Patch for transmucosal drug delivery

Abstract

Provided herein, in part, are transmucosal patches and methods of drug delivery thereof via a transmucosal route, wherein the mucosal linings of the oral or nasal cavity are utilized as sites for a thin film placement and consequent drug delivery.

Description

[0001] PATCH FOR TRANSMUCOSAU DRUG DEUIVERY

[0002] BACKGROUND

[0003] Transdermal thin-film patches for wear on outer skin (stratum comeum) for transdermal drug delivery are available for several drugs, e.g., nicotine, estradiol, fentanyl, etc. While these patches deliver the said drugs, their wear duration per day is long, ranging from 12 to 24 hours. During this period, the transdermal patch is adhered to the skin with an adhesive, and needs to withstand various life activities and mechanical stress and strain resulting from those, such as, perspiration, shower, physical activity, etc. Not only can these activities lead to dislodging of the patch due to mechanical stress and strain, but may also impair effective drug delivery due to other factors such as, water ingress, humidity, salt, and pH level changes on the skin surface due to sweating, etc. In addition, a long wear on skin surface for hours, can result in local skin irritation, inflammation, erythema, and edema. In the case of a drug which is colored, e.g., organometallic complexes such as those of Fe, Cu, Cr or Bi, etc., the coloration can discolor the skin, thereby causing patient non-compliance from being aesthetically unappealing.

[0004] In addition, iron deficiency (ID) is an underserved problem affecting 1.3 billion people worldwide and more than 10 million in the US. It predominantly affects women, exacerbated by menstrual bleeding / pregnancy, and children with a >30% prevalence. It also impacts the geriatric population due to increases in stomach acid pH causing loss of acidity and in turn impairing digestion, resulting in malabsorption of iron. Other underlying causes are GI bleeding, inflammatory bowel disease (IBD) particularly, Crohn’s and ulcerative colitis, chronic kidney disease (CKD) and post-bariatric surgery. Moderate-to- severe iron deficiency is diagnosed by a significant change in hematological indices: drop in hemoglobin, serum iron, ferritin, transferrin saturation and MCVs, with concurrent elevation of TIBC. This in turn manifests clinically as debilitating symptoms dramatically reducing life quality: physical fatigue, brain fog, shortness of breath, paleness of skin, heart palpitations, etc. Sustained ID untreated over long periods can cause irreversible cognitive decline, musculoskeletal and immunological damage. The standard-of-care for ID comprises oral iron supplements (pills, tablets, liquids) as the first line of treatment which has a failure rate of >50% especially for moderate-to-severe ID. This is due to poor absorption of iron from the gut, low bioavailability, resulting in GI adverse effects ranging from nausea, dyspepsia, diarrhea, stomach bloating and discomfort to constipation. The primary cause of poor GI tolerability, more in the case of non-heme iron (due to formation of insoluble Fe(OH)3) but also in case of heme iron, though to a lesser extent, is oxidative stress caused by iron. Excess iron in the intestinal tract can induce peroxidative damage through the production of reactive oxygen species, leading to damage of intestinal epithelial cells. The alternative to orals, is parenterals or injectables, either via intravenous (IV) or intra-muscular (IM) route. However, this is more invasive, has a risk of hypersensitivity reactions, and moderate-to-severe postinfusion adverse effects, necessitating clinical supervision and specialist’s Rx, and thus, long wait times both for specialist appointments as well as waitlist times at infusion clinics.

[0005] SUMMARY

[0006] To overcome the above issues, provided herein, in part, are methods of drug delivery via a transmucosal route instead of the classic transdermal route, wherein the mucosal linings of the oral or nasal cavity are utilized as sites for a thin film placement and consequent drug delivery. The inventions described herein relate to microneedle-free, passive, biodegradable polymeric transmucosal patch that can be placed on the inner cheek (oral) or inner nasal lining (nasal), containing a solution of a micronized iron form, that dissolves in under an hour in the mucosal environment, releasing the iron into the blood circulation via the mucosal epithelium for direct uptake by transferrin, bypassing the gut and avoiding all associated GI adverse effects. This novel solution combines the efficacy of parenterals with the convenience of orals, but without the adverse effects of either. Most commonly available small iron molecules (<1000Da molecular weight) in supplements are poorly water soluble. Our innovation comprises first, iron compound treatment and next, incorporation into polymeric formulation.

