Formulations and methods for delivery of dietary and pharmaceutical ingredients

Abstract

The present invention relates to a base gel formulation into which nutritional or pharmaceutical ingredients can be introduced. The basic preparation is designed for people with dysphagia. The base formulation comprises different amounts of three different gelling agents such that the formulated gel conforms to the International Dysphagia Diet Standardization Invocation (IDDS) 2019, characterized as type 1 to type 4 products. The invention relates to a gel composition comprising an alginate as the primary gelling agent, which is crosslinked by a divalent cation to provide its structural integrity, and which further alters the gelling properties by including secondary and third gelling agents, respectively low methoxyl pectin and agar. The gel contains a large amount of water (so Type 1 to 4 products are classified as drinks), but not Type 3 and 4 products can also be classified as foods. The gel further comprises a pH adjusting agent and a preservative, and may additionally comprise a flavoring agent.

Description

Technical Field

[0001] The present invention relates to formulations and methods for delivering dietary and pharmaceutical ingredients to patients with dysphagia or swallowing disorders. Background Art

[0002] Patients with dysphagia have problems swallowing food and drink. Therefore, dietary and pharmaceutical ingredients need to be delivered in a form that facilitates their ingestion.

[0003] While there are products on the market that are tailored to deliver specific ingredients to specific patient groups, it would be beneficial for patients and their caregivers to have a "base formulation" that could facilitate the ingestion of a variety of different dietary and pharmaceutical ingredients in a form that complies with the International Dysphagia Diet Standardisation Initiative (IDDSI) 2019 - see https: / / iddsi.org / IDDSI / media / images / Complete_IDDSI_Framework_Fin al_31July2019.pdf, which is incorporated by reference and pages 2 to 10 of which are attached as Annex 1.

[0004] The applicant has previously disclosed in WO2019215641 a gel formulation comprising agar (primary gelling agent) and alginate, which, when sucked, releases water by shear to facilitate ingestion. However, agar may form "plugs", which may pose a choking hazard to patients with dysphagia. In contrast, the present invention utilizes alginate (and selected divalent cations) as the primary gelling agent, adopting a gelling mechanism different from that of agar to cause gelation and to a large extent enable it to comply with the IDDSI framework for the production of gels with textures of types 1 to 4. However, such a gelling agent alone cannot achieve the desired texture, and it is necessary to utilize other gelling agents (secondary and tertiary gelling agents) with different gelling mechanisms and select a given cationic compound to achieve the desired result.

[0005] Other technologies identified include:

[0006] EP 3257528 discloses a jelly incorporating a medicine for patients with dysphagia. It utilizes low methoxyl (LM) pectin as the main gelling agent and the process and final product differ significantly from the claimed invention.

[0007] JPS6265652 discloses a citrus fruit endocarp-like food comprising agar and xanthan gum as primary gelling agents and will not produce the soft gel of the claimed invention.

[0008] JP2018027901 discloses a composition wherein the main gelling agent is low methoxyl pectin, which cannot achieve the texture of the claimed invention.

[0009] JP200325041 similarly relies on low methoxyl pectin which is unable to achieve the texture of the claimed invention.

[0010] JP2016202158 discloses a jelly containing drink and utilizes LM pectin and alginate interchangeably, alone or together, to produce the gel.

[0011] None of these techniques will produce or lead the skilled artisan to the products claimed and as set out in more detail below. Summary of the Invention

[0012] According to the present invention, there is provided a basic gel formulation that complies with the International Dysphagia Diet Standardization Initiative 2019 (IDDSI), the basic gel formulation comprising:

[0013] · Various gelling agents;

[0014] ·water;

[0015] pH adjuster;

[0016] Preservatives; and optionally

[0017] Flavoring

[0018] It is characterized in that the multiple gelling agents include one of the following:

[0019] Agar;

[0020] Alginate, as the primary gelling agent; and

[0021] Low methoxyl pectin

[0022] and at least one divalent cation.

[0023] The base formulation of the present invention provides a product having a consistency described as a "drink" under the IDDSI framework, including a consistency defined as:

[0024] (1) Slightly thick;

[0025] (2) slightly thick;

[0026] (3) medium thick; and

[0027] (4) Highly thick.

[0028] The present invention is based on combining three specific gelling agents with divalent ions to provide a stable base with a desired range of textures.

