Pharmaceutical preparations

Abstract

The present invention relates to pharmaceutical formulations, and more particularly to pharmaceutical formulations for active pharmaceutical ingredients (APIs) recognized as Class II pharmaceuticals under the Biopharmaceutical Classification System (BCS). In addition to the API, the formulation comprises a combination of gelling agents, including agar as a primary gelling agent, carrageenan as a secondary gelling agent, and alginate as a tertiary gelling agent, together with at least one cation donor, a pH adjuster, a preservative, and water.

Description

Technical Field

[0001] The present invention relates to pharmaceutical preparations, and more particularly to pharmaceutical preparations for active pharmaceutical ingredients (APIs) recognized as Class II pharmaceuticals under the Biopharmaceutics Classification System (BCS).

Background Art

[0002] APIs can be difficult to formulate because their properties vary from API to API. Two parameters that concern formulation chemists are the solubility and permeability of the API. Thus, APIs are defined as being classified into one of four broad classification types based on these two parameters. These four types are shown in Figure 1.

[0003] Class I APIs have high permeability and high solubility. a. As an example, there is metoprolol. b. Class I compounds are well absorbed, and their absorption rate is usually higher than the excretion rate.

[0004] Class II APIs have high permeability and low solubility. a. Examples include ibuprofen and naproxen. b. The bioavailability of these products is limited by their rate of solvation. A correlation can be found between in vivo bioavailability and in vitro solvation.

[0005] Class III APIs have low permeability and high solubility. a. As an example, there is cimetidine. b. Absorption is limited by the rate of permeation, but this medicine is solvated very quickly. If the formulation does not change permeability or gastrointestinal transit time, Class I criteria can be applied.

[0006] Class IV APIs have low permeability and low solubility. a. As an example, there is bifonazole. b. These compounds have low bioavailability. Their absorption through the intestinal mucosa is generally poor and is expected to be highly variable.

[0007] APIs are classified by the BCS based on their solubility, permeability, and even dissolution. The boundaries for solubility classification are based on the maximum dose of the immediate-release product. A drug is considered highly solubility if its maximum dose is soluble in 250 ml or less of an aqueous medium within a pH range of 1 to 7.5. The 250 ml volume determination originates from a typical bioequivalence study protocol that specifies administering the drug to fasted human volunteers with a glass of water.

[0008] The boundaries of permeability classification are indirectly based on the degree of absorption of the active pharmaceutical ingredient (API) in humans, and directly based on the measurement of the rate of mass transfer across the human intestinal mesenteric membrane. Alternatively, non-human systems that can predict drug absorption in humans can be used (e.g., in-vitro culture methods). An API is considered highly permeable if its absorption in humans is determined to be 90% or more of the administered dose, either based on mass balance determination or in comparison to the intravenous dose.

[0009] The boundary for dissolution classification includes immediate-release products, i.e., products that dissolve rapidly, specifically when, using USP Dissolution Apparatus 1 at 100 RPM or Apparatus 2 at 50 RPM, 85% or more of the indicated amount of active pharmaceutical ingredient dissolves within 15 minutes in a medium of 0.1 M HCl or artificial gastric solution, or pH 4.5 buffer and pH 6.8 buffer or artificial intestinal solution in a volume of 900 ml or less.

[0010] Most oral formulations come in the form of filled capsules or tablets. Other formulation types are also known, and the applicant has developed many oral gel formulations in fields such as glucose tolerance testing and nutraceutical delivery, see International Publication No. 2017 / 075672 and International Publication No. 2019215641, respectively.

[0011] The object of the present invention is to provide alternative pharmaceutical formulations for BCS class II drugs, such as ibuprofen and naproxen. Ibuprofen belongs to a drug classification called nonsteroidal anti-inflammatory drugs (NSAIDs).