[0007] In some embodiments, provided herein are transmucosal patches comprising a drug and one or more polymers.

[0008] In some embodiments, the patches described herein are of resorbable kind, such that they dissolve in the oral or nasal moisture. The rate of dissolution of the thin film of the patch in contact with the mucosal lining is a function of the water-soluble polymer material design and can be tuned from slow-dissolving to rapidly dissolving, depending on the desired pharmacokinetic profile of the drug to be delivered. In some embodiments, fast dissolution can range from, for example, 5 minutes to 2 hours, while a slow dissolution can range from, for example, 8 hours to 12 hours. In some embodiments, the nasal mucosal lining is a preferred site location for a slow release while the oral mucosal lining is a preferred site location for a fast or burst release. With the same given water-dissolution rate for a resorbable (hydrophilic) patch, the external environment in the oral mucosa has significantly higher moisture content than the external environment in the nasal mucosa, and therefore drives the dissolution kinetics faster.

[0009] In some embodiments, the target site regions for the transmucosal patches described herein include, but are not limited to, buccal subunit’s inner cheek (oral cavity) and vestibular non-cartilaginous wall (nasal cavity).

[0010] Due to the inherent wet surface conditions present in both the above mucosal regions, the chemical adhesive which is a mandatory component of conventional transdermal patch systems can, in some embodiments, be eliminated, thus simplifying patch construction, but ensuring that adhesion with the native thin film mucosal layer is present.

[0011] In some embodiments, the transmucosal patches described herein comprise one or more water-soluble polymers. In some embodiments, the transmucosal patches described herein comprise one or more hydrophilic drugs. In some embodiments, the transmucosal patches described herein comprise one or more hydrophobic drugs. In case of hydrophobic drugs, a microemulsion formulation may be used which is then encapsulated into the one or more water-soluble polymers in the same manner as a water-soluble drug.

[0012] Due to the 5-7 times higher permeability of the mucosal membranes compared to that of the stratum comeum, the standard small molecule (less than 500 Da) restrictions of transdermal drug delivery do not apply. The transmucosal system of drug delivery described herein thus enables larger macromolecular-sized drug delivery, ranging from greater than 500 Da to several kDa. A fast burst release and / or a slow controlled release can be achieved by tuning the dissolution rate of the constituent polymer mix.

[0013] BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Fig. 1 shows a plot of an in vitro release study of an exemplary patch described herein.

[0015] Fig. 2 shows a plot of an in vitro permeation test for an exemplary patch described herein.

[0016] Fig. 3A shows an exemplary image of a patch comprising Fe-cit.

[0017] Fig. 3B shows exemplary images of dissolving test for the patch comprising Fe-cit. Fig. 4. shows in vivo patch resorption over time in hamster model, from t=0 min to t=60 min.

[0018] Fig. 5. Shows an individual resorbable patch, 1cm x 1cm size, formulated with an iron compound.

[0019] Fig. 6 shows a pharmacokinetic profile showing systemic iron absorption with resorbable buccal patches in Fe-deficient hamsters.

[0020] Fig. 7 shows a pharmacokinetic profile showing systemic iron absorption with resorbable buccal patches in Fe-deficient hamsters.

[0021] DETAILED DESCRIPTION

[0022] Provided herein, in part, are transmucosal patches and methods of drug delivery via a transmucosal route instead of the classic transdermal route, wherein the mucosal linings of the oral or nasal cavity are utilized as sites for a thin film placement and consequent drug delivery.

[0023] In some embodiments, the transmucosal patches described herein comprise one or more water-soluble polymers. In some embodiments, the transmucosal patches described herein comprise one or more hydrophilic drugs. In some embodiments, the transmucosal patches described herein comprise one or more hydrophobic drugs. In case of hydrophobic drugs, a microemulsion formulation may be used which is then encapsulated into the one or more water-soluble polymers in the same manner as a water-soluble drug.

