WO2020242306A1

WO2020242306A1 - Pharmaceutical composition for treatment of vitamin deficiencies and mineral deficiencies after pancreaticoduodenectomy

Info

Publication number: WO2020242306A1
Application number: PCT/NL2020/050340
Authority: WO
Inventors: Sjoerd Arie Pieter VAN BERKEL
Original assignee: Espera Supplements B.V.
Priority date: 2019-05-28
Filing date: 2020-05-27
Publication date: 2020-12-03

Abstract

The invention relates to a pharmaceutical composition for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to pancreaticoduodenectomy, the pharmaceutical composition comprising at least one of vitamin A, vitamin D3, iron, zinc, copper, selenium, vitamin B6, vitamin B12, vitamin E. The invention also relates to a therapeutic combination for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to pancreaticoduodenectomy, such as the Whipple procedure, wherein the therapeutic combination comprises a combination of at least two of a first unit dose comprising vitamin D3; a second unit dose comprising vitamin A; a third unit dose comprising zinc; and a fourth unit dose comprising iron. Furthermore, the invention relates to a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to pancreaticoduodenectomy, such as the Whipple procedure, wherein the method comprises the daily administration to the patient in need thereof of at least one of vitamin A, vitamin D3, zinc, iron, vitamin B6, vitamin B12, selenium, copper, vitamin E.

Description

PHARMACEUTICAL COMPOSITION FOR TREATMENT OF VITAMIN DEFICIENCIES AND MINERAL DEFICIENCIES AFTER PANCREATICODUODENECTOMY

TECHNICAL FIELD

BACKGROUND

A benign cancer or a malignant cancer of the gastro-intestinal (Gl) tract, in particular pancreatic cancer, is regularly treated by surgical intervention. In addition, similarly pancreatitis is treated by applying pancreaticoduodenectomy (PD). A PD operation is an invasive and risky procedure consisting of removal of the pancreas(head), the proximal part of the small intestine (duodenum), the gallbladder and the bile duct. PD, such as the Whipple’s procedure, is the standard surgical resection for tumors of the duodenum, ampulla, distal common bile duct and the head of pancreas. It thus necessitates extensive resection and reconstruction of the upper gastrointestinal tract, which disrupts the normal digestive physiology.

Through partial removal of the Gl-tract, patients are left with a restricted surface area for (micro)nutrient absorption, the absence or reduced availability of bile, and clinical manifestations of decreased appetite. Taken all these aspects of malnutrition into consideration, PD patients may develop vitamin deficiencies and/or mineral deficiencies that impact their recovery, health status and most importantly, their quality of life. Indeed, for long-term survivors of PD, it has been noticed that post-Whipple procedure patients may be predisposed to develop trace element deficiencies and fat-soluble vitamin deficiencies, postoperatively. As a consequence, in long-term survivors of PD, diets rich in micronutrients have been advised, combined with screening for serum concentrations of trace elements and fat-soluble vitamins.

The number of PD surgeries for the treatment of Gl cancers and benign conditions is increasing. With current decreasing post-operative complications, PD-related comorbidities are becoming increasingly important for the patient’s functional status and quality of life. Patients who underwent the Whipple procedure most often experience difficulties in achieving adequate dietary intake as a consequence of the (partial) removal of the pancreas. In addition, the surgical intervention resulting in removal of at least part of the pancreas interferes often with sufficient adsorption of vitamins and minerals from the patient’s diet. Inadequate dietary intake combined with absorption loss due to altered Gl-tract anatomy and physiology, may result in multifactorial micronutrient deficiencies for the patient. Deficiencies such as a deficiency in one or more fat- soluble vitamins and mineral malabsorption may occur shortly after the surgery and at a time point weeks to months after the surgery was conducted. A deficiency may last for weeks to months or even years, or the deficiency or deficiencies may last for the rest of the patient’s lifespan if left untreated. Unfortunately, long-term effects (>1 year post resection, i.e. post Whipple procedure) of deficiencies on the patient’s health status and performance can be detrimental, though little is known about which patient is susceptible for deficiencies.

Currently patients are not monitored and studied systematically for presence or occurrence of vitamin/mineral deficiencies. Furthermore, assessment of vitamin/mineral supplementation efficacy, including dose-response assessment, in the patient population is essentially lacking until now. Presently, it is also not known which vitamin/mineral deficiencies are most common in the long-term pancreatic cancer survivors patient population who underwent PD-surgery more than 6 months ago. Even for short-term survivors post-surgery, insights in micronutrients deficiencies is minimal, hampering appropriate treatment regiments already from the onset of the post- pancreatic cancer life span or the post-pancreatitis life span of the patient who underwent the Whipple procedure. In addition, and as a consequence of these aforementioned shortcomings relating to lack of knowledge on post-treatment related complications accompanied by vitamin/mineral deficiencies and lack of standardized treatment protocol, design of an appropriate treatment plan for the individual patient is hampered until now. Prescribing a diet rich in deficient micronutrients has proven not be a solution to the apparent deficiencies. Moreover, supplementing the patient’s diet with conventional vitamin- and mineral supplements which comprise the recommended daily allowance of these micronutrients for healthy subjects, did also not adequately solve the observed problems of micronutrient deficiencies in this patient population. It is currently unknown which vitamins and minerals at which doses should be provided to the post-surgery (long-term survivors of) former pancreas cancer patients or pancreatitis patients, such that the observed micronutrient deficiencies are reduced.