[0012] There are various oral dosage forms, including oral tablets, oral capsules, oral suspensions, and chewable tablets. Examples of branded ibuprofen include: United States: Equate, Advil, and Motrin IB; Australia: Nurofen, Wagner Health, and Rafen; and United Kingdom: Boots, Nurofen, Calprofen, Ibuleve, Cuprofen, and Flarin.

[0013] Naproxen is also an NSAID. There are various oral dosage forms, including tablets, enteric-coated tablets, suspensions, and liquid-filled capsules. Examples of naproxen with trademarks include: Aflaxen, Aleve, Aleve Arthritis, Anaprox, Anaprox DS, EC Naprosyn, Naprelan, Naprelan 500, Naprelan Dose Card, and Naprosyn.

[0014] From a regulatory perspective, it is possible to obtain registration of new dosage forms using simplified processes, such as those provided by the FDA via the 505(B)(2) regulatory pathway. For example, see https: / / www.fda.gov / media / 156350 / download, which is referenced by reference.

[0015] The following dosage forms were identified through prior art searches: A chewable tablet comprising an API of omeprazole and a gel component containing carrageenan, sodium alginate, and agar in a ratio of 3-5:2-3:1, as disclosed in Chinese Patent No. 110833561.

[0016] A chewable tablet comprising the API idicalcidol and a gel component containing carrageenan, sodium alginate, and agar in a ratio of 3-5:2-3:1, as disclosed in Chinese Patent No. 111437261.

[0017] A gel formulation comprising a combination of fluvastatin and a gelling agent, disclosed in U.S. Patent Application Publication No. 2008 / 0160087, which improves taste and addresses syneresis. An oral pharmaceutical formulation comprising aripiprazole and one or more gelling agents, as disclosed in U.S. Patent Application Publication No. 2015 / 0174247.

[0018] Propolis foods containing a gelling agent, as disclosed in U.S. Patent No. 6,106,867; and A carrageenan-based ibuprofen preparation further comprising locust bean gum and xanthan gum, as disclosed in Japanese Patent Publication No. 2000-302670.

[0019] The object of the present invention is to develop alternative dosage forms for BSC Class II pharmaceuticals, such as those exemplified with respect to ibuprofen and naproxen, particularly "swallowable" gel formulations that can be used for patient groups who have difficulty swallowing tablets, such as the elderly and children. [Overview of the Initiative]

[0020] According to the present invention, there is provided an ingestible gel formulation for a Class II biopharmaceutics classification system (BCS) active pharmaceutical ingredient (API), comprising the following: i) A Class II active pharmaceutical ingredient (API) of the biopharmaceutics classification system (BCS), or a salt or solution thereof; ii) A combination of gelling agents comprising: a. A first gelling agent which is agar, b. A second gelling agent which is carrageenan, and c. A third gelling agent which is alginate; iii) At least one cation donor; iv) A pH adjuster; v) A preservative; and vi) Water.

[0021] Preferably, the BCS Class II formulation: vii) Further comprises a flavoring. The terms "first", "second", and "third" are used to indicate the relative proportions (weight percentages) of the respective gelling agents such that the first gelling agent is present in the greatest amount and the third gelling agent is present in the least amount relative to each other.

[0022] Selecting agar as the first gelling agent is important for making the formulation an "ingestible" gel because agar releases water when subjected to shear forces upon ingestion, thereby facilitating its uptake without "chewing", which differentiates the formulation from an "edible" gel.

[0023] Non-limiting examples of formulations containing a BCS Class II API include formulations where the API is ibuprofen or naproxen, or salts or solutions thereof.

[0024] Preferred formulations of ibuprofen or naproxen are their sodium salts or solutions.

[0025] Other exemplary BCS Class II APIs include the following: Hydrochlorothiazide and diclofenac. Hydrochlorothiazide is a diuretic and is often used to treat high blood pressure.

[0026] Diclofenac is another nonsteroidal anti-inflammatory drug. The alternative gel formulation of the present invention contains agar as the primary gelling agent because agar is sheared and releases water when inhaled, making this delivery system particularly attractive as a means of delivery for children and the elderly who have difficulty swallowing tablets. However, in order to accommodate different Class II APIs and provide dissolution, stability, and texture, the applicant has determined that both specific secondary and tertiary gelling agents are also necessary.