[0024] In some embodiments, a transmucosal patch of the present disclosure is manufactured using a process comprising the specific ratio of the polymers used in combination with the specific starting water volume to create the desired final mechanical texture, strength and flexibility. In some embodiments, a ratio of weights of HEC to PEG ranges from 1.3 to 0.3. In some embodiments, a ratio of weights of HEC to PEG ranges from 1.4 to 0.2. In some embodiments, a ratio of weights of HEC to PEG ranges from 1.5 to 0.1. In some embodiments, a ratio of weights of HEC to PEG ranges from 1.2 to 0.4. In some embodiments, a ratio of weights of HEC to PEG ranges from 1.1 to 0.5. The starting water volume for the weights used above ranges from 8mL to 12mL including the glycerol volume. The starting water volume for the weights used above ranges from 8 mL to 12 mL including the glycerol volume. The starting water volume for the weights used above ranges from 8 mL to 12 mL including the glycerol volume. The starting water volume for the weights used above ranges from 9 mL to 11 mL including the glycerol volume. The starting water volume for the weights used above ranges from 7 mL to 13 mL including the glycerol volume.

[0025] In some embodiments, a transmucosal patch has a final solvent concentration ranging from 8% to 25%. In some embodiments, a transmucosal patch has a final solvent concentration ranging from 10% to 22%. In some embodiments, a transmucosal patch has a final solvent concentration ranging from 12% to 20%. Final solvent concentration may vary depending on type of API and final desired dissolution time. In some embodiments, the present disclosure includes the discovery no adhesive is required for adhesion by the patch, as the final solvent concentration in the patch ensures a moist, sticky mucoadhesive effect. This feature enables stiction to the mucosal membrane without causing any irritation or toxicity or scar tissue formation on prolonged contact.

[0026] In some embodiments, a transmucosal patch comprises a hydrophilic or lipophilic drug that can be encapsulated in a microemulsion form mixed with the rest of the polymeric mix.

[0027] Without being limited by any theory, in some embodiments, the present disclosure includes the discovery that , a transmucosal patch with a high thickness of 0.1-0.3 cm enables a high drug pay load capacity of up to 1500mg. In some embodiments, a transmucosal patch has high thickness of 0.1 -0.3 cm. In some embodiments, a transmucosal patch has high thickness of 0.15-0.25 cm.

[0028] In some embodiments, the present disclosure includes the discovery that high thickness of patch ensures a slow controlled release rather than an instantaneous release associated with commercial thin films. In some embodiments, the present disclosure includes the discovery that slow controlled release is advantageous to control the levels of drug peak plasma concentrations avoiding hepatotoxic levels.

[0029] In some embodiments, the present disclosure includes the discovery patch-mucosa contact area is about 1cm x 1cm, which is an ideal usable size for oral and nasal cavities. Flexibility allows conformity to curved surfaces or regions. In some embodiments, total dissolution time ranges from 10 min to 90 min.

[0030] In some embodiments, provided herein are transmucosal patches comprising a drug and one or more polymers. In some embodiments, the patches described herein are resorbable. In some embodiments, the patches result in fast dissolution of a drug, for example, 5 minutes to 2 hours. In other embodiments, the patches result in slow dissolution of a drug, for example, 8 hours to 12 hours. In some embodiments, provided herein are methods of treating or preventing a condition, disease, or disorder in a subject in need thereof, comprising adhesion of a transmucosal patch described herein on the subject.

[0031] In some embodiments, the target site regions for the transmucosal patch described herein is the subject’s buccal subunit’s inner cheek (oral cavity) or the subject’s vestibular non-cartilaginous wall (nasal cavity).

[0032] In some embodiments, the transmucosal patches comprise a double-layered polymer structure comprising: an active faster dissolving layer comprising a first polymer encapsulating the drug and a protective slower dissolving backing layer comprising a second polymer. In some embodiments, the active faster dissolving polymer is suitable for the mucosal side (contact side). In some embodiments, the backing layer is suitable for the non- mucosal side (non-contact side). In some embodiments, the drug is released from the non- mucosal side into the oral or nasal cavity. In some embodiments, the drug is released systemically.

[0033] In some embodiments, the drug has a molecular size ranging from small (less than 500 Da) to large (greater than 500 Da).

[0034] In some embodiments, the drug comprises one or more minerals or compounds thereof, or combinations thereof. In some embodiments, the drug is small (less than 500 Da) to large (greater than 500 Da) molecules comprising one or more minerals or compounds thereof, or combinations thereof. In some embodiments, the one or more minerals or compounds thereof, or combinations thereof are substantially free of nanoparticles. In some embodiments, the one or more minerals are selected from the group consisting of iron, copper, zinc, magnesium, selenium, bismuth, molybdenum, calcium, gold, silver, platinum, sodium, potassium, phosphorus, sulfur and chlorides, and compounds thereof. In some embodiments, the mineral is iron or compounds thereof. In some embodiments, the drug comprises natural or synthetic amino acids or analogs thereof, or combinations thereof. In some embodiments, the drug is small (less than 500 Da) to large (greater than 500 Da) molecules comprising natural or synthetic amino acids or analogs thereof, or combinations thereof. In some embodiments, the drug comprises natural or synthetic peptides or analogs thereof, or combinations thereof. In some embodiments, the drug is small (less than 500 Da) to large (greater than 500 Da) molecules comprising natural or synthetic peptides or analogs thereof, or combinations thereof.

