Patent Description:
Rectally-delivered hydrocortisone has been shown to induce remission in patients with left-sided, distal ulcerative colitis. For patients with this disease, liquid enemas are often prescribed because the medication is distributed as far as the splenic flexure. For patients with sigmoid colitis, foam enemas are prescribed as the distribution of the medication extends to the sigmoid colon and partially to the descending colon. Although ulcerative colitis confined to the rectum, defined as ulcerative proctitis, can be treated with suppository formulations of hydrocortisone, no suppository formulation of hydrocortisone has been approved by the Food and Drug Administration (FDA) as a safe and effective treatment.

<CIT> and discloses a method for increasing the solubility of useful actives in siloxane matrix-forming preparations, and associated preparations.

<NPL> discloses applications of colloidal silicon dioxide in pharmaceutical formulations.

<CIT> and discloses a suppository composition having improved stability.

<CIT> and discloses a suppository which contains a suppository base comprising a fatty acid triglyceride, one or more C14-<NUM> fatty acid glycerides, and a base ingredient.

<CIT> and discloses a device for application to a body cavity.

<CIT> and discloses a suppository comprising hydrocortisone acetate in a hydrogenated cocoglyceride base for use in the treatment of inflamed hemorrhoids, post irradiation proctitis, chronic ulcerative colitis, cryptitis, other inflammatory conditions of the anorectum.

Accordingly, there is a need for safer and more effective hydrocortisone suppository formulations for the treatment of gastrointestinal (GI) diseases and disorders, including ulcerative colitis, Crohn's disease and inflammatory bowel disease (IBD).

The present invention relates to a suppository for use in treating inflammatory bowel disease, the suppository having a weight of <NUM> and comprising <NUM> hydrocortisone acetate, <NUM> to <NUM> colloidal silicon dioxide and a semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin, wherein the suppository has a melting temperature in the range of <NUM> to <NUM>. In an embodiment, the suppository comprises about <NUM>% by weight hydrocortisone acetate and about <NUM>% by weight colloidal silicon dioxide. The suppository additionally comprises an oleaginous base that includes triglycerides. In additional embodiments, the suppository also comprises butylated hydroxytoluene (BHT).

In other examples, the present invention relates to a suppository having a weight of about <NUM> grams (g), which comprises about <NUM> milligrams (mg) hydrocortisone acetate, and releases at least about <NUM>% of the hydrocortisone acetate at about <NUM> minutes following exposure to dissolution media comprising a buffered <NUM>% w/v sodium lauryl sulfate solution having a final pH in the range of about <NUM> - <NUM>. In a particular example, the suppository comprises about <NUM> hydrocortisone acetate, colloidal silicon dioxide, and an oleaginous base that includes triglycerides. The suppository weighs about <NUM>.

The formulations described herein have advantages over prior hydrocortisone suppository formulations, including, for example, improved retention by patients and reduced absorption variability. The disclosed formulations also have desirable release profiles of hydrocortisone acetate upon exposure to rectal fluid and, therefore, are less dependent than current hydrocortisone suppository formulations on melting temperature for the delivery of hydrocortisone to the patient.

In addition to the foregoing, embodiments of the invention are directed to the structure of the suppository. As known, certain diseases are treated by way of a suppository containing a drug (e.g., hydrocortisone acetate). Current suppositories have "torpedo" configurations and, therefore, can be difficult to apply in a rectum to effectuate a high level of drug delivery. Embodiments of the present invention provide for alternative configurations of suppositories that allow for easier application into the rectum and can provide greater surface area of the medication for which to expose tissues within the rectum.

Also disclosed is a drug delivery system (e.g., a suppository) that includes a component that changes shape or composition once inside the body and releases medication (e.g., hydrocortisone acetate) after being placed within the rectum. The component can be compact in shape and size for the administration into the body. Once the component is properly placed within the rectum, or at the anal-rectal line, the component changes shape or composition to administer the medication contained therein. The drug delivery component may be made of synthetic or biodegradable polymer impregnated with a medication. Alternatively, the component may be made of a metal with a polymer coating that is impregnated with the medication. The component may be composed of a water soluble base in combination with the drug. Alternatively, the component may encase or coat the drug in a water soluble film or coating.

One example includes a flexible ring that is made compact in shape and size before administration to the patient. The ring may be twisted or coiled to form a smaller ring within a ring. Alternatively, the ring may be folded to form a narrow loop, and, additionally, the ends of the narrow loop may be folded in on itself in the opposite direction, forming a compact shape of the ring. The ring may also be self-elongating in that it holds a small circumference before being placed within the body, at which time it expands in circumference to fit within the rectum.

Another example includes a "tree" shape drug delivery component configured to fold into a compact formation until the proper placement within the body. The component may have one or more sections at the top of the tree that may fold down to a form "I" formation before administration. The component may or may not have a center stem. Alternatively, the sections at the top of the tree may be self-elongating in that they hold the "I" formation before administration and extend to the tree formation after proper placement within the body.

The examples of the ring or tree shapes may have medicated filaments that attach to the component. The medicated filaments may hang from the component within the body to treat a larger area of the mucosa lining of the rectum. The filaments may degrade within the body or be expelled from the body after releasing the medication.

An alternative drug delivery system includes a fabric impregnated with medication or a film composed of the medication. The fabric may be folded or wound on itself before administration. After proper placement, the fabric may be unfolded or unwound to adhere to the lining of the rectum.

Another example includes a sponge impregnated with medication that is folded, compressed or wound on itself before administration to hold a more compact shape. After administration, the sponge may expand, unfold, or unwind to fit the shape and location within the rectum.

Another drug component includes a container that holds the medication in a compact shape or form until it is properly placed within the body. One example includes a water-soluble shell surrounding a drug composition. Once the drug component is properly placed within the rectum, the outer shell dissolves. The medication within the shell expands or changes shape or form and releases the drug to be absorbed by the body. The medication, in a solid state, may be formed in a variety of structural shapes as disclosed herein. When packaged within a delivery vessel, such as an inactive ingredient that is designed to change state over time after placement within the body to release medication contained therein, the medication may include, but is not limited to, the following forms: powder, liquid, gel, granule, or threads. The medication may increase its contact with the mucosa lining of the rectum by expanding in volume. Alternatively, the medication may increase its contact with the mucosa lining of the rectum by greater disbursement of the drug after being freed from the constraints of the outer shell.

Another example includes a water soluble shell surrounding a solid or semi- solid drug that expands or takes a different shape after the drug component is properly placed within the body.

The drug components described in this application can be administered to the patient using an insertion applicator to achieve proper placement within the body.