[0029] The three gelling agents are:

[0030] (a) Agar - for strength and stability;

[0031] (b) Alginate - for softness; and

[0032] (c) Low methoxyl pectin - for smoothness.

[0033] The latter two gelling agents require

[0034] (d) Divalent cations - for gelation.

[0035] Applicants have surprisingly determined that it is essential that alginate is the primary gelling agent (present in the largest amount) and that divalent cations in the form of gluconate are superior to the industry standard gelling agent calcium chloride. This was not expected.

[0036] Other ingredients in the base gel drink include:

[0037] (e) water;

[0038] (f) pH adjuster;

[0039] (g) a preservative; and optionally

[0040] (h) Flavorings.

[0041] By carefully controlling the relative concentrations of the three gelling agents, the formulation can be modified to obtain a formulation that meets the IDDSI consistency criteria (1) to (4).

[0042] As shown in Annex 1, each of Types 1 to 4 products is classified as a beverage based on the prescribed syringe test method (although products 3 and 4 may also be considered foods).

[0043] Thus, the universal base formulation comprises a gelling agent and divalent cations in the % amounts (by weight) of the base formulation as listed in Table 1a. The base formulation also includes a non-gelling agent component including water.

[0044]

[0045]

[0046] In one embodiment, the formulation is flavor-free, as listed in Table 1b.

[0047] Gelling agent weight% agar 0.01 to 0.60 Alginate 0.05 to 1.70 Low methoxyl pectin 0.05 to 0.50 Divalent cations 0.05 to 1.50

[0048] In another embodiment, the formulation includes a flavoring agent, as listed in Table 1c.

[0049] Gelling agent weight% agar 0.01 to 0.10 Alginate 0.40 to 2.00 Low methoxyl pectin 0.01 to 0.40 Divalent cations 0.10 to 1.20

[0050] Natural flavors, such as orange juice, may contain natural gelling agents, which may affect the actual amounts of primary, secondary, and tertiary gelling agents.

[0051] The preferred general base formulations are illustrated in Table 1d (with natural flavoring - eg orange juice) and Table 1e (no flavoring).

[0052] Table 1d

[0053] Gelling agent weight% agar 0.01 to 1.00 Alginate 0.40 to 2.00 Low methoxyl pectin 0.01 to 0.40 Divalent cations 0.10 to 1.20 Non-gelling agent pH adjusters, such as sodium hydroxide 0.20 to 0.50 Preservatives, such as potassium sorbate 0.02 to 0.06 Water (including flavoring) to 100%

[0054] Table 1e

[0055] Gelling agent weight% agar 0.01 to 0.60 Alginate 0.05 to 1.70 Low methoxyl pectin 0.05 to 0.50 Divalent cations 0.05 to 1.50 Non-gelling agent pH adjusters, such as citric acid 0.02 to 0.05 Preservatives, such as potassium sorbate 0.05 to 0.07 water to 100%

[0056] Thus, formulations meeting the IDDSI consistency standard (1) include those listed in Table 2a (gelling agent for base formulation), Table 2b (with natural flavoring - eg, orange juice), and 2c (no flavoring).

[0057] Table 2a

[0058] Gelling agent weight% agar 0.01 to 0.20 Alginate 0.05 to 0.80 Low methoxyl pectin 0.20 to 0.40 Divalent cations 0.10 to 1.20

[0059] Table 2b

[0060] Gelling agent weight% Preferred % agar 0.01 to 0.03 0.02 Alginate 0.40 to 0.80 0.47 to 0.78 Low methoxyl pectin 0.30 to 0.33 0.31 to 0.32 Divalent cations 0.10 to 1.20 0.16 to 1.17 Non-gelling agent pH adjusters, such as sodium hydroxide 0.20 to 0.50 0.39 to 0.47 Preservatives, such as potassium sorbate 0.02 to 0.06 0.04 Water (including flavoring) to 100% to 100%

[0061] Table 2c

[0062] Gelling agent weight% Preferred % agar 0.02 to 0.20 0.11 Alginate 0.05 to 0.70 0.36 Low methoxyl pectin 0.20 to 0.40 0.30 Divalent cations 0.12 to 0.15 0.13 Non-gelling agent pH adjusters, such as citric acid 0.02 to 0.02 0.02 Preservatives, such as potassium sorbate 0.05 to 0.05 0.05 water to 100% to 100%

[0063] Thus, formulations meeting the IDDSI consistency standard (2) include formulations as listed in Table 3a (gelling agent for base formulation), Table 3b (with natural flavoring - eg, orange juice), and 3c (no flavoring).