[0035] In some embodiments, wherein a transmucosal patch further comprises an amino acid. In some embodiments, a transmucosal patch further comprises an sulfur-containing amino acid. In some embodiments, wherein a transmucosal patch further comprises an amino acid. In some embodiments, a transmucosal patch further comprises an sulfur-containing amino acid. In some embodiments, a transmucosal patch further comprises an sulfur-containing amino acid selected from the group consisting of methionine, cysteine, homocysteine and taurine. In some embodiments, a transmucosal patch further comprises taurine. In some embodiments, a transmucosal patch further comprises a branched chain amino acid. In some embodiments, a transmucosal patch further comprises a branched chain amino acid selected from the group consisting of leucine, isoleucine and valine. In some embodiments, a transmucosal patch further comprises an amino acid selected from the group consisting of ysine, serine, asparagine, histidine, glutamine, and threonine.

[0036] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10%.

[0037] Also provided herein are methods of administering a drug to a subject in need thereof, comprising administering to the subject a transmucosal patch described herein.

[0038] In some embodiments, a therapeutically relevant dosage of the drug is delivered systemically. In some embodiments, the systemic drug delivery rate is tunable based on the rate of dissolution of the one or more polymers of the transmucosal patch. In some embodiments, the drug is released from a non-mucosal (non-contact) side into the oral or nasal cavity. In some embodiments, release of the drug from the patch is tunable by using a double-layered polymer structure comprising: an active faster dissolving layer comprising a first polymer encapsulating the drug and a protective slower dissolving backing layer comprising a second polymer. In some embodiments, a burst release or slow controlled release is achieved based on the constituent polymer matrix and the patch-mucosal interfacial contact area.

[0039] In some embodiments, the drug is selectively released i) unidirectionally from either non-mucosal (non-contact) side or from a mucosal (contact) side, or ii) bidirectionally from both non-mucosal and mucosal sides into the oral or nasal cavity.

[0040] In some embodiments, a multitude of drugs is encapsulated in multiple constituent polymer layers, each drug comprised within a particular layer, wherein the drug is released into the oral or nasal cavity, optionally in a time-dependent manner. In some embodiments, the drug or molecule incorporated into the transmucosal patch is a non-carbohydrate based small molecule. In some embodiments, the compound is an iron containing small molecule. In some embodiments, the iron containing small molecule has non-heme iron. In other embodiments, the iron containing small molecule has heme iron.

[0041] Iron compounds that can be delivered via the transmucosal route include ferrous salts, such as ferrous sulfate, ferrous fumarate, ferrous gluconate, ferrous glycine sulfate, ferrous bisglycinate, ferrous ascorbate, ferrous carbonate, ferrous tartrate, and / or ferrous succinate. Transmucosal patches of the present invention may contain one, or a combination of any of the iron compounds.

[0042] Iron compounds that can be delivered via the transmucosal route include ferric salts / complexes such as ferric citrate, ferric sulfate, ferric gluconate, ferric maltol and / or ferric pyrophosphate. Transmucosal patches of the present invention may contain one, or a combination of any of the iron compounds. In some embodiments, a transdermal patch contains ferric citrate. As used herein, the terms “ferric citrate,” “iron (III) citrate,” “Fe-cit,” and “FeC” are used interchangeably.

[0043] Iron compounds that can be delivered via the transmucosal route also include carbonyl iron and heme iron.

[0044] Transmucosal patches of the present invention may contain one type of iron containing small molecule, or the transmucosal patches may contain any combination of iron or iron based compounds.

[0045] Transmucosal patches of the present invention may contain amino acids, vitamins (B- 9, B-12, C, D, etc.) carboxylic acids, minerals (Cu, Zn) and peptides. In some embodiments, a transdermal patch contains vitamin B. In some embodiments, a transdermal patch contains vitamin B12. In some embodiments, a transdermal patch contains vitamin B9.