The invention relates to a suppository for use in treating inflammatory bowel disease, the suppository having a weight of <NUM> and comprising <NUM> hydrocortisone acetate and <NUM> to <NUM> colloidal silicon dioxide and a semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin, wherein the suppository has a melting temperature in the range of <NUM> to <NUM>. In other examples, the suppository comprises about <NUM>% to about <NUM>% by weight hydrocortisone acetate. For example, the suppository can comprise about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>%, or about <NUM>% to about <NUM>% by weight hydrocortisone acetate. In another example, the suppository may comprise about <NUM>% to about <NUM>% by weight hydrocortisone acetate. In a particular example, the suppository comprises about <NUM>% (e.g., <NUM>%, <NUM>%, <NUM>%) by weight hydrocortisone acetate.

In other examples, the suppository comprises about <NUM>% to about <NUM>% by weight colloidal silicon dioxide. For example, the suppository can comprise about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>%, or about <NUM>% to about <NUM>% by weight colloidal silicon dioxide. In another example, the suppository comprises about <NUM>% to about <NUM>% by weight colloidal silicon dioxide. In a particular embodiment, the suppository comprises about <NUM>% (e.g., <NUM>%, <NUM>%, <NUM>%) by weight colloidal silicon dioxide.

The suppository comprises a pharmaceutically-acceptable excipient that is an oleaginous base. The oleaginous base is a semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin. In certain examples, the oleaginous base includes monoglycerides, diglycerides and triglycerides. For example, the oleaginous base can include a mixture of monoglycerides, diglycerides and triglycerides, in a variety of ratios. In a particular example, the oleaginous base includes triglycerides (e.g., more than <NUM>% of the glyceride content is triglycerides).

Suitable oleaginous bases for use in the suppositories described herein include, for example, theobroma oil/cocoa butter, triglycerides from vegetable oils, hydrogenated coco-glycerides, trilaurin triglycerides (glycerol trilaurate, glyceryl trilaurate, glyceryl tridodecanoate, glycerin trilaurate and tridodecanoin), lecithin and hydrogenated lecithin, synthetic or semi-synthetic triglycerides and mixtures thereof. In the suppository for use according to the claims, the oleaginous base is a semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin. In a particular example, the oleaginous base comprises at least about <NUM>% triglycerides, and further comprises diglycerides and monoglycerides (e.g., less than about <NUM>% diglycerides and less than about <NUM>% monoglycerides). Examples of commercially available oleaginous bases that are useful for the suppository described herein include, for example, HYDRO-KOTE® <NUM> bases, and SUPPOCIRE® AML bases.

In other examples, the suppository comprises a pharmaceutically-acceptable excipient that is a water-soluble miscible base. Examples of water-soluble miscible bases include glycerinated gelatins or polyethylene glycol (PEG) polymers (e.g., PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>).

In certain embodiments, the suppository further comprises an additive (e.g., one additive, two or more additives). Additives include, but are not limited to, adsorbents, surface acting agents (e.g., mucosal adhesives, such as xanthan gum, lisinopril, hydroxypropyl methylcellulose, carboxy methylcellulose, and chitosan, among others), viscosity-influencing agents, suspending/dispersing agents (e.g., zinc oxide, alginic acid, crystalline cellulose), plasticizers (e.g., diethlyhexyl phthatale, glycerin), melting point-adjusting agents (e.g., white wax), antimicrobial agents (e.g., thimerasol), phospholipides (e.g., lecithin) and antioxidants (e.g., ascorbic acid, ascorbic palmitate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA)).

In some embodiments, the suppository comprises an additive that is an antioxidant. Particular examples of antioxidants that are suitable for inclusion in the suppositories described herein include butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), as well as combinations BHT and BHA, in a variety of ratios (e.g., a <NUM>:<NUM> ratio). In a particular embodiment, the suppository comprises butylated hydroxytoluene (BHT). For example, the suppository can comprise about <NUM>% to about <NUM>%, about <NUM>% to about <NUM>%, or about <NUM>% to about <NUM>% by weight BHT. In a particular embodiment, the suppository comprises about <NUM>% (e.g., <NUM>%, <NUM>%, <NUM>%) by weight BHT.

In general, the formulations described herein are solid or semi-solid formulations. Accordingly, in various embodiments, the formulations of the present invention are suitable for use in a suppository for administration (e.g., rectal administration) to a mammal (e.g., a human). Typically, the formulations described herein have one or more properties (e.g., melting temperature, solubility, stability) that are desirable for suppositories. For example, in some embodiments, the formulation releases the hydrocortisone acetate upon exposure to rectal fluid. Methods for assessing whether a formulation releases the hydrocortisone acetate upon exposure to rectal fluid are known in the art and include, for example, the method exemplified herein.

In additional examples, the suppository has a melting temperature in the range of about <NUM> to about <NUM>. Methods for determining the melting temperature of a suppository are known in the art and include, for example, the method exemplified herein.

In some embodiments, the formulation is stable (e.g., under storage conditions) at a temperature in the range of about <NUM> to about <NUM>. Methods for assessing whether a formulation is stable under storage conditions are known in the art and include, for example, the method exemplified herein.

In other examples, the invention relates to a suppository having a weight of about <NUM> grams (g), which comprises about <NUM> milligrams (mg) hydrocortisone acetate, and releases at least about <NUM>% of the hydrocortisone acetate at about <NUM> minutes following exposure to dissolution media comprising a buffered <NUM>% w/v sodium lauryl sulfate solution having a final pH in the range of about <NUM> - <NUM>. In a particular example, the dissolution media comprises <NUM>% w/v sodium lauryl sulfate:acetate buffer pH <NUM> (<NUM>:<NUM>) final pH adjusted to <NUM> - <NUM>.

Suitable concentrations of hydrocortisone acetate for use in the suppositories described herein include, for example, any of the concentrations of hydrocortisone acetate described herein as being suitable for the formulations of the invention. Suitable concentrations of colloidal silicon dioxide for use in the suppositories described herein include, for example, any of the concentrations of colloidal silicon dioxide described herein as being suitable for the formulations of the invention. In the suppository for use according to the claims, the suppository comprises <NUM> of hydrocortisone (e.g., hydrocortisone acetate) and about <NUM> to about <NUM> (e.g., about <NUM>) of colloidal silicon dioxide.

In the suppository for use according to the claims, the suppository comprises an oleaginous base as defined in the claims. In one embodiment, the oleaginous base includes triglycerides. Suitable oleaginous bases for use in the suppositories described herein include, for example, a semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin, or comprising at least about <NUM>% triglycerides, wherein the base further comprises diglycerides and monoglycerides.