Therefore, a solution still needs to be found that allows for patient diagnosis relating to the presence or occurrence of a vitamin deficiency and a mineral deficiency at the time a cancer patient or a patient suffering from pancreatitis undergoes PD, such as the Whipple procedure, or thereafter, wherein the patient stratification includes the selection of an adequate treatment protocol relating to administration of sufficient amounts of any vitamin or mineral if deficiencies of those vitamins/minerals is apparent. Hence, a need remains for a medicament or micronutrient composition which is capable of restoring vitamin balance and mineral balance in patients who underwent PD, such as the Whipple procedure as a consequence of previously suffering from pancreatitis or pancreas cancer.

SUMMARY

It is a first goal of the present invention to provide an improved treatment option for patients such as pancreas cancer patients and patients suffering from pancreatitis, who underwent pancreaticoduodenectomy, such as the Whipple procedure, and who suffer from a mineral deficiency and/or a vitamin deficiency.

It is an objective of the current invention to provide a solution to the problem of lack of adequate treatment options of a mineral deficiency, such as iron deficiency, selenium deficiency, copper deficiency, or zinc deficiency, and/or a vitamin deficiency, such as vitamin A deficiency, vitamin B6 deficiency, vitamin B12 deficiency, vitamin D3 deficiency, or vitamin E deficiency, in patients who suffer or suffered from a pancreas cancer or pancreatitis and will undergo or underwent surgery for at least partial removal of their pancreas, applying e.g. the Whipple procedure.

At least one of the above objectives is achieved by providing a pharmaceutical composition comprising one or more of vitamin A, vitamin B6, vitamin B12, vitamin D3, vitamin E, zinc, iron, copper, selenium, preferably at least vitamin A and/or iron, at sufficiently high amounts per unit dose, i.e. or e.g. per daily dose, to treat any of a deficiency in vitamin A, vitamin D3, zinc, iron, vitamin B6, vitamin B12, vitamin E, copper, selenium in a patient post-PD, such as post- Whipple procedure. It is one of the advantages of the pharmaceutical composition that in an embodiment the one or more of the vitamin A, vitamin B6, vitamin B12, vitamin D3, vitamin E, zinc, iron, copper, selenium, are comprised by a unit dose at such high amounts that the patient compliance is supported by the necessity of daily intake of only a single small-sized unit dose such as a tablet or a capsule. For example, the vitamin A dose in a unit dose administered once daily to the patient in need thereof, is at least 50% of the daily reference intake (DRI) of vitamin A, wherein the DRI refers to the reference intakes listed in the Regulation (EU) No 1 169/201 1 of the European parliament and the council of 25 October 201 1 on the provision of food information to consumers. Typically, the vitamin A dose in a unit dose administered once daily to the patient in need thereof, is at least 70% of the DRI, such as 75%. For example, the vitamin B6 dose in a unit dose administered once daily to the patient in need thereof, is at least 30% of the DRI of vitamin B6. Typically, the vitamin B6 dose in a unit dose administered once daily to the patient in need thereof, is at least 50% of the DRI, such as 70% or 150%. For example, the vitamin B12 dose in a unit dose administered once daily to the patient in need thereof, is at least 200% of the DRI of vitamin B12. Typically, the vitamin B12 dose in a unit dose administered once daily to the patient in need thereof, is at least 500% of the DRI, such as 5.000%, 14.000% or 30.000%. For example, the vitamin D3 dose in a unit dose administered once daily to the patient in need thereof, is at least 150% of the DRI of vitamin D3. Typically, the vitamin D3 dose in a unit dose administered once daily to the patient in need thereof, is at least 200% of the DRI, such as 2000% or 1500%. For example, the vitamin E dose in a unit dose administered once daily to the patient in need thereof, is at least 130% of the DRI of vitamin E. Typically, the vitamin E dose in a unit dose administered once daily to the patient in need thereof, is at least 170% of the DRI, such as 200% or 450%. For example, the iron dose in a unit dose administered once daily to the patient in need thereof, is at least 150% of the DRI of iron. Typically, the iron dose in a unit dose administered once daily to the patient in need thereof, is at least 200% of the DRI, such as 700% or 500%. For example, the zinc dose in a unit dose administered once daily to the patient in need thereof, is at least 125% of the DRI of zinc. Typically, the zinc dose in a unit dose administered once daily to the patient in need thereof, is at least 175% of the DRI, such as 300% or 225%. For example, the selenium dose in a unit dose administered once daily to the patient in need thereof, is at least 100% of the DRI of selenium. Typically, the selenium dose in a unit dose administered once daily to the patient in need thereof, is at least 150% of the DRI, such as 190% or 350%. For example, the copper dose in a unit dose administered once daily to the patient in need thereof, is at least 125% of the DRI of copper. Typically, the copper dose in a unit dose administered once daily to the patient in need thereof, is at least 200% of the DRI, such as 300% or 450%. Of course, it is also part of the invention that a pharmaceutical composition is provided comprising one or more of vitamin A, vitamin B6, vitamin B12, vitamin D3, vitamin E, zinc, iron, copper, selenium, preferably at least vitamin A and/or iron, at sufficiently high amounts per unit dose, e.g. per once, twice or thrice daily dose, to treat any of a deficiency in vitamin A, vitamin D3, zinc, iron, vitamin B6, vitamin B12, vitamin E, copper, selenium, preferably at least one of a vitamin A deficiency or an iron deficiency, in a patient post-PD, such as post-Whipple procedure. Such a unit dose comprises for example the daily dose of the one or more vitamins and/or the one or more minerals, preferably at least one of vitamin A and iron, or the half-daily dose, or one third of a daily dose, for administering to the patient in need thereof once daily, twice daily or thrice daily, respectively. It is one of the advantages of the pharmaceutical composition that the one or more of the vitamin A, vitamin B6, vitamin B12, vitamin D3, vitamin E, zinc, iron, copper, selenium, preferably at least one of vitamin A and iron, are comprised by a unit dose at such high amounts that the patient compliance is supported by the necessity of daily intake of only a single small-sized unit dose, or only two small-sized unit doses preferably each comprising a half-daily dose, or only three smallsized unit doses preferably each comprising one third of a daily dose, such as one, two or three tablet(s), respectively, or one, two or three capsule(s), respectively.