[0046] In certain embodiments, the iron compound is micronized. For example, the iron compound may be micronized using a ball milling technique. Once micronized, the iron compound is dissolved in a low pH or acidic solution. The solution is then sonicated with low frequency ultrasound.

[0047] In some embodiments, the present disclosure includes a transmucosal patch comprising: i) hydroxy ethyl cellulose; ii) glycerol; iii) polyethylene glycol; and iv) an iron salt, wherein the patch area is about 1cm x 1cm, with thickness equal to 0.1 - 0.3cm.

[0048] In some embodiments, the present disclosure includes a transmucosal patch comprising: i) hydroxy ethyl cellulose; ii) glycerol; iii) polyethylene glycol; and iv) ferric citrate, wherein the patch area is about 1cm x 1cm, with thickness equal to 0.1 - 0.3cm.

[0049] In some embodiments, the present disclosure includes a transmucosal patch comprising: i) hydroxy ethyl cellulose; ii) glycerol; iii) polyethylene glycol; iv) ferric citrate; and v) taurine, wherein the patch area is about 1cm x 1cm, with thickness equal to 0.1 - 0.3cm.

[0050] Also provided herein are methods of treating or preventing a condition, disease, or disorder in a subject in need thereof, comprising administering to the subject a transmucosal patch described herein.

[0051] EXAMPLES

[0052] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0053] Example 1:

[0054] Exemplary transmucosal patches are made by the following process:

[0055] 1) Mixture A: Hydroxyethyl cellulose (HEC) 0.126 g and glycerol ImL are dissolved in 4mL of DI water.

[0056] 2) Mixture B: Polyethylene glycol (PEG) 0.1g and water-soluble drug (e.g., ferric citrate (Fecit) or active pharmaceutical ingredient (API)) are dissolved in 4mL of DI water.

[0057] 3) Mixture B is added to Mixture A, and the combined mixture is stirred & let stand. The drug containing polymer mix ready. 4) Mixture prepared according to step 3) is in Teflon™ trays with heights equal to desired thickness of final patch.

[0058] 5) In a scaled-up version, silicone molds comprising multiple cavities are used, each cavity having a volume equal to -ImL.

[0059] 6) The poured mixture of step 4) is dehydrated in a temperature-controlled oven for 0.5h to 8h under optimal air flow speed, temperature and pressure.

[0060] 7) Alternative to temperature-controlled oven, the patches are first frozen instantaneously under liquid nitrogen, and dried under ultra-low pressure in a lyophilizer chamber for 3h to 30h, depending on temperature and pressure inside chamber, resulting in dried patches.

[0061] 8) At the desired solvent concentration between -8% - 25%, the patches are peeled to remove them from Teflon™ tray or silicone molds.

[0062] 9) Final patch area is ~lcm x 1cm, with thickness equal to 0.1 - 0.3cm.

[0063] Example 2:

[0064] Exemplary transmucosal patches are made by the following process:

[0065] 1) Mixture A: Hydroxyethyl cellulose (HEC) 0.189 g and glycerol ImL are dissolved in 5mL of DI water.

[0066] 2) Mixture B: Polyethylene glycol (PEG) 0.3g and water-soluble drug (e.g., ferric citrate (Fecit) or active pharmaceutical ingredient (API)) are dissolved in 4mL of DI water.

[0067] 3) Mixture B is added to Mixture A, and the combined mixture is stirred & let stand. The drug containing polymer mix ready.

[0068] 4) Mixture is poured in silicone molds and first pre-concentrated at 25°C in a rotavapor under high vaccum. Alternatively, mixture prepared according to step 3) is poured in Teflon™ trays with heights equal to desired thickness of final patch and pre-concentrated under vacuum.

[0069] 5) The poured mixture of step 4) is dehydrated in a temperature-controlled oven for 0.5h to 8h under optimal air flow speed, temperature and pressure.

[0070] 6) At the desired solvent concentration between -8% - 25%, the patches are peeled to remove them from Teflon™ tray or silicone molds.

[0071] 7) Final patch area is ~lcm x 1cm, with thickness equal to 0.1 - 0.3cm.

[0072] Example 3:

[0073] Exemplary transmucosal patches are made by the following process: 1) Mixture A: Hydroxyethyl cellulose (HEC) 0.189 g and glycerol ImL are dissolved in 4mL of DI water.

