CA3061488A1 - Coating - Google Patents

Abstract

ABSTRACT
A coating is described for use in delivery of substances to the colon of a subject in an oral dosage form, without release in the upper gastrointestinal tract. The coating comprises a perforated scaffold formed in part from non-fermentable dietary fiber, and a composition comprising a fermentable dietary fiber which is used to occlude the perforations of the scaffold. A method of forming the coating is described herein, which comprises preparing a perforated scaffold from the non-fermentable dietary fiber and applying to the scaffold a liquid composition comprising a fermentable dietary fiber so as to occlude the perforations of the scaffold with the fermentable dietary fiber containing composition, following which the coating is dried to a desired consistency for use in encasing substances for colonic delivery.

Description

COATING
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] None.
FIELD

[0002] The present disclosure relates generally to coatings used in oral delivery of substances for targeted delivery to the colon.
BACKGROUND

[0003] Enteric coatings are used as a barrier to encapsulate substances, such as medicines, intended for oral consumption but which are to be released slowly or in a timed manner within the upper gastrointestinal (GI) tract. Certain enteric coatings may dissolve when pH is reduced, such as in the presence of stomach acids. With transit through the upper GI tract ranging from 2 to 6 hours, enteric coatings may be designed to achieve full release of the encapsulated substance within this transit time. The upper GI
tract is the site of the majority of intestinal absorption of macronutrients, and is also the primary site of absorption of oral delivery medicines.

[0004] The lower GI tract (the colon) is responsible for reabsorption of water and electrolytes over a transit time ranging from 12 to 24 hours. Within the lunen of the colon, fermentation of residual dietary components occurs, specifically: those components that pass through the upper GI tract undigested and/or unabsorbed. Resident intestinal bacteria, a diverse population of aerobes and facultative anaerobes, is capable of fermenting certain carbohydrate polymers, such as starch and soluble fiber. However, the efficiency of the upper GI tract in digesting and absorbing starch in its constituent sugar molecules largely negates the arrival of undigested starch to the colon. Soluble dietary fibers, arrive unabsorbed to the colon after a transit through the upper GI tract. In the colon, the resident bacterial population can ferment soluble dietary fiber, thereby releasing short chain fatty acids of 2 ¨ 4 carbons in length (acetic, propionic and butyric acids), which can be absorbed f into the bloodstream from the lumen of the colon. Certain positive health effects of soluble fiber have been attributed to short chain fatty acid absorption'.

[0005] Oral coatings are known for use in delivery of medicine or other substances to the colon. People suffering from diseases such as colon cancer, irritable bowel syndrome (IBD) and inflammatory bowel disease (IBD) stand to benefit from targeted oral drug delivery forms, bringing the medicine into direct contact with the effected site, rather than relying on upper GI absorption to circulate medicines systemically before delivery to the effected site in the colon. Delivery of medicines to the effected site in the colon can thus reduce toxicity and side effects that are the hallmark of systemic delivery. Delayed release of medicines to the colon can be achieved by such dosage forms as nanoparticles, carbon nanotubes, dendrimers, and microparticles2. Further developments and advances in colonic delivery provide options for the consumer.
SUMMARY

[0006] Described herein are coatings for substances to be delivered to the colon.
The coating permits a wide variety of substances to transit the upper GI tract without disruption in the form of digestion or absorption. Once the coated substance arrives at the colon, release of the substance in the intended region is achieved by colonic fermentation of a soluble fiber component of the coating by the resident colonic bacteria.
Fermentation of the coating releases the substance to the intended site.

[0007] There is provided herein a coating for encapsulating a substance for colonic delivery comprising a fermentable dietary fiber. The coating may further comprise a non-fermentable fiber. The coating may be formed as a liquid composition for spraying onto the substance for delivery. Alternatively, the coating may be formed into a sheet which may be molded or otherwise manipulated into a shape to be filled with the substance for delivery.

[0008] Other aspects and features of the present disclosure will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments in conjunction with the accompanying figures.
BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Embodiments of the present disclosure will now be described, by way of example only, with reference to the attached Figures.

[0010] Figure 1 depicts a mesh scaffold of a non-fermentable dietary fiber sheet before (a) and after (b) mesh openings are filled and obstructed with a fermentable dietary fiber, to thereby form the coating. A schematic representation is shown in ( c) of a process for filling with two different fermentable dietary fiber compositions on a mesh scaffold to represent preparation of a bulk sheet of the coating.

[0011] Figure 2 depicts the coating, once formed as a sheet and shaped as an open-ended capsule to contain a substance for delivery to the colon. Depicted are both a pre-loaded form (a) and a filled form with a crimped closure to seal the substance for deliverywithin the capsule.
DETAILED DESCRIPTION

[0012] Generally, the present disclosure provides a coating for use in targeted delivery of substances to the colon.