[0027] As mentioned above, the primary gelling agent is agar. Agar stands out among hydrophilic colloids. Agar gels can be formed with very dilute solutions containing as little as 0.5% to 1.0% agar. These gels are hard, brittle, have a distinct shape, and possess sharp melting and gelling points. Furthermore, these gels clearly exhibit the interesting phenomena of syneresis (the spontaneous extrusion of water from the gel surface) and hysteresis (the temperature range between the melting temperature and the gelling temperature). Gelation occurs at temperatures much lower than the gel melting temperature. A 1.5% solution of agar forms a gel when cooled to approximately 32°C to 45°C, and the gel does not melt below 85°C. This hysteresis range is a characteristic property of agar and is widely used in food applications. The gel strength of agar is affected by concentration, time, pH, and sugar content. pH significantly affects the strength of agar gels; as pH decreases, the gel strength weakens. Sugar content also greatly affects agar gels. As sugar levels increase, the gel becomes firmer, but its texture cohesiveness decreases.

[0028] The second gelling agent is carrageenan, more specifically, kappa-carrageenan. Carrageenan is a highly flexible, large molecule that forms a curled, spiral structure. Therefore, it can form a variety of different gels at room temperature. It is widely used as a thickening and stabilizing agent in the food and other industries.

[0029] Carrageenans are all high molecular weight polysaccharides, mainly composed of alternating 3-linked β-D-galactopyranoses (G units) and 4-linked α-D-galactopyranoses (D units) or 4-linked 3,6-anhydro-α-D-galactopyranoses (DA units), forming the repeating disaccharide units of carrageenan.

[0030] There are mainly three types of carrageenan available commercially: • Kappa-type gel that forms a strong, hard gel in the presence of sodium and potassium ions. • Iota type, which forms a soft gel in the presence of calcium ions. • Non-gelling lambda type.

[0031] The third gelling agent is alginate. Examples of alginate include: Sodium alginate (NaC6H7O6), • Potassium alginate (KC6H7O6), and • Calcium alginate (CaC) 12 H 14 O 12 ).

[0032] These three gelling agents are best used in an approximate relative ratio (by weight) of agar:carrageenan:alginate of 4.5-2.6:2.5-1.5:1, and more preferably 4-3:2.5-1.5:1.

[0033] The preferred gelling agents are as follows: a. Agar-agar, b. Kappa carrageenan, c. Sodium alginate.

[0034] To promote gelation, one or more cation donors are carefully selected. Preferably, iii) At least one cation donor is one of a divalent cation or a monovalent cation, more preferably one of a calcium salt, a magnesium salt, or a potassium salt. Preferred salts include magnesium chloride and potassium chloride.

[0035] In a preferred embodiment, iii) The cation donor consists of or contains potassium chloride. Preferably, iv) At least one pH adjusting agent is an acidifying agent, an alkalizing agent, or a buffering agent. Exemplary adjusting agents include acetic acid, citric acid, hydrochloric acid, phosphoric acid, and sodium hydroxide.

[0036] In a preferred embodiment, the formulation containing the BCS class II API has citric acid as an acidifying agent. Citric acid can be used in amounts up to 2.88% (by weight).

[0037] Preferably, v) At least one preservative is selected from lactic acid, potassium sorbate, and sodium benzoate.

[0038] In a preferred embodiment, a formulation comprising a BCS class II API is v) Having potassium sorbate as at least one preservative. Potassium sorbate can be used in amounts of 0.07–0.12%.

[0039] In general, for formulations containing BCS class II APIs, the gelling agents include, as claimed, primary, secondary, and tertiary gelling agents in weight percentages of the total formulation, as follows: a. Agar - 0.47%~0.95% b. Carrageenan - 0.31%~0.47%, and c. Alginate - 0.16%~0.24%.