[0074] 2) Mixture B: Polyethylene glycol (PEG) 0.6g and water-soluble drug (e.g., ferric citrate (Fecit) or active pharmaceutical ingredient (API)) are dissolved in 5mL of DI water.

[0075] 3) Mixture B is added to Mixture A, and the combined mixture is stirred & let stand. The drug containing polymer mix ready.

[0076] 4) Mixture is poured in silicone molds and first pre-concentrated at 25°C in a rotavapor under high vaccum. Alternatively, mixture prepared according to step 3) is poured in Teflon™ trays with heights equal to desired thickness of final patch and pre-concentrated under vacuum.

[0077] 5) The poured mixture of step 4) is dehydrated in a temperature-controlled oven for 0.5h to 8h under optimal air flow speed, temperature and pressure.

[0078] 6) At the desired solvent concentration between ~8% - 25%, the patches are peeled to remove them from Teflon™ tray or silicone molds.

[0079] 7) Final patch area is ~lcm x 1cm, with thickness equal to 0.1 - 0.3cm.

[0080] A water resorbable patch was built using above formulation in which the model drug used was ferric citrate (Fe-cit). It was tested for dissolution in 5% dilute saliva with tap water to mimic oral salivary conditions of buccal mucosa. It was also tested for iron drug release across porcine buccal mucosa. Results:

[0081] The water-soluble polymer patch fully dissolved in diluted saliva in vitro, releasing the model drug (Fe-cit). (as shown in Fig. 1). Fig. 1 shows an in vitro release study conducted by immersing the resorbable patch into 5% diluted saliva solution, and sampling solution at definite time intervals (while replacing sampled solution volume with tap water); measured by ICP-OES as mg of Fe released into per mF of immersed solution. Also, the water-soluble polymer patch delivered the model drug (Fe-cit) via diffusion into porcine buccal skin in a Franz Diffusion Cell (FDC) (as shown in Fig. 2). Fig. 2 shows an in vitro permeation test (IVPT) conducted under pressurized clamped contact of the resorbable patch to porcine buccal skin using Franz Diffusion Cell, measured by ICP-OES as mg of Fe diffused into per g of porcine tissue. Sham patch contained 0% Fe, while treatment patch contained 3% Fe w / w. Duration of patch- skin contact: 2 hours. In addition, the model drug (Fe-cit) was detected and characterized in solution as well as biological tissue by ICP-OES technique. Fig. 3 A shows a polymer patch containing model drug (Fe-cit). Fig. 3B shows a dissolving test of the patch in diluted saliva at t=0, 15 mins, 30 mins, 40 mins, and 60 mins (left to right).

[0082] Fig. 4 shows the progression of in vivo patch resorption over time in hamster model from t=0 mins to t=60 mins. Fig. 5 shows an exemplary individual resorbable patch, 1cm x 1cm size, formulated with an iron compound.

[0083] Fig. 6 shows pharmacokinetic profile showing systemic iron absorption with resorbable buccal patches in Fe-deficient hamsters. Test compound denotes patch made with FeCit-Tau (CsHi2FeNOioS)and control denotes patch made with commercially available iron(III) citrate. This demonstrates successful systemic delivery of iron with FeCit-Tau infused buccal patch.

[0084] Fig. 7 shows pharmacokinetic profiles showing systemic iron uptake. A resorbable patch was formulated as described above, where ferric citrate (FeC) was dissolved in 5% HC1, and tested in vivo in the buccal cavity of an iron deficient hamster model. Blood was sampled at 30 min time intervals to determine the pharmacokinetic profile w.r.t. serum iron change.

[0085] 1) The water-soluble polymer patch fully dissolved in buccal cavity in vivo under Ih, releasing iron via buccal mucosa for systemic iron uptake, resulting in elevation of serum iron levels, (as shown in Fig. 7).

[0086] 2) FeC was compared to the positive control, a novel iron complex.

[0087] 3) While FeC was absorbed well, resulting in significant improvement of serum iron levels, it’s AUC and thus systemic bioavailability was lower than that of the positive control by 28.7%.

[0088] 4) Dose administered >60mg / kg BW of hamsters, was 6.3x higher than the equivalent human dose.

[0089] 5) Local buccal mucosa showed no signs of irritation, lesion, scar tissue or any abnormality even at the high iron dosage. No systemic toxicity was found under histopathological examination. Thus, the buccal iron formulation was assessed as safe and non-toxic.