[0013] A coating is described which comprises a perforated scaffold comprising a non-fermentable dietary fiber, and a composition comprising a fermentable dietary fiber occluding the perforations of the scaffold.

[0014] The coating may be used for encasing or enclosing a substance for delivery to the colon in an oral dosage form. Further, once the substance for delivery to the colon is so encased, the coating is used for delivery of a substance to the colon of a subject in need thereof in an oral dosage form.

[0015] A method of forming a coating is described herein, which comprises preparing a perforated scaffold comprising the non-fermentable dietary fiber and applying to the scaffold a composition comprising a fermentable dietary fiber so as to occlude the perforations of the scaffold with the fermentable dietary fiber containing composition.

[0016] Substances for Delivery to the Colon.

[0017] A wide variety of substances can be delivered to the colon, which can bypass digestion and absorption in the upper GI tract. Substances that are susceptible to low pH or gastric enzymes are not destroyed in the upper GI tract if coated during transit. Medicines, probiotics, or live cultures of restorative colonic bacteria may be delivered

[0018] Medicines. A variety of categories of medicine can be delivered to the colon.
Medicines for addressing colon cancer may include small molecules for chemotherapy or biologic molecules, such as for immunotherapy. For inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, and other disorders of the colon, medicines may be encapsulated into the coating. Such medicines as known to a research clinician, prescribing physician or pharmacist may be delivered in this manner.

[0019] Antibiotic or Probiotic Delivery. Probiotic delivery within edible substances such as yogurt is known. The coating may be used to deliver probiotic bacteria to the colon with reduced incidence of destruction as the bacteria pass through the various insults of the upper GI tract, including pH changes and digestive enzymes. Probiotic bacteria exposed to the upper GI tract may not be functional upon arrival at the colon. However, once a coated form of such probiotic bacteria arrive at the colon, the coating is fermented in such a way that the contents is then directly exposed to the colon. Thus, live bacteria so delivered have the opportunity to colonize the colonic lumen.

[0020] While systemic antibiotics are often used (via oral delivery) to treat infection, one of the negative side effects of a course of oral antibiotics is the destruction of colonic bacteria. However, antibiotic delivery using a fermentable coating would prevent upper GI
absorption, and reduce systemic exposure to antibiotics, in the event that the purpose of the antibiotics is to address bacterial overgrowth within the colon, for example at a post-surgical site, or following re-population with undesirable bacteria following a course of systemic antibiotics. The fermentation of the coating would thus release the encapsulated antibiotic for delivery to the colon without significant systemic absorption.

[0021] Fecal Transplant and Recovery from Long-Term Antibiotic Use.
Antibiotic use can result in decimation of the diversity of colonic bacteria. If a subject is experiencing difficulties of this nature, fecal transplant technologies are used to quickly re-populate the colon with a sample of mixed bacteria from a fecal sample derived from a healthy individual.
This technology shows promising results but has not been rapidly adopted in part due to the somewhat repugnant nature (as well as the logistics and regulatory considerations) of obtaining and delivering such samples. A delivery mode such as the current coating, that encapsulates the fecal material but permits release within the colon via colonic fermentation by the existing bacteria present in the individual receiving the transplant, could be one way in which the fecal material to be transplanted could at least be kept in an air-excluded environment whilst en route.

[0022] Dietary Fibers.

[0023] The coating may be formed entirely of fermentable dietary fiber material, or may be formed from a mixture of fermentable and non-fermentable fibers, provided that the materials are not significantly degraded within the digestion process of the upper GI
tract. There are a number of materials that do not degrade within the upper GI, and which do not degrade in the colon. Many of these materials are simple inert non-food components. While such components can be used within the coating, one advantage of using food-grade components is the public perception and regulatory advantages of using ingredients with a long history of human consumption, which are "generally recognized as safe" (GRAS) to ingest.
Consumers, including patients looking to ameliorate a disease or condition, prefer to consume food components rather than what may be viewed as "chemicals" or additives". In certain embodiments, the coating is largely formed from dietary fibers. The USFDA
maintains an inventory of GRAS notices for foods that have been consumed safely for many years. Dietary fibers that are USFDA GRAS acceptable include but are not limited to polysaccharide complexes, such as for example, wheat bran, oat bran, rice hull fiber, konjac glucomannan (konjac), sodium alginate, xanthan gum (polysaccharide complex KAX), guar gum, distarch phosphate, isomaltodextrin, enzyme-modified dextrins, pectin, citrus fibers, pea fiber, citrus pulp fiber, beta glucans (whether oat fiber isolates or other), corn hull fiber, oat hull fiber, barley fiber, potato fiber, sweet lupin fiber, gum acacia, alpha-cyclodextrin, carrot fiber, inulin, oligofructose, psilium, etc. Resistant starch, as may be found in potatoes and other grains can be categorized as a dietary fiber, as it is a polymeric carbohydrate that is capable of traversing the upper GI undigested, but is then capable of degradation by intestinal flora once it reaches the colon.