[0064] Table 3a

[0065] Gelling agent weight% agar 0.01 to 0.20 Alginate 0.35 to 1.00 Low methoxyl pectin 0.20 to 0.40 Divalent cations 0.10 to 0.80

[0066] Table 3b

[0067] Gelling agent weight% Preferred % agar 0.01 to 0.03 0.02 Alginate 0.60 to 0.80 0.67 to 0.79 Low methoxyl pectin 0.30 to 0.32 0.31 Divalent cations 0.10 to 0.80 0.20 to 0.59 Non-gelling agent pH adjusters, such as sodium hydroxide 0.20 to 0.50 0.47 Preservatives, such as potassium sorbate 0.02 to 0.06 0.04 Water (including flavoring) to 100% to 100%

[0068] Table 3c

[0069] Gelling agent weight% Preferred % agar 0.02 to 0.20 0.11 Alginate 0.35 to 1.00 0.66 Low methoxyl pectin 0.20 to 0.40 0.30 Divalent cations 0.10 to 0.40 0.24 Non-gelling agent pH adjusters, such as citric acid 0.02 to 0.02 0.02 Preservatives, such as potassium sorbate 0.05 to 0.05 0.05 water to 100% to 100%

[0070] Thus, formulations meeting the IDDSI consistency standard (3) include formulations as listed in Table 4a (gelling agent for base formulation), Table 4b (with natural flavoring - eg, orange juice), and 4c (no flavoring).

[0071] Table 4a

[0072] Gelling agent weight% agar 0.01 to 0.2 Alginate 0.40 to 1.60 Low methoxyl pectin 0.05 to 0.50 Divalent cations 0.05 to 0.65

[0073] Table 4b

[0074] Gelling agent weight% Preferred % agar 0.01 to 0.09 0.02 Alginate 0.70 to 1.40 0.78 to 1.37 Low methoxyl pectin 0.30 to 0.40 0.31 Divalent cations 0.30 to 0.65 0.31 to 0.61 Non-gelling agent pH adjusters, such as sodium hydroxide 0.20 to 0.50 0.23 to 0.47 Preservatives, such as potassium sorbate 0.02 to 0.06 0.04 Water (including flavoring) to 100% to 100%

[0075] Table 4c

[0076] Gelling agent weight% Preferred % agar 0.01 to 0.20 0.11 Alginate 0.40 to 1.60 0.98 Low methoxyl pectin 0.05 to 0.50 0.28 Divalent cations 0.05 to 0.40 0.21 Non-gelling agent pH adjusters such as citric acid 0.02 to 0.02 0.02 Preservatives such as potassium sorbate 0.05 to 0.05 0.05 water to 100% to 100%

[0077] Thus, formulations meeting the IDDSI consistency standard (4) include formulations as listed in Table 5a (gelling agent for base formulation), Table 5b (with natural flavoring - e.g., orange juice), and 5c (no flavoring).

[0078] Table 5a

[0079] Gelling agent weight% agar 0.05 to 0.60 Alginate 0.10 to 2.00 Low methoxyl pectin 0.01 to 0.30 Divalent cations 0.10 to 1.50

[0080] Table 5b

[0081] Gelling agent weight% Preferred % agar 0.08 to 0.10 0.09 Alginate 1.90 to 2.00 1.94 to 1.95 Low methoxyl pectin 0.01 to 0.20 0.01 to 0.19 Divalent cations 0.40 to 0.50 0.44 Non-gelling agent pH adjusters, such as sodium hydroxide 0.20 to 0.50 0.23 Preservatives, such as potassium sorbate 0.02 to 0.06 0.04 Water (including flavoring) to 100% to 100%

[0082] Table 5c

[0083] Gelling agent weight% Preferred % agar 0.05 to 0.60 0.34 Alginate 0.10 to 1.70 0.88 Low methoxyl pectin 0.10 to 0.30 0.23 Divalent cations 0.10 to 1.50 0.24 to 0.40 Non-gelling agent pH adjusters, such as citric acid 0.02 to 0.05 0.02 to 0.05 Preservatives, such as potassium sorbate 0.05 to 0.07 0.05 to 0.07 water to 100% to 100%

[0084] The formulations of the present invention preferably comprise calcium ions as divalent cations.