[0090] 6) 100% of the iron was systemically delivered via buccal mucosa, and not via GI tract, as confirmed by internal GI tract examination.

[0091] 7) Peak plasma concentration of iron is achieved in about 90 min, with full absorption wrt serum iron in about 180 min.

Claims

CLAIMSWhat is claimed:

1. A transmucosal patch comprising a drug and one or more polymers.

2. The transmucosal patch of claim 1, wherein the one or more polymers is water-soluble.

3. The transmucosal patch of claim 1 or 2, wherein the drug is hydrophilic.

4. The transmucosal patch of claim 1 or 2, wherein the drug is hydrophobic.

5. The transmucosal patch of any one of claims 1-4, comprising multiple polymers.

6. The transmucosal patch of claim 5, wherein the polymers are hydroxyethyl cellulose (HEC) and polyethylene glycol (PEG).

7. The transmucosal patch of claim 5, wherein the polymers weight ratio of HEC to PEG ranges from 1.3 to 0.3.

8. The transmucosal patch of claim 5, wherein the ratio of starting water volume to glycerol volume ranges from 8 to 11.

9. The transmucosal patch of claim 5, wherein the final solvent concentration ranges from 8% to 25%.

10. The transmucosal patch of claim 5, wherein the mucosal contact area ranges from 0.25cm2to 4cm2.

11. The transmucosal patch of claim 5, wherein the thickness ranges from 0.1 to 0.3cm.

12. The transmucosal patch of claim 5, wherein the drug compound weight encapsulated can be less than or equal to 1500mg.

13. The transmucosal patch of claim 5, wherein the full dissolution time of the patch ranges from 10 min to 90 min.

14. The transmucosal patch of claim 5, wherein the drug release is controlled by the contact area, thickness of patch and dissolution time, and typically results in a non-instantaneous, controlled or sustained release, rather than a bolus release.

15. The transmucosal patch of claim 5, wherein no chemical or synthetic adhesive is employed, as the semi-dried, moist polymeric mix in the final patch serves as the ‘water- mucoadhesive’ layer.

16. The transmucosal patch of claim 5, wherein drying of the patch is performed under air or vacuum, at sub-zero or low temperatures or high temperatures, depending on API sensitivity to temperature.

17. The transmucosal patch of claim 5, wherein polymeric mix with API is pre-concentrated under vacuum for up to Ih to reduce final drying time.

18. The transmucosal patch of claim 5, wherein polymeric mix with API is poured into molds during drying process to effect the desired final patch thickness, shape and size.

19. The transmucosal patch of any one of claims 1-18, wherein the patch is suitable for use in an oral cavity.

20. The transmucosal patch of any one of claims 1-18, wherein the patch is suitable for use in a nasal cavity.

21. The transmucosal patch of any one of claims 1-20, comprising a double-layered polymer structure comprising: an active faster dissolving layer comprising a first polymer encapsulating the drug and a protective slower dissolving backing layer comprising a second polymer.

22. The transmucosal patch of claim 21, wherein the active faster dissolving polymer is suitable for the mucosal side (contact side).

23. The transmucosal patch of claim 21 or 22, wherein the backing layer is suitable for the non-mucosal side (non-contact side).

24. The transmucosal patch of any one of claims 21-23, wherein the drug is released from the non-mucosal side into the oral or nasal cavity.

25. The transmucosal patch of any one of claims 21-23, wherein the drug is released into the oral or nasal cavity for local on-site absorption, or systemic absorption into blood circulation via the transmucosal membrane.

26. The transmucosal patch of any one of claims 1-25, wherein the drug has a molecular size ranging from small (less than 500 Da) to large (greater than 500 Da).

27. The transmucosal patch of any one of claims 1-26, wherein the drug is small (less than 500 Da) to large (greater than 500 Da) molecules comprising one or more minerals or compounds thereof, or combinations thereof.

28. The transmucosal patch of claim 27, wherein the one or more minerals or compounds thereof, or combinations thereof are substantially free of insoluble nanoparticles.

29. The transmucosal patch of claim 27 or 28, wherein the one or more minerals are selected from the group consisting of iron, copper, zinc, magnesium, selenium, bismuth, molybdenum, calcium, gold, silver, platinum, sodium, potassium, phosphorus, sulfur and chlorides, nitrates, citrates, bicarbonates, and compounds thereof.