[0024] Fermentability of Dietary Fibers, Whilst there is a tendency to categorize plant-based dietary fibers as either entirely fermentable (as is the perception of oat bran fiber) or entirely non-fermentable (as is the perception of wheat bran fibers), the fact is that there is a spectrum of fermentability for most non-starch plant-derived polysaccharides.
Further, an individual with a rapid colonic transit time (for example due to a disease state or a condition such as irritable bowel syndrome) may experience less colonic fermentation of the same fermentable substrate as compared with a healthy person having a longer transit time.

[0025] Acknowledging this spectrum of fiber fermentability, the fibers referred to herein are categorized in terms of fermentabiliy, referred to as either "fermentable" or "non-fermentable". Highly fermentable (herein referenced as "fermentable" or "soluble" fibers) include psyllium, oat bran, pectins, beta-glucans, guar gum, inulin and oligofructose. Some of the fermentable fibers are also capable of thickening or creating a viscous constitution in a food product, such as glucomannans, beta-glucans, pectins, guar gum and psyllium. These viscous fibers are also effective at forming coatings and may be readily used in the coating described herein. Resistant starch is also a component capable of forming a fermentable component of the coating described herein.

[0026] Dietary fibers that are less fermentable, and herein referenced as "non-fermentable" (or insoluble) include wheat bran, fiber from green leafy vegetables, and other cellulosic sources of fiber.

[0027] A skilled person can readily determine the solublility, and hence fermentability of a given dietary fiber source by conducting the rapid enzymatic assay taught by Asp et al., (1983)4.

[0028] In order to mitigate rate at which the fermentation of the coating occurs, non-fermentable dietary fibers may be included in the structure of the coating to a greater or lesser extent.

[0029] Coating Formulation. An aqueous or solvent-based formulation may be used in order to mix the coating to a desired consistency which may be spray dried, or dried in a sheet form in order to be later molded or manipulated to the desired shape. Food-grade or drug-approved solvents, such as ethanol, may be used and subsequently evaporated.

[0030] Coating Methodologies. In order to coat the substance to be delivered, known methodologies may be employed, such as spray or dip coating followed by drying, or forming moldable/malleable sheets. Pre-formed sheets may employ regions of higher fermentability so that a perforated effect can be achieved when the coated substance reaches the colon and is worked upon by the colonic bacteria of the subject individual.

[0031] Spray or Dip Coating. Medicines may be formed into solid tablets or other shapes, and subsequently sprayed, dipped, or otherwise immersed in the coating in a liquid form.

[0032] Sheets for Forming Containing Means. Sheets of coating may be formed by pouring and drying the coating into flat forms of desired homogenous thickness. The coating so formed as a sheet may be dried to the extent that it remains malleable to be shaped into the desired form, such as the two sides of a capsule, or a container that may be closed at one end once the substance to be delivered is placed therein. A crimping or sealing mechanism may be used, once the substance is loaded into the capsule or container form.

[0033] Mesh with variably fermentable regions. The coating may take the form of a scaffold with orifices or openings, such as in the form of a mesh, lattice or perforated structure. The scaffold non-fermentable fiber lattice with regular openings, whether circular, square, or random, etc. Once such a scaffold is formed of the non-fermentable fiber, the orifices or perforations within the scaffold may be filled, clogged, or otherwise obscured by a fermentable fiber, such as by spray coating over the scaffold in a liquid form. The coating may be dried to a point where it is malleable and able to take a shape capable of encasing or otherwise enclosing the substance to be delivered to the colon.

[0034] Figure 1 depicts a mesh scaffold of a non-fermentable dietary fiber sheet before (a) and after (b) mesh openings are filled and obstructed with a fermentable dietary fiber, to thereby form the coating. The scaffold may be made of a combination of cellulosic fibers with fermentable fibers. A schematic representation is shown in (c) of a process for filling with two different fermentable dietary fiber compositions onto a mesh scaffold to represent preparation of a bulk sheet of the coating. More than one fermentable fiber may be applied to the scaffold in layers, using a spray technique, followed by drying, and subsequently rolling. The coating formed as a continuous sheet (the start of which is not shown) is malleable, and may be rolled for later use. The inset view shows a highly magnified version of the scaffold once filled with the fermentable fiber composition to form the coating.