[0040] Regarding the weight percentage figures, these are based on the essential components specified in the claim, and exclude optional excipients such as fragrances, which may be added in amounts up to 2% by weight.

[0041] The actual amount will vary depending on the selected API. In the first embodiment, where the API is ibuprofen, the gelling agent is present in the following amounts by weight: a. Agar - 0.47%~0.71% b. Carrageenan - 0.31%~0.47%, and c. Alginate - 0.16%~0.24%.

[0042] More specifically, the formulations are as shown in Table 1 below.

[0043] [Table 1]

[0044] The actual amounts of excipients are shown in Tables 2a and 2b below.

[0045] [Table 2]

[0046] In the second embodiment, where the API is naproxen, the gelling agent is present in the following amounts by weight: a. Agar - 0.63%~0.95% b. Carrageenan - 0.31%~0.47%, and c. Alginate - 0.16%~0.24%.

[0047] More specifically, the formulations are as shown in Table 3 below.

[0048] [Table 3]

[0049] The actual amounts of excipients are shown in Table 4 below.

[0050] [Table 4]

[0051] In the third embodiment, where the API is diclofenac, the gelling agent is present in the following amounts by weight: a. Agar - 0.47%~0.71% b. Carrageenan - 0.32%~0.47%, and c. Alginate - 0.16%~0.24%.

[0052] More specifically, the formulations are as shown in Table 5 below.

[0053] [Table 5]

[0054] The actual amounts of excipients are shown in Table 6 below.

[0055] [Table 6]

[0056] In the fourth embodiment, where the API is hydrochlorothiazide, the gelling agent is present in the following amounts by weight: a. Agar - 0.47%~0.71% b. Carrageenan - 0.32%~0.47%, and c. Alginate - 0.16%~0.24%.

[0057] More specifically, the formulations are as shown in Table 7 below.

[0058] [Table 7]

[0059] The actual amounts of excipients are shown in Table 8 below.

[0060] [Table 8]

[0061] The present invention may be further described as merely an example with reference to the drawings, embodiments, and detailed description below. Embodiments of the present invention will be further described below with reference to the accompanying drawings. [Brief explanation of the drawing]

[0062] [Figure 1] Figure 1 shows the Biopharmaceutical Classification System (BCS). [Figure 2] Figure 2 is a graph showing the elution of the five individual gels. [Figure 3] Figures 3a and 3b are graphs showing the dissolution of preferred tripartite formulations containing 200 mg and 220 mg of ibuprofen, respectively, compared to Advil and Motrin (alternative formulations). [Modes for carrying out the invention]

[0063] In developing alternative formulations for BCS Class II API formulations, the applicant investigated various standard gelling agents using a first exemplary API (ibuprofen). Experiment Series 1 Several monogel formulations were prepared from a stock solution of ibuprofen (Table 9 below), and their dissolution was tested.

[0064] [Table 9]

[0065] Using this stock solution gel, the following monogels were prepared, and the formulations are shown in Tables 10 to 14. 1) Agar

[0066] [Table 10]

[0067] 2) Kappa Carrageenan

[0068] [Table 11]

[0069] 3) Low acylgeran gum

[0070] [Table 12]

[0071] 4) Sodium alginate

[0072] [Table 13]

[0073] 5) Pectin

[0074] [Table 14]

[0075] result The dissolution data for these formulations is shown in Figure 2. As can be seen from Figure 2, the results showed that the "gels" had different performance characteristics.

[0076] Two "gels" that did not actually gel in the given formulation, namely sodium alginate (red circle) and pectin (blue diamond), showed the fastest dissolution, perhaps not surprising given their state, with the entire dose released within 5 minutes.