In additional embodiments, the suppository further comprises an additive. Suitable additives for use in the suppositories described herein include, for example, any of the additives described hereinabove as being suitable for the suppositories of the invention. In a particular embodiment, the suppository comprises BHT. Suitable concentrations of BHT for use in the suppositories described herein include, for example, any of the concentrations of BHT described hereinabove as being suitable for the suppositories of the invention.

The suppositories described herein can have a weight in the range of about <NUM> to about <NUM> and generally include from about <NUM> to about <NUM> of hydrocortisone (e.g., hydrocortisone acetate). In the suppository for use according to the invention, the suppository weighs about <NUM> (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>). In one embodiment, the suppository weighs about <NUM> and comprises about <NUM> (e.g., <NUM>, <NUM>, <NUM>) hydrocortisone acetate. In a further embodiment, the suppository weighs about <NUM> and comprises about <NUM> hydrocortisone acetate and about <NUM> (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>) colloidal silicon dioxide. In a further embodiment, a suppository weighs about <NUM> and comprises about <NUM> hydrocortisone acetate, about <NUM> colloidal silicon dioxide and about <NUM> (e.g., <NUM>, <NUM>, <NUM>) BHT.

In some examples, the suppository has a weight of about <NUM>, comprises about <NUM> of hydrocortisone acetate, and releases at least about <NUM>% of the hydrocortisone acetate at about <NUM> minutes following exposure to a dissolution media comprising <NUM>% w/v sodium lauryl sulfate:acetate buffer pH <NUM> (<NUM>:<NUM>) final pH adjusted to <NUM> - <NUM>.

In some embodiments, the present invention relates to a suppository having an oblong shape. In other embodiments, the oblong shape further comprises a cylindrical shape. In certain embodiments, the suppository has a shape that allows contact between the outer surface of the suppository and the mucosal membrane of the rectum when the suppository is situated in the rectum. In other embodiments, the suppository formulation releases the hydrocortisone acetate upon exposure to rectal fluid.

Methods and devices for administering suppositories are known in the art and include, for example, those described in <CIT>. Such methods and devices are useful for administration of the formulations (e.g., suppositories) described herein.

The formulations (e.g., suppositories) described herein are useful for the treatment of gastrointestinal diseases and disorders, including, for example, inflammatory bowel disease (IBD), bowel ailments and other diseases for which systemic or local rectal hydrocortisone is an appropriate therapeutic intervention. Such gastrointestinal diseases and disorders include, but are not limited to, colitis (e.g., ulcerative colitis, collagenous colitis, lymphocytic colitis), Crohn's disease, proctitis (e.g., ulcerative proctitis), and hemorrhoids (e.g., internal hemorrhoids). The invention relates to a suppository (as defined in the claims) for use in treating inflammatory bowel disease, such as ulcerative colitis.

In some embodiments, the formulations (e.g., suppositories) described herein can be administered in combination with other therapeutic agents that are useful for treating gastrointestinal diseases and disorders. In one embodiment, the formulations (e.g., suppositories) described herein can be administered in combination with mesalamine (e.g., oral mesalamine, a suppository containing mesalamine). In general, the other agent(s) being administered in combination with the hydrocortisone formulations will be administered separately from the hydrocortisone formulation (e.g., in a different form (e.g., a pill or capsule) or suppository). In some embodiments, the formulations (e.g., suppositories) described herein can be administered in combination with a local anesthetic (e.g., lidocaine).

Ailments and diseases of the bowel are common and have varying degrees of severity. One of the difficulties of treating patients with bowel disorders and symptoms is targeting the affected area. Oral medications must pass through the metabolism before offering therapeutic benefit and are systemic in their reach. Increasingly, the intravenous infusion therapies are being used to treat bowel disease and are targeted to modify the immune system.

One subset of patients with digestive disease suffer from ulcerative proctitis which affects the rectum and cannot be treated with oral or intravenous medications. Treatment for ulcerative proctitis is best accomplished with local therapy using medications that can treat the venous inflammation topically. Current drug therapy for ulcerative proctitis includes the use of suspension enemas, suppositories and creams or ointments. In the case of internal ulcers, the target area is the anal-rectal line and the lower rectum where inflamed veins originate and are sometimes prolapsed.

Suspension enemas are designed to treat the sigmoid or left side of the colon and place the drug too far above the lower rectum and the affected area. Enema medication is also difficult to retain, and often patients must be sedated in order to complete the therapy. Suppositories administered with a finger are placed too shallow within the anal canal and do not reach the lower rectum and anal-rectal line. Additionally, the suppository medication is difficult to retain and often leaks from inside to outside the body. Creams and ointments are primarily used to treat external sores and, when used internally, do not reach the targeted area for ulcers due to ulcerative proctitis inside the rectum at or above the anal-rectal line.

A drug component that places medication in the targeted location of the lower rectum is the optimal way to treat ulcerative proctitis. When placed in the targeted location, not only does the drug avoid contact with the sphincter muscles that signal the brain to release the contents of the colon, but also the drug is placed at the origins of hemorrhoid inflammation.

Targeted topical therapy would be a benefit in the treatment of inflammatory bowel disease, in particular, ulcerative proctitis. Affecting the lower <NUM> (six inches) of the colon, ulcerative proctitis is best treated with topical therapy. However, in order to prevent the advancement of the disease, the area of treatment should be at the highest point of the inflammation. Treatment of ulcerative proctitis patients has similar drawbacks to the treatment of resulting ulcers with suspension enemas and suppositories.

<FIG> illustrates the use of an insertion applicator <NUM> for the administration of a drug component into the body of the patient in its pre-insertion shape or form. An example of an insertion applicator is described in <CIT>, now <CIT>. In an example , the drug component <NUM> is placed in a distal end <NUM> of an insertion barrel <NUM> in its pre-insertion form or shape. In a different example, the drug component <NUM> is placed in a proximal end <NUM> of the barrel <NUM>. A plunger <NUM> is thereafter placed in the proximal end of the barrel <NUM>. After inserting the applicator <NUM>, filled with the drug component, into the anus, the plunger <NUM> is advanced from the proximal end to the distal end of the barrel, thereby releasing the drug component <NUM> to the proper positioning within the rectum (see also <FIG>). Once the drug component <NUM> is properly positioned within the body, the drug component changes shape or form and releases its therapeutic medication to the mucosa lining of the rectum (see also <FIG>).