The present invention will be described with respect to particular embodiments but the invention is not limited thereto but only by the claims.

Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. The terms are interchangeable under appropriate circumstances and the embodiments of the invention can be used or combined in other sequences than described or illustrated herein.

The embodiments of the invention described herein can operate in combination and cooperation, unless specified otherwise.

Furthermore, the various embodiments, although referred to as“preferred” or“e.g.” or“for example” or“in particular” are to be construed as exemplary manners in which the invention may be implemented rather than as limiting the scope of the invention.

The term“comprising”, used in the claims, should not be interpreted as being restricted to the elements or steps listed thereafter; it does not exclude other elements or steps. It needs to be interpreted as specifying the presence of the stated features, integers, steps or components as referred to, but does not preclude the presence or addition of one or more other features, integers, steps or components, or groups thereof. Thus, the scope of the expression “a pharmaceutical composition comprising A and B” should not be limited to a pharmaceutical composition consisting only of components A and B, rather with respect to the present invention, the only enumerated components of the a pharmaceutical composition are A and B, and further the claim should be interpreted as including equivalents of those components.

In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element are present, unless the context clearly requires that there is one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one".

A first aspect of the invention relates to a pharmaceutical composition for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas and/or duodenum, comprising at least one of:

- vitamin A or a source thereof;

- vitamin D3 or a source thereof;

- iron or a source thereof; and

- zinc or a source thereof;

and further comprising a pharmaceutically acceptable carrier, wherein the patient in need thereof is administered by means of said pharmaceutical composition per day at least one of: 300 pg - 1200 pg vitamin A, 10 pg - 200 pg vitamin D3, 10 mg - 60 mg zinc and 10 mg - 200 mg iron. Preferably, the pharmaceutical composition comprises the vitamin A, the vitamin D3, the iron and the zinc.

An embodiment is the pharmaceutical composition for use according to the invention, wherein the patient in need thereof is at least administered by means of said pharmaceutical composition per day 300 pg - 2500 pg vitamin A.

An embodiment is the pharmaceutical composition for use according to the invention, wherein the patient in need thereof is at least administered by means of said pharmaceutical composition per day 10 mg - 200 mg iron.

An embodiment is the pharmaceutical composition for use according to the invention, wherein a unit dose of the pharmaceutical composition comprises at least: 300 pg - 2500 pg vitamin A, preferably 450 pg - 1800 pg, more preferably 600 pg - 1200 pg; and/or

10 mg - 200 mg iron, preferably 20 mg - 150 mg, more preferably 28 mg - 70 mg or 50 mg - 100 mg.

An aspect of the invention relates to a pharmaceutical composition for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas and/or duodenum, comprising at least one of:

- vitamin A or a source thereof;

- vitamin B6 or a source thereof;

- vitamin B12 or a source thereof;

- vitamin D3 or a source thereof;

- vitamin E or a source thereof;

- iron or a source thereof;

- copper or a source thereof;

- selenium or a source thereof; and

- zinc or a source thereof;

and further comprising a pharmaceutically acceptable carrier, wherein the patient in need thereof is administered by means of said pharmaceutical composition per day at least one of: 300 pg - 2500 pg vitamin A, such as 300 pg - 1200 pg vitamin A, 0,4 mg - 2,5 mg vitamin B6, 25 pg - 20.000 pg vitamin B12, 4 pg - 200 pg vitamin D3, such as 10 pg - 200 pg vitamin D3, 14 mg - 60 mg vitamin E, 10 mg - 200 mg zinc, such as 10 mg - 60 mg zinc, 1 ,2 mg - 10 mg copper, 60 pg - 250 pg selenium and 10 mg - 200 mg iron. Preferably, the pharmaceutical composition comprises the five vitamins and the four minerals.