[0085] These are most preferably in the form of calcium gluconate.

[0086] The formulations of the present invention all have a pH between pH 4 and pH 6, even more preferably pH 5 to pH 6.

[0087] Preferred pH control agents are sodium hydroxide and citric acid.

[0088] A preferred preservative is potassium sorbate.

[0089] Optionally, the formulation includes a flavoring agent.

[0090] According to a second aspect of the present invention, there is provided a base gel formulation which is the IDDSI Type 1 to 3 formulation according to the first aspect of the present invention, packaged in a container that facilitates ingestion of the container contents by drinking or sucking.

[0091] Preferably, the container is a pouch, a sachet or a straw.

[0092] According to a third aspect of the present invention, there is provided a method of providing a patient with a dietary and / or pharmaceutical ingredient, the method comprising including the ingredient in an IDDSI Type 1 to 3 drinkable base gel formulation according to the first aspect of the present invention, and allowing the patient to drink or suck the formulation.

[0093] Compared with aspects 2 and 3, the IDDSI Type 4 basic gel formulation is still consumed without chewing, but it cannot flow freely like a drink.

[0094] All 4 types can be delivered in volumes ranging from 5 mL to 200 mL, depending on the meal and / or medication ingredients. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Embodiments demonstrating various aspects of the present invention are further described below with reference to the accompanying drawings, in which:

[0096] Figure 1 The diagram shows the seven product categories covered by the IDDSI framework, and

[0097] Figures 2A-2E This is an extract from the referenced IDDSI document providing details of syringe testing for Type 1 to 4 products. DETAILED DESCRIPTION

[0098] refer to Figure 1 , these seven categories are categorized as either food or beverages. Beverages start at 0 (thin) and become increasingly thicker, reaching 4 (very thick). Categories 3 (medium thick) and 4 (very thick) intersect with food categories, with category 3 being equivalent to liquid foods and category 4 being equivalent to pureed foods.

[0099] In arriving at the base formulation(s) of the present invention, the applicants conducted extensive experiments in order to find gelling agents that complement each other so that they provide a flexible matrix that can be adjusted to meet the different requirements of IDDSI "drink" formulations, as defined in categories 1 to 4.

[0100] Agar was initially considered an ideal candidate due to its ability to "release" water when sheared. However, as illustrated in Comparative Example 1, agar alone proved to be unsuitable.

[0101] Comparative Example 1 (agar)

[0102] Table 6

[0103] Components Weight % (range) Gelling agent - agar 0.40 to 0.90 Preservative - Potassium Sorbate 0.30 pH Control - Sodium Hydroxide 0.00 to 0.20 Flavored Water-Orange Juice to 100%

[0104] From several experiments carried out within this range it became apparent that agar by itself was too hard and produced large chunks that did not break apart when squeezed.

[0105] Based on this, two alternative gelling agents were tested (as stand-alone agents), as illustrated in Comparative Examples 2 and 3.

[0106] Comparative Example 2 (sodium alginate)

[0107] Table 7

[0108] Components Weight % (range) Gelling agent-sodium alginate 1.00 to 2.90 Preservative - Potassium Sorbate 0.30 pH Control - Sodium Hydroxide 0.00 to 0.20 Divalent cations - calcium chloride 0.00 to 0.20 Flavored Water-Orange Juice to 100%

[0109] From the experiments performed it became apparent that sodium alginate gels are often too thin and require thickening.

[0110] Comparative Example 3

[0111] Table 9

[0112] Components Weight %.(Range) Gelling agent - low methoxyl pectin 0.40 to 0.80 Preservative - Potassium Sorbate 0.10 to 0.30 pH Control - Sodium Hydroxide 0.00 Divalent cations - calcium chloride 0.20 to 2.90 Flavored Water-Orange Juice to 100%

[0113] It is evident from many experiments that low methoxyl pectins produce thick and sticky gels. However, they are not as stable as other stand-alone gels.

[0114] It is apparent from each of these individual gelling agents that each has disadvantages. Applicants therefore explored whether a combination could be used to address the disadvantages of each alone.