<FIG> illustrates example of folded (collapsed) medicated rings 402a, 402b, 402c, and 402d' (collectively <NUM>) in their pre-insertion shape and their new shape after proper positioning within the body. After deployment, the medicated ring <NUM> unfolds, uncoils, or expands (412a, 412b, 412c, 412d) depending on the way it was compressed to the smaller shape. The medicated ring <NUM> unfolds or expands to a size whereby it is thereafter configured to press on tissue of the rectum (see also <FIG>). The unfolded or expanded state of ring <NUM> is indicated for the examples in <FIG> at 402a', 402b', 402c' and 402d". Once in position, the medicated ring <NUM> releases the medication contained within the component. The component thereafter either degrades within the body or is released during the evacuation of the contents of the colon.

As illustrated in <FIG>, a flexible ring <NUM> is made compact in shape and size before administration to the patient. For example, ring 402a may be twisted or coiled to form a smaller ring (loop) within a ring (loop). The ring 402a untwists or uncoils (412a) after proper placement within the body. In another example, ring 402b may be folded to a loop in a long "I" formation before placement and is configured to unfold (412b) after placement within the body. A ring 402c may also be self-elongating (e.g., self-expanding, as shown at 412c) in that it holds a small circumference before and until being placed within the body, at which time it expands in circumference to fit within the rectum. Alternatively, ring 402d-<NUM> may be folded to form a narrow loop 402d-<NUM>, and, additionally, opposite ends of the narrow loop may be folded in on themselves (402d-<NUM>), forming a compact shape of the ring 402d' before insertion. The ring 402d' then unfolds (412d) to an expanded shape 402d", after proper placement.

<FIG> illustrates cross sections of drug components, such as rings <NUM> of <FIG>, that may be circular <NUM> in cross section or straight (e.g., flat) <NUM> in cross section. An outer side of the drug components may have one or more raised bumps to aid in the adherence to the mucosa lining of the rectum. For example, component <NUM> is circular in cross section and includes raised bumps <NUM> arranged around its perimeter. In another example, component <NUM> is flat in cross section and includes raised bumps <NUM> on at least one side. Alternatively, the drug components may be corrugated <NUM> with alternating grooves <NUM> that aid in the positioning within the rectum.

<FIG> illustrate a process by which a person inserts a suppository (e.g., a medicate drug component) <NUM> into a rectum <NUM> through use of a suppository insertion device <NUM>. In <FIG>, a barrel <NUM> of the insertion device <NUM> is inserted into an anal canal <NUM> below the anal-rectal line <NUM>. A suppository <NUM> and plunger <NUM> may be inside the barrel <NUM> during the insertion of the barrel. In <FIG>, the person pushes the plunger <NUM> toward the anal-rectal line <NUM>, which, in turn, pushes the suppository <NUM> toward and into the rectum <NUM>, at or above the anal-rectal line and past the sphincter muscles <NUM>. Once released from the insertion device <NUM>, the suppository <NUM> can change shape or form, e.g., expand, as illustrated at <NUM>'. <FIG> illustrates the suppository in an expanded form <NUM>" in which the suppository's expanded size causes it to have contact with internal walls of the rectum <NUM>. The applicator <NUM> is withdrawn, leaving the suppository in place. The suppository <NUM>" is thereafter removed from the rectum through normal discharge of contents from the bowel in accordance with various examples of the suppository, as described herein.

<FIG> illustrate examples of folded medicated tree components 602a, 602b, 602c, 602d, and 602e (collectively, <NUM>) in their pre-insertion shape and their new shape 602a', 602b', 602c', 602d' and 602e' after proper positioning within the body. The medicated tree <NUM> unfolds or self expands (612a, 612b, 612c, 612d, 612e) depending on the way it was compressed to the smaller shape. The medicated tree <NUM> unfolds or expands to a size whereby it will be configured to press on the tissue of the rectum. The tree <NUM> may have a center stem (632a, 632b, 632d, 632e) or a center ring (see, e.g., <NUM> and 636i in <FIG>) from which the arms (634a, 634b, 634d, 634e) of the tree radiate. Alternatively, a tree 602c can have arms 634c radiating from a central point and not have a center stem. Once in position, the medicated tree releases the medication contained within the drug component. The drug component either degrades within the body or is released during the evacuation of the contents of the colon.

The "tree trunk" may be made of the same material as the "branches" of the tree and degrade in the body. Alternatively, the tree trunk may be made of a soft cushiony material that causes no harm and holds a shape that can be expelled with the contents of the bowel.

<FIG> illustrates top views of tree-shaped drug components. The tree-shaped drug components (602f, <NUM>, <NUM> and 602j) may have one or more arms (634f, <NUM>, <NUM> and 634j) radiating out from a center position (632f, <NUM>, <NUM>, 632j). The arms may be in a straight stick (634f, 634j) or a petal formation (<NUM>, <NUM>). The arms may meet at the center point (632f, <NUM>) or they may radiate from a ring (<NUM>, 636j) surrounding the center point (<NUM>, 632j), thereby allowing gas to flow through the center of the drug component.

<FIG> illustrates a tree drug component 602e unfolding (612e) upside down, with the center post 632e and the free ends of the tree branches 634e entering the body first.

<FIG> illustrates medicated filaments (e.g., mediated threads) attached to the drug component. Three example configurations are shown. One or more medicated filaments 740a, 740b, and 740c can be attached, or otherwise coupled, to a ring-shaped drug component 702a, tree-shaped drug component 702b (having a center portion and arms), and flower-shaped drug component 702c (having a center stem and petals). A drug (e.g., an active ingredient) can be carried by or embedded into the filaments. The medicated filaments 740a, 740b, 740c may hang from the component within the body to treat a larger area of the mucosa lining of the rectum. The filaments may degrade within the body or be expelled from the body after releasing the medication.

<FIG> illustrates a medicated film 802a and a medicated fabric 802b. The drug and a water soluble binding agent may compose the film 802a. The fabric 802b may be impregnated with the drug or have raised bumps on the fabric that contain the drug. Both examples can be rolled (802c), folded (802d') or draped (802e) before insertion, and can unwind (812c) or unfold (812d, 812e) to a new shape (802c', 802d" and 802e') after proper placement within the body. The film or fabric may be folded multiple times, e.g., along one axis (802d-<NUM>) and then along another, e.g., perpendicular, axis 802d-<NUM>. The fabric or film may adhere to the lining of the rectum and deliver the medication to the area within which it comes in contact. The medicated film or fabric provides localized therapy to an affected area, which can be of benefit when treating specific areas of the colon, for example, the anal-rectal line, where the swelling of hemorrhoid veins originate.