The patient has for example been subjected to PD surgery, such as the Whipple procedure, for the treatment of a Gl cancer or a benign condition. The pharmaceutical composition comprises any one or more of the vitamin A, vitamin D3, iron and zinc, if the patient is deficient in any one or more of these vitamins and minerals. The pharmaceutical composition comprises any one or more of the vitamin A, vitamin B6, vitamin B12, vitamin D3, vitamin E, iron, copper, selenium and zinc, if the patient is deficient in any one or more of these vitamins and minerals. Thus, if a patient is deficient in vitamin A, the pharmaceutical composition comprises vitamin A; if a patient is deficient in vitamin A and vitamin D3, the pharmaceutical composition comprises at least vitamin A and vitamin D3, etc., etc. For example, the pharmaceutical composition of the invention comprises vitamin A, vitamin B6, vitamin B12, vitamin D3, vitamin E, iron, zinc, selenium, copper, such as outlined in Table 2 and 3.

By administering the pharmaceutical composition to a patient in need thereof who underwent e.g. the Whipple procedure, for example between 40% and 300%, preferably 60%- 200% such as 75%-150% of the daily reference intake (DRI) of vitamin A is provided to the patient, preferably about 75% or about 150%, wherein the DRI refers to the reference intakes listed in the Regulation (EU) No 1 169/201 1 of the European parliament and the council of 25 October 201 1 on the provision of food information to consumers. By administering the pharmaceutical composition to a patient in need thereof who underwent e.g. the Whipple procedure, for example between 300% and 5000%, preferably 700%-3500% such as 1000%-2000% of the DRI of vitamin D3 is provided to the patient, and/or for example between 125% and 1000%, preferably 250%- 800% such as 400%-650% of the DRI of iron is provided to the patient, and/or for example between 125% and 600%, preferably 180%-400% such as 200%-300% of the DRI of zinc is provided to the patient. As said, if the patient in need thereof suffers pre-operation and/or post- PD, such as post Whipple procedure from two or more of a deficiency in vitamin A, vitamin D3, iron and zinc, the patient is administered a pharmaceutical composition comprising at least those two or more vitamin(s) and/or mineral(s). Typically, the pharmaceutical composition comprises 400 mg - 1600 mg vitamin A, such as 600 mg or 1200 mg. Additively or alternatively, the pharmaceutical composition comprises 5 mg - 200 mg vitamin D3 (cholecalciferol), such as 10 mg or 75 mg. Additively or alternatively, the pharmaceutical composition comprises 8 mg - 200 mg iron, such as 28 mg or 70 mg or 50 mg - 100 mg. Typically, the iron is provided as ferrous fumarate. Additively or alternatively, the pharmaceutical composition comprises 6 mg - 80 mg zinc, such as 15 mg or 22,5 mg or 40 mg. Typically, the zinc is provided as zinc citrate.

The pharmaceutical composition for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas, is typically administered to a patient who suffered from any of pancreatic carcinoma, papillary carcinoma, duodenal carcinoma, cholangiocarcinoma, intraductal papillary mucinous neoplasm (IPMN), neuroendocrine tumor (NET), pancreatitis, pancreatic gastro-intestinal stromal tumor (GIST), intraductal oncocytic papillary neoplasm (IOPN) of the pancreas, a benign or malignant cancer of the gastro-intestinal tract.

A second aspect of the invention relates to a therapeutic combination for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas and/or duodenum (e.g. the Whipple procedure), wherein the therapeutic combination comprises a combination of at least two of:

(a) a first unit dose comprising 4 pg - 200 pg vitamin D3;

(b) a second unit dose comprising 300 pg - 2500 pg vitamin A;

(c) a third unit dose comprising 5 mg - 70 mg zinc; and

(d) a fourth unit dose comprising 10 mg - 200 mg iron.

For example, the therapeutic combination comprises or consists of a first unit dose comprising the vitamin A, vitamin D3, zinc, and/or comprises or consists of the fourth unit dose comprising or consisting of the iron. The fourth unit dose may also comprise copper, at an amount of for example 100% - 600%, or between 1 mg and 5 mg, such as about 1 ,9 mg.

An embodiment is the therapeutic combination for use according to the invention, wherein the therapeutic combination comprises a combination of at least:

- the second unit dose comprising 400 pg - 2000 pg vitamin A, preferably 500 pg - 1500 pg, more preferably 600 pg - 1200 pg; and/or

- the fourth unit dose comprising 15 mg - 150 mg iron, preferably 20 mg - 100 mg, more preferably 28 mg - 70 mg or 50 mg - 100 mg.

A further aspect of the invention relates to a therapeutic combination for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas and/or duodenum (e.g. the Whipple procedure), wherein the therapeutic combination comprises a combination of at least two of:

(a) a first unit dose comprising 4 pg - 200 pg vitamin D3;

(b) a second unit dose comprising 300 pg - 2500 pg vitamin A;

(c) a third unit dose comprising 5 mg - 70 mg zinc;

(d) a fourth unit dose comprising 10 mg - 200 mg iron;

(e) a fifth unit dose comprising 1 ,5 mg - 6 mg copper;

(f) a sixth unit dose comprising 50 mg - 400 mg selenium;

(g) a seventh unit dose comprising 0,4 mg - 2,0 mg vitamin B6;

(h) an eighth unit dose comprising 150 pg - 800 pg vitamin B12; and

(i) a ninth unit dose comprising 10 mg - 50 mg vitamin E.

For example, the therapeutic combination comprises or consists of a first unit dose comprising the vitamin A, vitamin B6, vitamin B12, vitamin D3, vitamin E, zinc, and/or comprises or consists of the fourth unit dose comprising or consisting of the copper and the iron.