[0115] Therefore, in further development, the three gelling agents were combined in different amounts by weight to obtain a product that complies with the IDDSI guidelines.

[0116] Methods and preferred preparations are listed below:

[0117] Examples 4 to 7

[0118] General method (with natural flavoring - such as orange juice)

[0119] Weigh potassium sorbate, calcium gluconate, sodium hydroxide, flavoring, and water into a beaker and stir until dissolved. Heat the ingredients until the solution temperature reaches approximately 95°C. When the temperature reaches 95°C, add agar and LM pectin, and continue heating and stirring the formulation until dissolved. Slowly add sodium alginate and stir until dissolved. Then remove the beaker from the hot plate and use a high shear laboratory mixer ( The mixture was stirred for about 2 minutes at 1500-2000 rpm to obtain a homogeneous and smooth formulation. The gel was then allowed to cool at room temperature. When a flavor-free formulation was used, citric acid was used instead of sodium hydroxide.

[0120] Example 4a (IDDSI Type 1)

[0121] Using the method described above, Formulation 1 was prepared according to the following Table 10a:

[0122]

[0123] IDDSI Type 1 is described as being thicker than water and can flow through pipettes and syringes. The IDDSI flow test shows that the test liquid should flow through a 10 mL slip tip syringe, leaving 1-4 mL in the syringe after 10 seconds. The Example 4a formulation had 2.6 mL of residual liquid remaining in the syringe.

[0124] Example 4b (IDDSI Type 1)

[0125] Using the method described above, a Type 1 formulation was prepared according to the following Table 10b:

[0126]

[0127] IDDSI Type 1 is described as being thicker than water and can flow through pipettes and syringes. The IDDSI flow test shows that the test liquid should flow through a 10 mL slip-fit ​​syringe, leaving 1-4 mL in the syringe after 10 seconds. The Example 4b formulation had 2.5 mL of residual liquid remaining in the syringe.

[0128] Example 5a (IDDSI Type 2)

[0129] Using the method described above, Type 2 formulations were formulated according to the following Table 11a:

[0130]

[0131] IDDSI Type 2 is described as a liquid that flows from a spoon, is sipable, and requires only slight effort to drink through a standard straw. The IDDSI flow test shows that the test liquid should flow through a 10 mL slip-fit ​​syringe, leaving 4-8 mL in the syringe after 10 seconds. The Example 5a formulation had 5.0 mL of liquid remaining in the syringe.

[0132] Example 5b (IDDSI Type 2)

[0133] Using the method described above, Type 2 formulations were formulated according to the following Table 11b:

[0134]

[0135] IDDSI Type 2 is described as a liquid that flows from a spoon, is sipable, and requires only slight effort to drink through a standard straw. The IDDSI flow test shows that the test liquid should flow through a 10 mL slip-fit ​​syringe, leaving 4-8 mL in the syringe after 10 seconds. The Example 5b formulation had 6.0 mL of liquid remaining in the syringe.

[0136] Example 6a (IDDSI Type 3)

[0137] Using the method described above, Type 3 formulations were prepared according to the following Table 12a:

[0138]

[0139]

[0140] IDDSI Type 3 is described as a liquid that can be drunk from a cup, eaten with a spoon, and swallowed directly without lumps. The IDDSI flow test indicates that the test liquid should flow through a 10 mL slip-fit ​​syringe, leaving >8 mL in the syringe after 10 seconds. The Example 6a formulation had 9.0 mL of liquid remaining in the syringe.

[0141] Example 6b (IDDSI Type 3)

[0142] Using the method described above, Type 3 formulations were prepared according to the following Table 12b:

[0143]

[0144] IDDSI Type 3 is described as a liquid that can be drunk from a cup, eaten with a spoon, and swallowed directly without lumps. The IDDSI flow test indicates that the test liquid should flow through a 10 mL slip-fit ​​syringe, leaving >8 mL in the syringe after 10 seconds. The Example 6b formulation had 8.8 mL of liquid remaining in the syringe.