<FIG> illustrates medicated sponges 902a, 902b, 902c and 902d (collectively, <NUM>) that can be compressed (902a), wound on itself (902b), or folded (902c, 902d) to take a smaller pre-insertion shape and size. Folding can include folding the sponge once (902c-<NUM>), as illustrated, or multiple times, e.g., along different axes. After proper positioning within the body, the sponges <NUM> may expand (912a), unwind (912b), or unfold (912c, 912d) to a new shape (902a', 902b', 902c' and 902d') and release the medication within.

<FIG> illustrates various examples of water soluble shells 1042a, 1042b, 1042c, and 1042d (collectively, <NUM>) that contain medication. The shells can have any suitable shape, such as spherical, cylindrical, rectangular and triangular and the like. The medication includes an active drug ingredient and can be contained in the shell in a stable form. The shells <NUM> are configured to dissolve (<NUM>) and release (<NUM>) the medication. The medication, which may be contained in the shell <NUM> in any suitable form, can be released in a new form <NUM>, such as powder or granules 1048a, embedded or attached to filaments 1048b, a liquid 1048c, or a gel 1048d. The new form can differ from the stable form.

<FIG> is a flow diagram <NUM> illustrating an example of the change in a form that the drug component makes after proper positioning in the body. The drug component may be administered to the patient using an insertion applicator. At <NUM>, a drug component is provided that includes medication contained in a shell or other suitable container. At <NUM>, the drug component is administered to achieve proper positioning in the body. Once properly positioned in the body, the shell dissolves (<NUM>), thereby allowing the medication to be released in a new form (<NUM>), including, but not limited to, powder or granules, filaments, liquid or gel (see also <FIG>). At <NUM>, the medication may be completely absorbed by the body. Alternatively or in addition, inactive ingredients in the suppository may be expelled with the contents of the colon. There may be more than one change in form. After a first dissolution of an outer shell and release of a medication, there may be a second shell to dissolve and, thus, release another treatment of medication in the same or different form from the first release.

As used herein, the term "about" when used in the context of the weight of a suppository, or the amount or percent by weight of a particular ingredient in a formulation, means the absolute stated value and other values proximal to the stated value that are sufficient to achieve a formulation that has an appropriate melting temperature, stability and dissolvability for use as a suppository. Appropriate melting temperatures, stability and dissolvability for a suppository, and methods for determining such properties of a formulation (e.g., suppository), are disclosed herein.

In contrast, the term "about" when used in the context of a temperature, means the absolute stated value and other values within a range of +/- <NUM>% of the stated value.

Several different prototypes of hydrocortisone formulations were made by formulating <NUM> of hydrocortisone acetate with one or more excipients into a <NUM> suppository. The excipients tested included the polyethylene glycol bases PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, and PEG <NUM>, and the oleaginous bases WECOBEE® M, HYDRO-KOTE® C and HYDRO-KOTE® <NUM>, WITEPSOL® H-<NUM>, and SUPPOCIRE® A, AS2, AML, and BS2. A subset of these initial prototypes also included either colloidal silicone dioxide or alginic acid as a suspending/dispersing agent.

Selection criteria were established. The top level criteria were melt point, stability and dissolution (release of the drug) (see Example <NUM> herein).

Second level criteria were hardness, consistency, suspension and appearance. Formulations that were too soft or brittle, showed signs of fracture or cracking, exhibited clumping or settling, or signs of water developing between the suppository and the shell were eliminated.

The final criterion was release from the casing. Formulations that were difficult to remove from the shells after cooling due to sticking were eliminated.

Upon evaluation, eight formulations, designated prototype numbers <NUM>-<NUM>, were selected for further development and testing. The compositions of these eight formulations are indicated in Table <NUM>. Each of these eight prototypes included colloidal silicon dioxide as an additive. Colloidal silicon dioxide is an adsorbent and is widely used in drugs, food, and even wine. This additive was important for preventing the hydrocortisone acetate from clumping and settling. In addition, the colloidal silicon dioxide facilitated keeping the hydrocortisone acetate in suspension, and promoted desired levels of consistency, dispersal, stability and release.

The eight prototype formulations selected in Example <NUM> were tested for melt point, stability and dissolution.

To assess melting point, each suppository containing one of the eight formulations was cut into three slices to produce a small, medium and large (large indicating that it fills the entire sample adaptor) slice, each of which was analyzed further to determine the drop point, which is the moment the first drop falls from the suppository. This was done to ensure that the size of the slice did not affect the drop point that was recorded. The slices were placed in a heating apparatus containing an oil bath and the temperature was increased steadily over time. At the moment the first drop fell from the suppository, both the temperature of the sample and the temperature of the oil bath were recorded. Then, the average sample temperature of the three drop points was calculated and used as the melting point for the formulation. Six of the prototypes were shown to have a melting point in the desired range of <NUM> to <NUM> after six weeks under storage conditions (see Table <NUM>). The storage conditions included maintaining the formulations at a temperature of <NUM>/<NUM>% relative humidity (RH) or <NUM>/<NUM>% RH for <NUM>, <NUM> or <NUM> weeks. The two formulations outside of the desired temperature range are highlighted with an asterisk (*) in Tables <NUM>-<NUM>.

Surprisingly, all eight of the prototypes tested are stable at both <NUM> and <NUM> after two and four weeks under storage conditions (see Tables <NUM> and <NUM>, respectively). A <NUM>% recovery cut-off was used as an indicator of desirable stability. Failure to meet this <NUM>% threshold by two of the formulations is most likely due to manual error in the sampling process, as each of the eight formulations is expected to have sufficient stability.

The release of hydrocortisone acetate from each of the eight formulations was evaluated using a dissolution assay (see Example <NUM>). For the dissolution assay, a media that contains glacial acetic acid and sodium lauryl sulfate (SLS), and which replicates the pH and environment of the rectum, was chosen.

The dissolution profile for each of the eight formulations after four weeks under storage conditions is shown in <FIG>. SUPPOCIRE® A and SUPPOCIRE® AML shows the greatest percent released over a period of <NUM> minutes. In fact, SSUPPOCIRE® A and SUPPOCIRE® AML shows the greatest percent released up to the100 minute mark. Based on the dissolution profile shown in <FIG>, SUPPOCIRE® A and SUPPOCIRE® AML suggests ideal candidates for formulation.

The dissolution rates of hydrocortisone acetate in the formulations discussed in Example <NUM> and shown in <FIG> were determined by high-performance liquid chromatography (HPLC). Specifically, the samples were run on a reverse phase HPLC system with UV detection at <NUM> nanometer (nm).