It is preferred that the therapeutic combination for use in a method for the treatment of at least one of a vitamin deficiency and mineral deficiency, is administered to the patient in need thereof, wherein the patient suffered pre-treatment (thus before subjecting the patient to PD, such as to the Whipple procedure) from any one or more of headache, skin rash, rheumatoid arthritis, dry skin, deprivement of energy, fatigue, chronical fatigue lasting for at least 3 months, decreased resistance, attention disorder, pale skin, memory disorder, a sensory problem such as deafness and tingling, depression, anxiety, distress, impaired wound healing, impaired haemostasis, declined taste, declined hearing, declined smell, aphthous stomatitis, and hair loss. These disorders and health problems typically occur as a consequence or symptom of a deficiency in the patient for any one or more of vitamin A, vitamin D3, iron, zinc, vitamin B6, vitamin B12, selenium, copper, vitamin E. Administering to the patient in need thereof the pharmaceutical composition after surgery, treats or ameliorates or augments the deficiency/deficiencies and supplements the patient with the vitamin(s)/mineral(s) needed for relieving the patient from said disorders and health issues related to the deficiency/deficiencies.

It is part of the invention that a unit dose may comprise a combination of two or more of the vitamins and/or minerals. For example, the first unit dose may also comprise one or more of vitamin A, vitamin B6, vitamin B12, vitamin E, selenium, zinc, etc., and for example the fourth unit dose may also comprise e.g. copper. Any of the unit doses may contain a combination of two or more of the minerals and/or vitamins.

A third aspect of the invention relates to a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to PD such as the Whipple procedure, wherein the method comprises the daily administration to the patient in need thereof of at least one of:

300 pg - 2500 pg vitamin A, preferably 450 pg - 2000 pg, more preferably 600 pg - 1200 pg, such as about 600 pg or about 1200 pg;

4 pg - 200 pg vitamin D3, preferably 6 pg - 150 pg, more preferably 10 pg - 75 pg, such as about 10 pg or about 75 pg;

4 mg - 70 mg zinc, preferably 8 mg - 60 mg, more preferably 15 mg - 40 mg, most preferably 20 mg - 30 mg, such as 22,5 mg; and

A further aspect of the invention relates to a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas and/or duodenum such as pancreaticoduodenectomy, wherein the method comprises the daily administration to the patient in need thereof of at least one of:

300 pg - 2500 pg vitamin A, preferably 450 pg - 2000 pg, more preferably 600 pg - 1200 mo;

4 pg - 200 pg vitamin D3, preferably 6 pg - 150 pg, more preferably 10 pg - 75 pg;

4 mg - 70 mg zinc, preferably 8 mg - 60 mg, more preferably 15 mg - 40 mg, most preferably 20 mg - 30 mg, such as 22,5 mg;

10 mg - 200 mg iron, preferably 20 mg - 150 mg, more preferably 28 mg - 70 mg or 50 mg - 100 mg;

0,3 mg - 5 mg vitamin B6, such as 0,5 mg - 3 mg, preferably 0,7 mg - 2,5 mg, such as about 0,98 mg;

20 pg - 1 .000 pg vitamin B12, preferably 100 pg - 600 pg, more preferably 200 pg - 500 pg, such as about 350 pg;

8 mg - 100 mg vitamin E, preferably 12 mg - 50 mg, more preferably 16 mg - 35 mg, such as about 24 mg;

1 mg - 10 mg copper, preferably 2 mg - 6 mg, more preferably 2,5 mg - 5 mg, such as about 3 mg; and

35 pg - 500 pg selenium, preferably 60 pg - 300 pg selenium, more preferably 80 pg - 250 pg, such as about 105 pg.

An embodiment is the method according to the invention, wherein the method comprises the daily administration to the patient in need thereof of at least:

300 pg - 2500 pg vitamin A, preferably 450 pg - 2000 pg, more preferably 600 pg - 1200 pg; and/or

Typically, in the method, the patient who underwent PD such as the Whipple procedure and who is in need of mineral/vitamin supplementation, is administered a pharmaceutical composition for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas as herein described, or is administered a therapeutic combination for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas (e.g. the Whipple procedure), as herein described.

DEFINITIONS

The term‘ harmaceutical composition’ as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.

The term‘pharmaceutically acceptable’ as used herein has its conventional meaning and refers to compounds, material, compositions and/or dosage forms, which are, within the scope of sound medical judgment suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.

The term ‘excipient as used herein has its conventional meaning and refers to a pharmaceutically acceptable ingredient, which is commonly used in the pharmaceutical technology for preparing a granulate, solid or liquid oral dosage formulation.

The term‘treatment’ as used herein has its conventional meaning and refers to curative, palliative and prophylactic treatment.

The term‘unit dose’ has its conventional meaning and refers to a dosage form which has the capacity of being administered as such to a subject, preferably a human, to be effective, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising the therapeutic agent. Typical examples of unit doses are tablets and capsules.

The term‘fixed dose combination' as used herein has its conventional meaning and refers to a combination of defined doses of two or more minerals or vitamins presented in a single unit dose (e.g. a tablet or a capsule) which is administered as such.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1. Dosage regimen for patients undergoing pancreaticoduodenectomy surgery, e.g. the Whipple procedure, who are subsequently administered a pharmaceutical composition comprising vitamins and minerals, when presented with micronutrient deficiencies, e.g. vitamin A deficiency and/or vitamin B6 deficiency and/or vitamin B12 deficiency and/or vitamin E deficiency and/or iron deficiency and/or zinc deficiency and/or vitamin D3 deficiency and/or selenium deficiency and/or copper deficiency, post-surgery.

