] Handling procedure. Gum base is spread on the sugar-coated pans and placed in the oven at 185 - 200°F for a minimum of 2 - 3 hours. Melted gum is then mixed in a mixer with all other ingredients, except lubricant, until they are all incorporated. Mixture is dried on trays for a minimum of 24 hours (humidity below 40% is mandatory for this formula). Dried gum is ground with hammer mill and loaded into coating pan and mixed for 2-5 minutes with lubricant. Finally, the gum powder was screened and pressed using standard gum punches and pressed gum tablets were dispensed into foil pouch (FIG. 7).

[0069] Sensorial evaluation. Trained panel (n=3) evaluated the gum and found it uniform in size, color, surface shine and shape, high crumbliness, impact, hydration, sweetness, freshness and intensity of notes, and low hardness, elasticity, string, smoothness, and tack to teeth. Example 6 - Additional Uses for the Compositions

[0070] The current use of the proprietary topical oral compositions will be used to test their efficacy in removing buprenorphine in saliva of patients diagnosed with opioid use disorder and receiving sublingual buprenorphine as treatment in a clinical study. The inventors plan on conducting evaluation of real- world saliva levels of buprenorphine in 24 patients on sublingual buprenorphine and collect chewed gum samples from 6 patients using prototype formulation for analytical method development in next few months for future clinical study. They will continue working on the formulations, testing topical oral compositions capacity to scavenge other drug or food related toxins that reside in oral cavity, but also the influence of these compositions on bacterial strains in oral microbiome.

[0071] All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims.

[0072] VI. References

[0073] The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

[0074] 1. SAMHSA, Key Substance Use and Mental Health Indicators in the United States: Results from the 2021 National Survey on Drug Use and Health, world-wide-web at samhsa.gOv / data / sites / default / files / reports / rpt39443 / 2021NSDUHFFRRev010323. pdf 2021, 1-162.

[0075] 2. Han, B.; Jones, C. M.; Einstein, E. B.; Compton, W. M., Trends in and Characteristics of Buprenorphine Misuse Among Adults in the US. JAMA Netw Open 2021, 4 (10), e2129409.

[0076] 3. Shulman, M.; Wai, J. M.; Nunes, E. V., Buprenorphine Treatment for Opioid Use Disorder: An Overview. CNS Drugs 2019, 33 (6), 567-580.

[0077] 4. Ling, W., Buprenorphine implant for opioid addiction. Pain Manag 2012, 2 (4), 345- 50.

[0078] 5. Larochelle, M. R.; Jones, C. M.; Zhang, K., Change in opioid and buprenorphine prescribers and prescriptions by specialty, 2016-2021. Drug Alcohol Depend 2023, 248, 109933.

[0079] 6. Krawczyk, N.; Rivera, B. D.; Jent, V.; Keyes, K. M.; Jones, C. M.; Cerda, M., Has the treatment gap for opioid use disorder narrowed in the U.S.?: A yearly assessment from 2010 to 2019". Int J Drug Policy 2022, 110, 103786.

[0080] 7. FDA, FDA warns about dental problems with buprenorphine medicines dissolved in the mouth to treat opioid use disorder and pain, world-wide-web at fda.gov / media / 155352 / download?attachment. 2022.

[0081] 8. Etminan, M.; Rezaeianzadeh, R.; Kezouh, A.; Aminzadeh, K., Association Between Sublingual Buprenorphine-Naloxone Exposure and Dental Disease. JAMA 2022, 328 (22), 2269-2271.

[0082] 9. Brothers, T. D.; Lewer, D.; Bonn, M., Sublingual Buprenorphine-Naloxone Exposure and Dental Disease. JAMA 2023, 329 (14), 1224.

[0083] 10. W02005 / 013712 A2

[0084] 11. W02010 / 121619

[0085] 12. U.S. Patent, 846, 500

[0086] 13. U.S. Patent 8,512,681 U.S. Patent 5,380,530 U.S. Patent 5,693,334 U.S. Patent 6,365,130 Singh et al., Plant Biotechnology Journal (2021) 19, pp. 2113-2125. Zheng et al., Pharm. Res. (2024), doi.org / 10.1007 / sl l095-024-03755-6. Zheng et al., Original Res. (2024), doi: 10.1097 / ADM000000000001401. Nogourani et al, J. Dentistry (2012), 569327, 2012. WHO, “Opioid overdose,” world-wide-web at who.int / news-room / fact- sheets / detail / opioid-overdose (2023). FDA, “FDA warns about dental problems with buprenorphine medicines dissolved in the mouth to treat opioid use disorder and pain,” (2022).

Claims

WHAT IS CLAIMED IS:

1. An oral composition comprising an absorbent and / or adsorbent.

2. The composition of claim 1, wherein the oral composition comprises a gum, such as at up to 30% wt / wt of the composition.

3. The composition of claim 1 or claim 2, wherein the absorbent / adsorbent is Fullers Earth, diatomaceous earth, bentonite, zeolite, kaolin, charcoal, silica, diatomaceous earth, kaolin, starch, sodium aluminosilicate, or any synthetic, surface modified or coated absorbent / adsorbent.

4. The composition of any one of claims 1-3, wherein the composition further comprises one or more of a saliva stimulator, a flavoring agent, an anti-microbial agent, an anti-fungal agent, a topical anesthetic, a buffering agent, and an antibiofilm material.

5. The composition of any one of claims 1 -4, wherein the composition is in the form of an oral patch, a film, a wafer, a periodontal chip, or a chewable pellet.

6. A method of removing a substance from the oral cavity of a subject comprising (i) delivering the composition of any one of claims 1 -5 for a set period of time, depending on adsorption / absorption behavior of the trapped substance and (ii) removing said composition after the end of said set period of time.

7. The method of claim 6, wherein the set period of time is up to 60 mins or up to 15-20 mins.

8. The method of claim 6 or claim 7, wherein the substance is a drug, metabolite, toxin or bioagent, such as an opioid.

9. The method of any one of claims 6-8, wherein the subject is an opioid (ab)user, such as an opioid abuser undergoing medication-assisted treatment.

10. The method of claim 9, wherein medication-assisted treatment is in the form of sublingual buprenorphine.

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