A protocol for the assay is described below.

General personal protection attire (lab coat, gloves, safety goggles, etc.) should be worn at all times.

Alternate volumes of any preparation may be prepared by adjusting volumes and weights proportionately, with the exception that the weight of the standard preparations may not be reduced.

Water is used as mobile phase A. Obtain <NUM> of Water.

ACN is used as mobile phase B. Obtain <NUM> of Acetonitrile.

If a stable standard is available for which standard agreement has already been demonstrated, preparation of fresh standards may be omitted. Accurately weigh and transfer approximately <NUM> ± <NUM> of Hydrocortisone reference standard material to a <NUM> milliliter (mL) volumetric flask. Dissolve in and dilute to volume with Acetonitrile and mix well. Prepare in duplicate (S1 and S2). Nominal concentration: <NUM>/mL of Hydrocortisone.

Hydrocortisone Acetate (Approx. RT): <NUM> minutes.

Perform any number of equilibration injections of any standard prior to starting the analysis sequence. Do not re-inject from the vial used for equilibration injections after equilibration is complete. Clearly identify the equilibration injections as data not used. During analysis, it is preferable but not required to perform no more than one injection from a single vial.

Determine system suitability at the beginning of the sequence with five injections of S1, two injections of S2 and at least one Diluent injection. System suitability injections may be performed in any order.

Sample injections should be bracketed by standard injections and no more than twelve samples should be run within a bracket. A standard that passes the criterion mentioned in Precision section, relative to one other standard preparation must be used as a bracketing standard.

Calculate the average peak area and % RSD obtained for the Hydrocortisone peak in each of the initial five standards (S1) injections. The % RSD must be ≤ <NUM>.

For each bracketing standard throughout the run, calculate the % difference for the Hydrocortisone peak area in comparison to the average Hydrocortisone peak area from the five precision injections. The % difference for each bracketing standard must be ≤ <NUM>.

Compare the average peak area for Hydrocortisone in the five system suitability injections of standard S1 with the peak area for Hydrocortisone in the two injections of standard S2. Agreement must be within <NUM> ± <NUM>%.

Standard agreement may be omitted from system suitability evaluation if a standard within its stability window has been shown to agree with another standard for Hydrocortisone.

No significant interference greater than <NUM>% of the Hydrocortisone average standard area (n=<NUM>) should be seen in an injection of Diluent.

The tailing factor for Hydrocortisone peak calculated for all the system suitability injections and bracketing standards must be ≤ <NUM>.

Set the minimum peak area for integration to not more than <NUM>% of the average Hydrocortisone injector precision peak area. For all system suitability standard injections, integrate Hydrocortisone peak. Accurately integrate all the peaks in a sample chromatogram. It is permissible not to integrate peaks resulting from Diluent.

Calculate the concentration of Hydrocortisone in the standard as follows: <MAT> Where: W1 = weight of standard used to prepared the standard (mg)
PF* = purity factor of the reference standard taken from the certificate of
analysis (in decimal form)
Calculation of Drug Substance Content.

Calculate the % of Hydrocortisone in samples as follows: <MAT> Where: AreaSmp1= Area of Urea in the sample.

AreaStd = Area of Urea in the five precision standard injections
SC = Standard concentration (mg/mL)
W1 = Nominal weight of the Hydrocortisone in a unit, typically <NUM>
V1 = Vessel volume (typically <NUM>).

The studies herein include formulating different prototypes of hydrocortisone acetate suppositories and evaluating the prototypes for physical and chemical stability prior to refining the formulations based upon critical quality attributes (CQAs), such as melting point and the Active Pharmaceutical Ingredient (API) release profile. The final drug product that was chosen is a solid body of <NUM> weight containing <NUM> of API in a fatty base adapted for introduction into the rectal orifice of the human body, which melts at about body temperature.

The studies herein have also evaluated aluminum shells and plastic shells for container closure system and found that both aluminum and plastic shells are compatible with the product based upon parameters such as ease of filling, visualization of the filled product, and product sticking to the shells. The current container closure system for the products are plastic suppository shells which accommodate up to <NUM> grams of product.

The selection of base is one of the important aspects in the development of the suppositories. The selected base can influence the mechanism of action. Initially, placebo prototypes <NUM>-<NUM> (compositions shown in Table <NUM>) were made to evaluate the aesthetics and ease of filling. The bases were weighed according to the composition and melted. The colloidal silicon dioxide was then added to the melted base and solubilized (for prototypes with colloidal silicon dioxide). The melted preparation was then poured into the shells. During the filling operation, it was observed that prototypes <NUM>, <NUM>, and <NUM> were very viscous and difficult to fill into the shells even at higher temperatures such as <NUM> degrees Celsius (°C). Conversely, prototypes <NUM>-<NUM> were less viscous when compared to prototypes <NUM>, <NUM>, and <NUM> and were easy to fill into the shells at a temperature of <NUM>. The shells were sealed and the suppositories were allowed to solidify. After a few days, the suppositories were evaluated for aesthetics. Prototypes <NUM>, <NUM>, and <NUM> exhibited cracks in the suppositories whereas prototypes <NUM>-<NUM> did not exhibit any cracks.

The Table <NUM> observations and previous published studies indicate that PEG-based suppositories can cause irritancy. Thus, prototypes <NUM>, <NUM>, and <NUM> were eliminated from further study. Building upon the data that was provided in Table <NUM>, active formulations using hydrocortisone acetate (<NUM>) were prepared. The compositions of active prototypes <NUM>-<NUM> are shown in Table <NUM>. The active prototypes were kept in stability chambers at two conditions: <NUM>) <NUM>/<NUM>% relative humidity (RH); and <NUM>) <NUM>/<NUM>% RH, for one month prior to the stability study that were used to evaluate physical and chemical stability.

The suppositories in Table <NUM> were evaluated for physical stability such as cracks within the suppositories, discoloration and feel. Prototypes <NUM>-<NUM> did not exhibit cracks within the suppositories, discoloration or unsatisfactory feel. The suppositories in Table <NUM> were then stored at <NUM>/<NUM>% RH and allowed to solidify at room temperature for further evaluations.

Prototypes <NUM>-<NUM> were next evaluated for Critical Quality Attributes (CQAs) such as melting point (as the mechanism of action for fat based suppositories is melting), and release profile for the API in order to identify the lead formulation. Table <NUM> shows the melting point data for prototypes <NUM>-<NUM>.