30. The transmucosal patch of claim 27 or 28, wherein the mineral is iron or compounds thereof, optionally wherein the iron compound is iron citrate or iron citrate-taurine complex.

31. The transmucosal patch of claim 30, wherein the iron compound is a ferrous salt.

32. The transmucosal patch of claim 31, wherein the iron compound comprises a compound selected from the group consisting of ferrous sulfate, ferrous fumarate, ferrous gluconate, ferrous glycine sulfate, ferrous bisglycinate, ferrous ascorbate, ferrous carbonate, ferrous tartrate, ferrous succinate and combinations thereof.

33. The transmucosal patch of claim 30, wherein the iron compound is a ferric salt.

34. The transmucosal patch of claim 33, wherein the iron compound comprises a compound selected from the group consisting of ferric citrate, ferric sulfate, ferric gluconate, ferric maltol, ferric pyrophosphate and combinations thereof.

35. The transmucosal patch of claim 30, wherein the iron citrate is iron (III) citrate.

36. The transmucosal patch of claims 1-35, wherein the transmucosal patch further comprises an amino acid.

37. The transmucosal patch of claim 36, wherein the amino acid is a sulfur-containing amino acid.

38. The transmucosal patch of claim 37, wherein the sulfur-containing amino acid is selected from the group consisting of methionine, cysteine, homocysteine and taurine.

39. The transmucosal patch of claim 38, wherein the sulfur-containing amino acid is taurine.

40. The transmucosal patch of claim 39, wherein the iron citrate-taurine complex is iron (III) citrate-taurine complex.

41. The transmucosal patch of claim 36, wherein the amino acid is a branched-chain amino acid.

42. The transmucosal patch of claim 41, wherein the branched-chain amino acid is selected from the group consisting of leucine, isoleucine and valine.

43. The transmucosal patch of claim 36, wherein the amino acid is selected from the group consisting of glycine, lysine, serine, asparagine, histidine, glutamine and threonine.

44. The transmucosal patch of claim 27 or 28, wherein the one or more minerals or compounds thereof, or combinations thereof is a mixture comprising iron (III) citrate and taurine.

45. The transmucosal patch of any one of claims 1-44, wherein the drug is small (less than 500 Da) to large (greater than 500 Da) molecules comprising a natural or synthetic amino acid or an analog thereof, or a combination thereof.

46. The transmucosal patch of any one of claims 1-44, wherein the drug is small (less than 500 Da) to large (greater than 500 Da) molecules comprising a natural or synthetic peptide or analog thereof, or a combination thereof.

47. The transmucosal patch of any one of claims 1-44, wherein the drug is small (less than 500 Da) to large (greater than 500 Da) molecules comprising a vitamin, and analog thereof, or combinations thereof.

48. The transmucosal patch of claim 47, wherein the vitamin is selected from the group consisting of vitamin B, vitamin C, and vitamin D.

49. The transmucosal patch of claim 48, wherein the vitamin is vitamin B.

50. The transmucosal patch of claim 48, wherein the vitamin B is vitamin B12 or vitamin B9.

51. A method of administering a drug to a subject in need thereof, comprising administering to the subject a transmucosal patch of any one of claims 1-50.

52. The method of claim 51, wherein a therapeutically relevant dosage of the drug is delivered systemically.

53. The method of claim 52, wherein the systemic drug delivery rate is tunable based on the rate of dissolution of the one or more polymers of the transmucosal patch.

54. The method of any one of claims 51-53, wherein the drug is selectively released i) unidirectionally from either non-mucosal (non-contact) side or from a mucosal (contact) side, or ii) bidirectionally from both non-mucosal and mucosal sides into the oral or nasal cavity.

55. The method of any one of claims 51-54, where a multitude of drugs is encapsulated in multiple constituent polymer layers, each drug comprised within a particular layer, wherein the drug is released into the oral or nasal cavity, optionally in a time-dependent manner.

56. The method of any one of claims 51-55, wherein release of the drug from the patch is tunable by using a double-layered polymer structure comprising: an active faster dissolving layer comprising a first polymer encapsulating the drug and a protective slower dissolving backing layer comprising a second polymer.

57. The method of any one of claims 51-56, wherein a burst release or slow controlled release is achieved based on the constituent polymer matrix and the patch-mucosal interfacial contact area.

58. A method of treating or preventing a condition, disease, or disorder in a subject in need thereof, comprising administering to the subject a transmucosal patch of any one of claims 1-

Images