[0077] On the other hand, agar (yellow diamond) and gellan gum (pink triangle) took about 60 minutes to completely release ibuprofen. Surprisingly, kappa-carrageenan, which forms a gel by ionic bonding with potassium ions, showed the fastest dissolution profile with 0.02% potassium chloride, releasing the entire dose of ibuprofen within 5 minutes. This gel had a soft, elastic texture and disintegrated completely. While this was excellent as a therapeutic agent, it showed a lack of temperature stability, so in a second series of experiments (Experimental Series 2), we investigated using kappa-carrageenan and modifying it with other gelling agents to improve its stability (and texture).

[0078] Experiment Series 2 Agar was introduced to strengthen the kappa-carrageenan gel base. In contrast to kappa-carrageenan, agar forms a gel by cold-set gelation. Agar was dissolved and dispersed in boiling water. Upon cooling, interchain helices were formed between the polymer chains, resulting in a three-dimensional network. When agar was introduced and combined with kappa-carrageenan, a semi-solid gel was produced compared to when kappa-carrageenan was used alone. However, the gel remained soft and elastic, rather than being hard and rigid.

[0079] At agar concentrations of 0.20–0.32%, a soft gel was formed that crumbled when pressed. At agar concentrations of 0.44–0.55%, a harder gel was formed that fell apart when crushed. When the kappa-carrageenan concentration was varied from 0.28–0.75%, the gel texture remained soft, but no significant differences were observed. Therefore, contrary to the suggestions from Experiment Series 1, agar acted as the primary gelling agent, and kappa as the secondary gelling agent.

[0080] Two exemplary gel combinations are shown in Table 15 below.

[0081] [Table 15]

[0082] However, while the two gelling agent compositions possessed appropriate elution and stability properties, their texture was insufficient. Therefore, a third gelling agent was introduced (Series 3).

[0083] Experiment Series 3 After extensive experimentation, the applicant determined that sodium alginate should be added, resulting in a desirable formulation with temperature stability.

[0084] Examples of formulations are shown in Table 16 below.

[0085] [Table 16]

[0086] However, the pH of the ibuprofen sodium solution was 9.90. Therefore, a series of experiments were conducted to change the pH. Hydrochloric acid and citric acid were tested as pH adjusters. Hydrochloric acid precipitated and was not compatible with the formulation. Citric acid significantly altered the pH. As a result, citric acid was selected as the preferred pH adjuster.

[0087] Further details of the ibuprofen gel of the present invention are described in Example 1. Example 1 (Ibuprofen) Preferred ibuprofen preparations are shown again in Tables 2a and 2b below.

[0088] [Table 17]

[0089] We modified a selected ibuprofen gel formulation to produce a product that is "bioequivalent" to an approved ibuprofen formulation, enabling expedited approval using the FDA's 505 pathway.

[0090] Gel formulation To prepare the ibuprofen solution, dissolve the sodium hydroxide pellet in water. Slowly add the ibuprofen powder until completely dissolved. Add citric acid to adjust the pH to approximately 7. Heat the ibuprofen solution to 95°C using a stirring hot plate. Add the agar and mix until completely dissolved and clear. Add the potassium sorbate, magnesium chloride, and potassium chloride and mix until dissolved. Add the citric acid and mix. Slowly add the remaining gelling agent, kappa-carrageenan, and sodium alginate and mix until completely dissolved. Fill the pouch with the hot gel and immediately cap it. Allow to cool to room temperature. If using a pouch, air may be needed to inflate the pouch before filling.

[0091] Preparation of gel for dissolution testing Once it has cooled and solidified, squeeze the pouch five times before opening it. Dissolution test Fill the elution container with 900 mL of buffer (phosphate-buffered saline, PBS pH 7.2). Using a paddle attachment, set the rotation speed to 50 rpm and the water bath temperature to 37.5°C. Dispense the crushed gel from the pouch into the elution container and start the experiment. Sample the buffer at 5, 10, 15, 20, 30, 45, 60, and 120 minutes, and filter immediately after sampling. Replenish with the removed buffer after sampling.

[0092] High-performance liquid chromatography HPLC was performed as shown in Table 17 below.

[0093] [Table 18]

[0094] confirmation This assay was validated based on repeated samples at three concentrations, and was considered effective if accuracy and precision were within ±10%.