Fig. 2. Dosage regimen (treatment scheme) for post-PD such as post-Whipple procedure patients who previously suffered from cancer or pancreatitis, and who were presented with micronutrient deficiencies, e.g. vitamin A deficiency and/or vitamin B6 deficiency and/or vitamin B12 deficiency and/or vitamin E deficiency and/or iron deficiency and/or zinc deficiency and/or vitamin D3 deficiency and/or selenium deficiency and/or copper deficiency at least 6 months post-surgery.

DETAILED DESCRIPTION

For patients suffering from pancreatitis or pancreatic cancer, potentially curative surgery is used when results of exams and tests suggest that it is possible to completely resect the cancer. Curative surgery is done mainly to treat cancers in the head of the pancreas. The so-called ‘Whipple procedure’ (a type of pancreaticoduodenectomy) is the most common surgical operation to remove a cancer in the head of the pancreas. During this operation, the surgeon removes the head of the pancreas and sometimes the body of the pancreas as well. Nearby structures such as part of the small intestine, part of the bile duct, the gallbladder, lymph nodes near the pancreas, and sometimes part of the stomach are also removed. The remaining bile duct and pancreas are then attached to the small intestine so that bile and digestive enzymes can still go into the small intestine. The end pieces of the small intestine (or the stomach and small intestine) are then reattached so that food can pass through the digestive tract (gut).

Besides the great benefits of the curative surgery such as the Whipple procedure for patients suffering from a benign pancreatic cancer or malignant pancreatic cancer or from pancreatitis, there are also disadvantages for the patients such as hampered food intake, trouble with the stomach emptying after eating, trouble digesting some foods, changes in bowel habits, diabetes, and nutrient deficiencies resulting from malabsorption. Post-operatively, post-PD patients, such as Whipple procedure patients are at increased risk of developing (micro)nutrient deficiencies because of decreased food intake, food intolerance, reduction of gastric secretions, and reduced absorption surface areas. Indeed, it has been reported that post-PD patients can have inadequate dietary intake of fat-soluble vitamins. Up to one third of post-PD patients may suffer from malnutrition. These issues altogether combine to an important factor in causing nutritional deficiencies.

Furthermore, for post-PD, e.g. post-Whipple procedure patients, there is a tendency of reduced food intake amongst those patients, contributing to a risk for mineral deficiencies and vitamin deficiencies. Indeed, based on some anecdotal evidence, reported deficiencies found in patients which have been subjected to PD such as the Whipple procedure, include vitamin A deficiency, vitamin B6 deficiency, vitamin E deficiency, zinc deficiency, selenium deficiency, iron deficiency, copper deficiency. The deficiencies that occur after the surgery are mostly the result of an inadequate intake and malabsorption of essential micronutrients. Moreover, for post-PD patients it has also been observed that dietary intake of micronutrients did not correlate with observed serum levels for minerals and vitamins in those patients. It has been established that supplementing the diet of post-PD patients such as post-Whipple procedure patients with micronutrients at conventional doses, e.g. at amounts of about 50%-100% of the recommended daily intake, does not improve the extent of the deficiencies. Moreover, prescribing diet rich in micronutrients does not improve the micronutrient deficiency status of the post-surgery patients.

Indeed, in attempts to balance observed micronutrient deficiencies in patients which have been subjected to PD, these patients are prescribed standard multivitamin supplements, which supplements generally comprise 100% of the recommended daily allowance (RDA) for copper, selenium, zinc, iron, vitamin A, vitamin B6, vitamin E and other vitamins. However, in the clinical studies carried out by the present inventors it has now been shown that a prescribed diet rich in micronutrients and/or the administration of such standard multivitamin preparations did not result in solving the micronutrient deficiencies commonly observed in these types of former pancreatic cancer patients or former pancreatitis patients who underwent PD such as the Whipple procedure. The normal site for the absorption of micronutrients (duodenum and upper jejunum) is removed during PD, the availability of bile is altered and the interaction site of bile and food is altered, and therefore it could be that parenteral supplementation of conventionally recommended daily amounts of micronutrients does not provide for resolution of these deficiencies when clinical consequences develop.

The pharmaceutical composition according to the present invention, and the use of the pharmaceutical composition in a method for the treatment of micronutrient deficiencies, aims to solve these problems.

- vitamin A or a source thereof;

- vitamin D3 or a source thereof;

- iron or a source thereof; and

- zinc or a source thereof;

and further comprising a pharmaceutically acceptable carrier, wherein the patient in need thereof is administered by means of said pharmaceutical composition per day at least one of: 300 pg - 1200 pg vitamin A, 10 pg - 200 pg vitamin D3, 10 mg - 60 mg zinc and 10 mg - 200 mg iron. Typically, the vitamin A, vitamin D3, iron and zinc are provided as the compound listed in Table 4.