Table <NUM> shows that the average melting point of prototypes <NUM>-<NUM> is between approximately <NUM> to <NUM>. The average melting point of prototype <NUM> was found to be slightly higher at approximately <NUM>. As the melting point of all the prototypes studied was found to be quite close, the API release profile was next evaluated to identify the lead formulation from the group of prototypes.

In order to assess the API release profile from the prototypes in Example <NUM> to identify a lead formulation, a robust dissolution method was developed. Solubility studies were performed on the API for the selection of dissolution media. For these studies, the active concentration of the dissolution media was <NUM> milligrams per milliliter (mg/mL). The results of the solubility of <NUM>/mL hydrocortisone acetate in various dissolution medias is shown in Table <NUM>.

According to USP guidelines (on sink conditions) the solubility needs to be at least <NUM> times the proposed active concentration. As shown in Table <NUM>, sodium lauryl sulfate (SLS) achieved the highest percent solubility of the API (hydrocortisone acetate). The studies next turned to the use of higher hydrocortisone acetate concentrations (<NUM>/mL). The solubility of <NUM>/mL hydrocortisone acetate in various dissolution media is shown in Table <NUM>.

As shown in Table <NUM>, the solubility percent of <NUM>/mL hydrocortisone acetate in SLS still remained high. In order to avoid ionization of the hydrocortisone acetate in the dissolution media, a buffer of pH <NUM> was used in combination with <NUM>% w/v SLS. The final composition of the dissolution media was <NUM>% w/v SLS:acetate buffer (pH <NUM>) in <NUM>:<NUM> combination with the pH of the final combination adjusted to <NUM> - <NUM>. The average recovered solubility of <NUM>/mL hydrocortisone acetate in the proposed dissolution media was <NUM>%.

According to the results shown in Tables <NUM> and <NUM>, the optimized dissolution parameters include:.

Prototypes <NUM>-<NUM> were then tested for hydrocortisone acetate release under the optimized dissolution parameters obtained from Table <NUM>. Table <NUM> shows the hydrocortisone acetate release profile of prototypes <NUM>-<NUM>.

As shown in Table <NUM>, prototypes <NUM>, <NUM>, <NUM>, and <NUM> were identified as having the best dissolution. The dissolution profile for each of the prototypes <NUM>-<NUM> is shown in <FIG>. Prototypes <NUM>, <NUM>, <NUM>, and <NUM> show the greatest percent of hydrocortisone acetate released over a period of <NUM> minutes. In fact, prototypes <NUM>, <NUM>, <NUM>, and <NUM> show the greatest percent of hydrocortisone acetate released at <NUM> minutes. Based on the hydrocortisone acetate release profile for each of the prototypes shown in <FIG>, prototypes <NUM>, <NUM>, <NUM>, and <NUM> were selected for lead formulation.

Based on the melting point profile (Table <NUM>), release profile (Table <NUM>) and <FIG>, prototypes <NUM>, <NUM>, <NUM>, and <NUM> were identified as the lead formulations. However, prototypes <NUM> and <NUM> were removed from the studies by taking into consideration the compendial status of the base used in prototype <NUM> and the high melting point of prototype <NUM>. Thus, prototypes <NUM> and <NUM> were selected as the top two formulations (Table <NUM>).

Taking the composition of WITEPSOL® H-<NUM> base (contains hydrogenated coco-glycerides which might have polymorphism issues) into consideration, prototype <NUM> was selected as the backup formulation. Thus, the prototype <NUM> composition containing SUPPOCIRE® AML base (Table <NUM>) was selected as the lead formulation.

The results from these studies led to the selection of the SUPPOCIRE® AML active prototype formulation as the lead formulation based on its superior physical and dissolution properties. The selected lead formulation includes hydrocortisone acetate <NUM>, colloidal silicon dioxide <NUM> and SUPPOCIRE® AML <NUM>, which provides a suppository with a total weight of <NUM>. This lead formulation was then subjected to physical and chemical stability, and dissolution studies.

The selected lead formulation (prototype <NUM>: hydrocortisone acetate <NUM>, colloidal silicon dioxide <NUM> and SUPPOCIRE® AML <NUM>) was subjected to physical and chemical stability studies. The study employed two storage conditions in order to demonstrate compatibility with the selected excipients and to give confidence that the formulations are appropriate for longer storage. The conditions include:.

The results of the physical and chemical stability studies showing the assay and impurity results for SUPPOCIRE® AML active prototypes under storage conditions (standard and accelerated) are summarized in Table <NUM>.

The results from the initial and one month through three month stability studies for the lead prototype (SUPPOCIRE® AML with hydrocortisone acetate <NUM> and colloidal silicon dioxide <NUM>) shows negligible amounts of total impurities after three months of storage (Table <NUM>). These studies demonstrate that the lead formulation remains stable for at least three months under the conditions tested.

The selected lead formulation <NUM> (hydrocortisone acetate <NUM>, colloidal silicon dioxide <NUM> and SUPPOCIRE® AML <NUM>) was next subjected to dissolution studies (Table <NUM>). Samples stored at both <NUM>/<NUM>% RH and <NUM>/<NUM>% RH were subjected to the dissolution testing. Samples stored at <NUM>/<NUM>% RH were subjected to dissolution testing at initial (Time (T)=O), <NUM> month (T=<NUM>) and <NUM> months (T=<NUM>) of storage. Samples stored at both <NUM>/<NUM>% RH and <NUM>/<NUM>% RH were subjected to testing at <NUM> months (T=<NUM>) and <NUM> months (T=<NUM>) of storage.

The results of the dissolution studies (Table <NUM>) show that the dissolution profile for hydrocortisone acetate remains consistent even after <NUM> months of storage at standard storage conditions (<NUM>/<NUM>% RH). However, storage at accelerated conditions (<NUM>/<NUM>% RH) after <NUM> months resulted in a decrease of hydrocortisone acetate release from the lead formulation.

These results led to the selection of a SUPPOCIRE® AML active prototype formulation with hydrocortisone acetate <NUM> and colloidal silicon dioxide <NUM> as the lead formulation for the hydrocortisone acetate suppository studies based on its desirable properties, as indicated by the assay results (Table <NUM>) and dissolution release profile (Table <NUM>).

The specification and dissolution profile for the <NUM> gram suppository containing <NUM> of hydrocortisone acetate and colloidal silicon dioxide (prototype <NUM>) is shown in Table <NUM>.