[0095] result Figures 3a and 3b show the dissolution profiles of 200 mg and 220 mg ibuprofen preparations compared to Advil and Motrin preparations, respectively.

[0096] Example 2 (Naproxen)

[0097] [Table 19]

[0098] Example 3 (Diclofenac)

[0099] [Table 20]

[0100] Example 4 (Hydrochlorothiazide)

[0101] [Table 21]

Claims

1. An oral gel formulation for Class II active pharmaceutical ingredients (APIs) of the Biopharmaceutical Classification System (BCS): i) Class II active pharmaceutical ingredients (APIs) of the Biopharmaceutical Classification System (BCS), or their salts or solutions; ii) Combinations of gelling agents including the following: a. The first gelling agent is agar. b. A second gelling agent which is carrageenan, and c. Alginate-based tertiary gelling agents; iii) At least one cation donor; iv) pH adjusters; v) Preservatives; and vi) Water, A drinkable gel formulation containing [the specified ingredient].

2. vii) A drinkable gel formulation according to claim 1, further comprising a fragrance.

3. i) The drinkable gel formulation according to claim 1 or 2, wherein the API is ibuprofen, naproxen, diclofenac, or hydrochlorothiazide, or a salt or solution thereof.

4. i) The drinkable gel formulation according to claim 3, wherein the ibuprofen, naproxen, or diclofenac is a sodium salt or a solution.

5. ii) a. The agar is agar, b. The carrageenan is kappa-carrageenan, c. The drinkable gel formulation according to any one of claims 1 to 4, wherein the alginate is sodium alginate.

6. iii) The drinkable gel formulation according to any one of claims 1 to 5, wherein the at least one cation donor is one of a calcium salt, a magnesium salt, or a potassium salt.

7. iii) The drinkable gel formulation according to claim 6, wherein the at least one cation donor comprises magnesium chloride and potassium chloride.

8. iii) The drinkable gel formulation according to claim 6, wherein the at least one cation donor is potassium chloride.

9. iv) The drinkable gel formulation according to any one of claims 1 to 8, wherein the at least one pH adjusting agent is citric acid.

10. v) The drinkable gel formulation according to any one of claims 1 to 9, wherein the at least one preservative is potassium sorbate.

11. ii) The gelling agent is a. Agar - 0.47% to 0.95% b. Carrageenan - 0.31% to 0.47%, and c. Alginate - 0.16% to 0.24% An ingestible gel preparation according to any one of claims 1 to 10, present in a weight percentage.

12. ii) The gelling agent is a. Agar - 0.47% to 0.71% b. Carrageenan - 0.31% to 0.47%, and c. Alginate - 0.16% to 0.24% The drinkable gel formulation according to claim 11, which is present in a weight percentage amount.

13. ii) The gelling agent is a. Agar - 0.63% to 0.95% b. Carrageenan - 0.31% to 0.47%, and c. Alginate - 0.16% to 0.24% The drinkable gel formulation according to claim 11, which is present in a weight percentage amount.

14. The drinkable gel formulation according to claim 12, comprising the excipients shown in Table 1 within the ranges shown below. Table 1

15. In terms of average weight, Table 2 A drinkable gel formulation according to claim 14, including the above.

16. The drinkable gel formulation according to claim 13, comprising the excipients shown in Table 3 within the ranges shown below. Table 3

17. The drinkable gel formulation according to claim 16, comprising the excipients shown in Table 4 in the following average weights. Table 4

18. The drinkable gel formulation according to claim 11, comprising the excipients shown in Table 5 within the ranges shown below. Table 5

19. The drinkable gel formulation according to claim 18, comprising the excipients listed in Table 6 in the following average weights. Table 6

20. The drinkable gel formulation according to claim 11, comprising the excipients shown in Table 7 within the ranges shown below. Table 7

21. The drinkable gel formulation according to claim 20, comprising the excipients listed in Table 8 in the following average weights. Table 8

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