Preferred is the pharmaceutical composition for use according to the invention, wherein a unit dose of the pharmaceutical composition comprises at least one of: 300 pg - 2500 pg vitamin A, preferably 450 pg - 1800 pg, more preferably 600 pg - 1200 mo;

4 pg - 200 pg vitamin D3, preferably 5 pg - 150 pg, more preferably 10 pg - 75 pg;

10 mg - 200 mg iron, preferably 20 mg - 150 mg, more preferably 28 mg - 70 mg or 50 mg - 100 mg; and

10 mg - 200 mg zinc, preferably 15 mg - 40 mg, more preferably 20 mg - 30 mg, most preferably about 22,5 mg.

A pharmaceutical composition for use according to the invention is preferred, wherein a unit dose of the pharmaceutical composition comprises at least two, preferably at least three, more preferably four of:

300 pg - 2500 pg vitamin A, preferably 450 pg - 1800 pg, more preferably 600 pg - 1200 mo;

Equally preferred is the pharmaceutical composition for use according to the invention, wherein two or more unit doses of the pharmaceutical composition comprises in combination at least one of:

10 mg - 200 mg zinc, preferably 15 mg - 40 mg, more preferably 20 mg - 30 mg, most preferably about 22,5 mg. Preferably, the two or more unit doses, such as two, three, four or five unit dose, each contain the same amount of pharmaceutical composition. For example, when the patient in need thereof is administered by means of the pharmaceutical composition per day at least one of: 300 pg - 1200 pg vitamin A, 10 pg - 200 pg vitamin D3, 10 mg - 60 mg zinc and 10 mg - 200 mg iron, in two unit doses, each unit dose comprises 50% of said daily amount of one or more vitamins and/or one or more minerals. For example, the pharmaceutical composition of Table 3 or 3A is administered to the patient in need thereof as two unit doses per day, each unit dose comprising 50% of the daily amount administered to the patient. The two or more unit doses are administered together or separately during the day, with a time interval between administration of subsequent unit doses.

An embodiment is the pharmaceutical composition for use according to the invention, wherein a unit dose of the pharmaceutical composition comprises at least:

300 pg - 2500 pg vitamin A, preferably 450 pg - 1800 pg, more preferably 600 pg - 1200 pg; and/or 10 mg - 200 mg iron, preferably 20 mg - 150 mg, more preferably 28 mg - 70 mg or 50 mg - 100 mg.

The pharmaceutical composition for use according to the invention can in some embodiments comprise vitamin K. For example, the composition listed in Table 3 and Table 3A may further comprise vitamin K. Typically, the daily amount of vitamin K administered to the patient is 2 mg or less, such as 2 mg, 1 mg, 0,5 mg, 0,2 mg, 0,1 mg, or less, such as 0,05 mg. Alternatively, the pharmaceutical composition for use according to the invention does not comprise vitamin K. For example see Table 3 and Table 3a for a typical pharmaceutical composition of the invention, without vitamin K. An embodiment is the pharmaceutical composition for use according to the invention, wherein the patient in need thereof is administered vitamin K, such as vitamin K at a daily dose of 2 mg or less, such as 2 mg, 1 mg, 0,5 mg, 0,2 mg, 0,1 mg, or less, such as 0,05 mg. An alternative embodiment is the pharmaceutical composition for use according to the invention, wherein the patient in need thereof is not supplemented with vitamin K.

An embodiment is the pharmaceutical composition for use according to the invention, wherein the patient in need thereof is further administered a second composition comprising or consisting of vitamin D3 as the active ingredient, preferably consisting of vitamin D3 as the active ingredient. Preferably, the amount of administered vitamin D3 by the second composition is 75 mg or less, such as 5, 10, 20, 25, 40, 60, 75 mg vitamin D3, preferably 10 mg or 75 mg.

An embodiment is the pharmaceutical composition for use according to the invention, wherein the patient in need thereof is further administered a third composition comprising or consisting of vitamin A as the active ingredient, preferably consisting of vitamin A as the active ingredient. Preferably, the amount of administered vitamin A by the third composition is 3000 mg or less, such as 300, 600, 900, 1200, 1500, 1800, 2100, 2400, 2700 mg vitamin A, preferably 600 mg or 1200 m9·

An embodiment is the pharmaceutical composition for use according to the invention, wherein the patient in need thereof is further administered a fourth composition comprising or consisting of iron as the active ingredient, preferably consisting of iron as the active ingredient. Preferably, the daily amount of administered iron by the fourth composition is 100 mg or less, such as 90, 80, 70, 60, 50, 40, 30, 20, 10 mg iron, preferably 70 mg or 10 mg. The iron is preferably provided as ferrous fumarate. The fourth composition may comprise 0,5 mg - 10 mg copper as a second active ingredient, such as about 1 ,9 mg or about 3 mg. The copper is for example provided as copper gluconate. Therewith, the daily amount of administered copper by the fourth composition is 10 mg or less, such as 9, 8, 7, 6, 5, 4, 3, 2, 1 mg copper, preferably about 3 mg or 1 ,9 mg.

An embodiment is the pharmaceutical composition for use according to the invention, wherein the patient in need thereof is further administered a fifth composition comprising or consisting of zinc as the active ingredient, preferably consisting of zinc as the active ingredient. Preferably, the daily amount of administered zinc by the fifth composition is 250 mg or less, such as 200, 180, 150, 125, 100, 80, 70, 50, 25, 20, 10 mg zinc, preferably about 22,5 mg or 45 mg. The zinc is preferably provided as zinc citrate.