[0035] Capsules and Encapsulating Forms. Once a coating is formed, for example, with a thickness of from 0.1 mm to 5 mm in thickness, appropriate shapes such as capsules may be formed for containing the substance to be delivered.

[0036] Figure 2 depicts a coating, taking the form of a capsule. The coating is formed as a sheet having off-set mesh perforations that are generally rectangular in shape.
The scaffold is formed form a finely ground non-fermentable fiber such as wheat bran together with a finely ground psyllium component in lower amounts (such as from 55:45 to 95:5), mixed with water in an amount to result in an extrudable form. The scaffold is filled with an overlay of a fermentable fiber composition formed of pectin and psyllium, finely =
ground and with water added to render a gel-like composition overlayed onto the scaffold to form a sheet of the coating. The sheet, once dried, is shaped as an open-ended capsule, ready to be filled with a substance for delivery to the colon. Depicted are the coating in a capsule shape in both a pre-loaded form (a) and a filled form with a crimped closure at one end, used to seal the substance for delivery within the capsule. The capsule once closed is adequately small in size (such as for example, from 10 mm ¨ 1 cm in height) so as to be readily consumed by a human without any notice, irritation or discomfort. The capsule could take the size of medicinal capsules which are in regular use in the art of medicinal formulations.

[0037] More than one type of fermentable fiber may be used in the composition applied to the scaffold, or a single type may be used. The fiber is mixed with adequate amounts of water to be sprayable or applicable to the scaffold, in a manner that fills or obscures the holes or perforations therein. Further, more than one fermentable fiber composition can be applied to the scaffold in succession, to give the coating desirable properties.

[0038] Maintaining Good Health with Dietary Fiber. A balanced and varied diet is helpful in the avoidance of illness. However, careful attention to diet, exercise and weight control are no guarantee of good health or the avoidance of the need for medicine or therapies requiring delivery to the colon. Noting that persons consuming a high-fiber diet may be less susceptible to various ailments of the colon, an exemplary cookie recipes adapted to include high-fiber components is provided below in Table 1.
Table 1 Cookie Recipe Including Components High in Dietary Fiber Quantity Ingredient 250 mL Butter 125 mL Granulated Sugar 250 mL Brown Sugar, packed 2 Eggs mL Vanilla 500 mL Whole wheat flour (non-fermentable fiber contributor) 500 mL Rolled Oats (fermentable fiber contributor) 5 mL Baking soda 5 mL Baking Powder 5 mL Salt 500 mL Butterscotch chips 15-30 Maraschino cherries, quartered, blotted dry Cream butter and sugars. Beat in eggs. Add Vanilla. Measure in remaining ingredients. Mix. Drop by spoonful onto greased baking sheet. Top with quartered cherry. Bake at 180 C oven for 8-10 minutes. Makes 6 dozen.

[0039] In the preceding description, for purposes of explanation, numerous details are set forth in order to provide a thorough understanding of the embodiments.
However, it will be apparent to one skilled in the art that these specific details are not required.

[0040] The above-described embodiments are intended to be examples only.

Alterations, modifications and variations can be effected to the particular embodiments by those of skill in the art. The scope of the claims should not be limited by the particular embodiments set forth herein, but should be construed in a manner consistent with the specification as a whole.

[0041] References

[0042] The following publications are incorporated by reference herein.

[0043] 1. Marsman, K.E. & McBurney, M.I. Dietary fibre and short-chain fatty acids affect cell proliferation and protein synthesis in isolated rat colonocyte. J. Nutrition, 1996, 126(5): 1429-37.

[0044] 2. Belali, N et al., Advances in orally targeted drug delivery to colon. J
Adv Pharm Technol Res. 2019 Jul-Sep; 10(3): 100-106. doi:
10.4103/japtr.JAPTR_26_19.

[0045] 3. Pare, Jean. Butterscotch Oat Drops. Company's Coming Cookies.
Company's Coming Publishing Limited, Edmonton Canada. 2006. p.13.

[0046] 4. Asp, N, et al., Rapid Enzymatic Assay of Insoluble and Soluble Dietary Fiber. J. Agric. Food Chem 1983 31, 476-482.

Claims (4)

CLAIMS:

1. A coating comprising a perforated scaffold comprising a non-fermentable dietary fiber, and a composition comprising a fermentable dietary fiber occluding the perforations of the scaffold.

2. Use of the coating of claim 1 for encasing a substance for delivery to the colon in an oral dosage form.

3. Use of the coating of claim 1 for delivery of a substance to the colon of a subject in need thereof in an oral dosage form.

4. A method of forming a coating comprising preparing a perforated scaffold comprising the non-fermentable dietary fiber and applying to the scaffold a composition comprising a fermentable dietary fiber so as to occlude the perforations of the scaffold with the fermentable dietary fiber containing composition.