The hydrocortisone acetate (<NUM>) suppository was packaged in <NUM> gram polyethylene/polyvinyl chloride (PE/PVC) suppository shells and subjected to standard CQAs for <NUM> days under <NUM>/<NUM>% RH storage conditions. As shown in Table <NUM>, the appearance, melting temperature and stability of the <NUM> suppository hydrocortisone acetate <NUM> remained constant and virtually unchanged after <NUM> days of storage under accelerated conditions (<NUM>/<NUM>% RH). Total impurities that were generated over a period of <NUM> days remained negligible (<<NUM>%) under accelerated storage conditions (<NUM>/<NUM>% RH). Moreover, the dissolution studies under our standard protocol have also shown that the <NUM> suppository releases at least about <NUM>% of the hydrocortisone acetate at about <NUM> minutes following exposure to dissolution media comprising <NUM>% w/v sodium lauryl sulfate:acetate buffer pH <NUM> (<NUM>:<NUM>) final pH adjusted to <NUM> - <NUM>. At about <NUM> minutes following exposure to dissolution media comprising <NUM>% w/v sodium lauryl sulfate:acetate buffer pH <NUM> (<NUM>:<NUM>) final pH adjusted to <NUM> - <NUM>, the <NUM> suppository releases at least about <NUM>% of the hydrocortisone acetate.

The CQAs are melting point, release profile, color, appearance, content uniformity, assay and dissolution study. The specifications for the CQAs are shown in Table <NUM>.

General experimental techniques for Examples <NUM>-<NUM> can be accomplished by the methods described herein.

General Dissolution Method: M-CCO-LC-<NUM> and DOP-QC-<NUM>.

General Assay Method: M-CCO-LC-<NUM> and DOP-QC-<NUM>.

Hydrocortisone Acetate, United States Pharmacopeia (USP) reference standard or suitable equivalent characterized standard.

Water is used as mobile phase A. Obtain <NUM> of Water.

If a stable standard is available for which standard agreement has already been demonstrated, preparation of fresh standards may be omitted. Accurately weigh and transfer approximately <NUM>±<NUM> of Hydrocortisone Acetate reference standard material to a <NUM> volumetric flask. Add <NUM> of ACN. Heat it in oven at <NUM> for <NUM> minutes and sonicate to dissolve. Cool it to room temperature. Dilute to volume with dissolution media and mix well. Nominal concentration: <NUM>/mL of Hydrocortisone Acetate.

Preparation of <NUM>% weight/volume (w/v) Sodium Lauryl Sulfate Dissolve <NUM> of Sodium Lauryl Sulfate in <NUM> of water. Heat the solution if necessary to ensure dissolution. Scale as necessary.

Dissolve <NUM> of Sodium Acetate trihydrate in <NUM> of water. Add <NUM> of 2N acetic acid. Adjust the pH to <NUM>±<NUM> with 2N acetic acid. Scale as necessary.

For each liter of dissolution media, combine <NUM> of <NUM>% w/v SLS and <NUM> of Acetate buffer pH <NUM>. Adjust the pH to <NUM> ± <NUM> with 5N NaOH. Sonicate for <NUM>.

Note: Samples are stable for <NUM> days at room temperature.

Hydrocortisone Acetate USP reference standard or suitable equivalent characterized standard.

Obtain <NUM> of Water. Add <NUM> of TFA. Mix well and degas.

Obtain <NUM> of ACN. Add <NUM> of TFA. Mix well and degas.

If a stable standard is available for which standard agreement has already been demonstrated, preparation of fresh standards may be omitted. Accurately weigh and transfer approximately <NUM>±<NUM> of Hydrocortisone Acetate reference standard material to a <NUM> volumetric flask. Add <NUM> of ACN. Sonicate if necessary. Dilute to volume with ACN and mix well. Nominal concentration: <NUM>/mL of Hydrocortisone Acetate.

Stability of Standard: Standard solution is stable tor <NUM> days at room temperature.

Accurately weigh <NUM> units of suppositories and transfer into a <NUM> volumetric flask and add <NUM> of Acetonitrile using an appropriate graduated cylinder. Place a stir bar and heat it in a water bath at <NUM> for <NUM> minutes at <NUM> RPM. Remove the stir bar and cool to room temperature. Filter <NUM> of sample through a <NUM> PTFE syringe filter to a <NUM> plastic syringe. Discard the first <NUM> and collect the filtrate to a scintillation vial. Pipette <NUM> of the filtrate to a <NUM> volumetric flask and dilute to volume with ACN. Nominal concentration: <NUM>/mL of Hydrocortisone Acetate.

Stability of Sample: Sample solution is stable for <NUM> days at room temperature.

Accurately weigh out a unit of suppository and transfer into a <NUM> volumetric flask and approximately add <NUM> of Acetonitrile. Place a stir bar in the flask and heat it in a water bath at <NUM> for <NUM> minutes at <NUM> RPM. Remove the stir bar and cool to room temperature. Dilute to volume with Acetonitrile and mix well. Filter <NUM> of sample through a <NUM> PTFE syringe filter to a <NUM> plastic syringe. Discard the first <NUM> before collecting sample for analysis. Nominal concentration: <NUM>/mL of Hydrocortisone Acetate. Stability of Sample: Sample Solutions is stable for <NUM> days at room temperature.

The lead formulation was manufactured (both active and placebo) and subjected to stability studies at two different conditions: <NUM>) <NUM>/<NUM>% RH; and <NUM>) <NUM>/<NUM>% RH.

Preparation of the base: The stainless steel vessel identification number and tare weight was recorded. Into the vessel, was add the weighed amount of base and begin melting the base using a hot stir plate and water bath, low shear sweep/side scrape mixing (hand mix was used in the lab for small scale operations) until all the base was completely melted. The temperature was maintained at <NUM> ± <NUM> (Tf).

Addition of colloidal silicon dioxide: A silverson mixer (or similar homogenizer) was set up. The required amount of colloidal silicon dioxide was weighed and added to the melted base. The colloidal silicon dioxide was then allowed to hydrate by mixing using a square shape mesh. The mixing speed was maintained between <NUM>-<NUM> RPM. The temperature was maintained at <NUM> ± <NUM> (Tf).

Addition of hydrocortisone acetate: The required amount of hydrocortisone acetate was weighed and added to the main batch while mixing with homogenizer set at <NUM>-<NUM> RPM and equipped with a square shape mesh for ten minutes or until visibly uniformly dispersed. The temperature was maintained at <NUM> ± <NUM> (Tf).

Claim 1:
A suppository for use in treating inflammatory bowel disease, the suppository having a weight of <NUM> and comprising <NUM> hydrocortisone acetate and <NUM> to <NUM> colloidal silicon dioxide and a semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin, wherein the suppository has a melting temperature in the range of <NUM> to <NUM>.