[0145] Example 7a (IDDSI Type 4)

[0146] Using the method described above, 4 formulations were prepared according to the following Table 13a:

[0147]

[0148] Example 7b (IDDSI Type 4)

[0149] Using the method described above, 4 formulations were prepared according to the following Table 13b:

[0150]

[0151]

[0152] IDDSI Type 4 is described as a puree that can be eaten with a spoon and not drunk from a cup because it does not flow easily, cannot be sucked through a straw, and has no clumps. The IDDSI flow test is not applicable to texture (4), but the fork pressure test, fork drip test, and spoon tilt test are applicable to texture (4).

[0153] The fork pressure test showed that the puree should be smooth, free of lumps and minimal particles. When the fork was pressed against the surface of the puree, the tines of the fork could form a clear pattern on the surface, or the food could retain an indentation from the fork. The fork drip test showed that the sample piled up on the fork, with a small amount flowing between the tines and forming a short tail under the tines, but not continuously dripping through the tines. The spoon tilt test showed that the product should be cohesive enough to hold its shape on the spoon, and that a spoonful would inevitably drop the spoon if the spoon was turned to one side. The formulations of Examples 7a and 7b met all three test criteria.

[0154] Before arriving at a preferred formulation, the applicants noted that the selected cation, calcium chloride, often looked "speckled" and contained "clumps," which were more noticeable in "thicker" formulations. Therefore, they tested and compared calcium chloride with alternative cations including:

[0155] a. magnesium chloride; and

[0156] b. Calcium gluconate.

[0157] The results of these tests (see Example 8 below) showed that calcium gluconate strongly preferred orange juice based gels.

[0158] Example 8

[0159] Table 14

[0160]

[0161] The formulation developed containing calcium chloride produced undesirable spotting and clumping. Calcium chloride is a common ingredient used to crosslink alginate. Due to its high solubility, it causes rapid and poorly controlled gelation. A less water-soluble calcium salt, calcium gluconate, exhibited significantly less spotting and clumping, significantly outperforming the other salts.

[0162] Magnesium ions very slowly form bonds and networks with the alginate over a period of 2-3 hours. However, while magnesium chloride also produces fewer spots and clots, it has proven impractical due to its slower gel formation.

Claims

1. A basic gel formulation that complies with the International Dysphagia Diet Standardization Initiative (IDDS) 2019, comprising: · Various gelling agents; ·water; pH adjuster; • a preservative; and optionally • a flavoring; It is characterized in that The plurality of gelling agents include one of each of the following: Agar; Alginate, as the primary gelling agent; and Low methoxyl pectin and at least one divalent cation.

2. The base gel formulation of claim 1, wherein the gelling agent is present in an amount of Table 1a by weight based on the total weight of the base gel. Table 1a 。 3. The base gel formulation of claim 2, wherein the gelling agent is present in an amount of Table 2a by weight based on the total weight of the base gel. Table 2a And the gel is a Texture 1 gel as defined by the IDDSI flow test standard.

4. The base gel formulation of claim 2, wherein the gelling agent is present in an amount of Table 3a by weight based on the total weight of the base gel. Table 3a And the gel is a Texture 2 gel as defined by the IDDSI flow test standard.

5. The base gel formulation of claim 2, wherein the gelling agent is present in an amount of Table 4a by weight based on the total weight of the base gel. Table 4a And the gel is a Texture 3 gel as defined by the IDDSI flow test standard.

6. The base gel formulation of claim 2, wherein the gelling agent is present in an amount of Table 5a by weight based on the total weight of the base gel. Table 5a And the gel is a Texture 4 gel as defined by the IDDSI flow test standard.

7. The base gel formulation according to any one of the preceding claims, wherein the divalent ions are calcium ions.

8. The base gel formulation of claim 7, wherein the calcium ions are present in the form of calcium gluconate.

9. The base gel formulation of any one of the preceding claims, wherein the pH adjuster maintains the pH between 4 and 6.

10. The base gel formulation according to claim 9, wherein the pH adjuster is sodium hydroxide or citric acid.

11. The base gel formulation of any preceding claim, wherein the preservative is potassium sorbate.

12. The base gel formulation according to any one of claims 2 to 5, which, when packaged in a container, facilitates ingestion of the container contents by drinking or sucking.

13. The base gel formulation of claim 12, wherein the container is a pouch, a sachet or a straw.

14. A method of providing a patient with a dietary and / or pharmaceutical ingredient, the method comprising incorporating the ingredient into a base gel formulation as claimed in any one of claims 2 to 5 and allowing the patient to drink the formulation.

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