Thus, a preferred pharmaceutical composition comprises about 600 pg vitamin A, or about 1200 pg, about 10 pg vitamin D3, or about 75 pg, about 28 mg iron, or about 50 mg iron, or about 70 mg or about 100 mg iron, and about 22,5 mg zinc. In addition, the pharmaceutical composition comprises any one or more of vitamin B6, vitamin B12, vitamin E, selenium, copper, at amounts such as for example listed in Table 2 and Table 3 and Table 3A, preferably the amounts listed in Table 3. Typically, the pharmaceutical compositions comprises the compounds listed in Table 3, at amounts listed therein. Also preferred is the pharmaceutical composition for use according to the invention, as outlined in Table 3A. Typically, the patient in need thereof is administered the pharmaceutical composition of Table 3A, together with a fourth composition comprising iron as here above described.

Thus, a patient is administered a pharmaceutical composition for use according to the invention, and optionally is also administered vitamin K, and/or the second composition comprising vitamin D3, and/or the third composition comprising vitamin A, and/or the fourth composition comprising iron, and/or the fifth composition comprising zinc.

An embodiment is the pharmaceutical composition for use according to the invention, wherein the patient in need thereof is further administered a sixth composition comprising or consisting of vitamin B6 as the active ingredient, preferably consisting of vitamin B6 as the active ingredient. Preferably, the daily amount of administered vitamin B6 by the sixth composition is 3 mg or less, such as 2,5, 2,2, 1 ,8, 1 ,5, 1 ,2, 0,98, 0,6 mg vitamin B6, preferably about 0,49 mg or 0,98 mg.

An embodiment is the pharmaceutical composition for use according to the invention, wherein the patient in need thereof is further administered a seventh composition comprising or consisting of vitamin B12 as the active ingredient, preferably consisting of vitamin B12 as the active ingredient. Preferably, the daily amount of administered vitamin B12 by the seventh composition is 1 mg or less, such as 0,8, 0,6, 0,4, 0,35, 0,3, 0,2, 0,1 mg vitamin B12, preferably about 0,2 mg or 0,35 mg.

An embodiment is the pharmaceutical composition for use according to the invention, wherein the patient in need thereof is further administered an eighth composition comprising or consisting of selenium as the active ingredient, preferably consisting of selenium as the active ingredient. Preferably, the daily amount of administered selenium by the eighth composition is 0,6 mg or less, such as 0,5, 0,4, 0,3, 0,2, 0,1 mg selenium, preferably about 200 mg, 105 mg, 50 mg. The selenium is preferably provided as sodium selenite.

The inventors of the present invention remarkably found that in order to avoid any deficiency of iron, zinc, vitamin A, vitamin B6, vitamin B12, vitamin D3 and vitamin E in patients that have been subjected to PD, increased doses of said micronutrients need to be administered, compared to the doses related to about 33%-100% of the RDA commonly provided with regular and conventional multivitamin capsules, such as about 50%. Moreover, with the provision of a single unit dose of the pharmaceutical composition of the invention, containing relatively high amounts of the micronutrients compared to conventional compositions known in the art, patient compliance is supported and improved since the patients only have to swallow a single unit dose in order to support the elevation of their serum levels of micronutrients.

The inventors established that post-PD patients suffer from any one or more of a blood serum deficiency of vitamin A, vitamin B6, vitamin B12, vitamin D3, vitamin E, iron, zinc. Reference is made to the EXAMPLES section here below. All tested patient cohorts presented with numeral patients suffering from at least one micronutrient deficiency and most often from two or more deficiencies such as both vitamin A and iron deficiency. Patients presenting post-PD e.g. post- Whipple procedure with any one or more of a deficiency in vitamin A, vitamin B6, vitamin B12, vitamin D3, vitamin E, zinc, iron, are administered the pharmaceutical composition, such that serum levels of these micronutrients increase and ultimately reach normal levels.

Without wishing to be bound by theory, vitamin A is absorbed from the upper gastro-intestinal tract. It aggregates with other lipids in the stomach prior to being exposed to bile salts and pancreatic lipases in the duodenum. This mechanism is presumably disturbed by PD, resulting in vitamin A deficiencies in a relatively large number of post-PD patients in the patient cohorts 1 -5.

Without wishing to be bound by theory, vitamin B6 is mainly absorbed in the proximal small bowel, of which the entire duodenum and approximately 20 cm of the jejunum are typically lost after PD. Vitamin B6 deficiency can lead to normocytic, microcytic, or sideroblastic anemia due to impairment of heme synthesis.

Without wishing to be bound by theory, trace elements such as iron and selenium are mainly absorbed in the duodenum and the upper jejunum, which are removed during PD. Iron has to be soluble in the chyme to be absorbed. The solubility depends on the redox status which is increased by low gastric pH and reduced by alkaline pancreatic juice, allowing balanced absorption in health. Gastric acid secretion may be impaired by reduced gastrin secretion after PD. The balance of absorption can further be upset by pancreatic insufficiency. The absorption of iron requires transferrin to be secreted by the duodenum, which duodenum is however removed during PD. Poor iron absorption appears to be a physiological consequence of PD.

Without wishing to be bound by theory, copper deficiency can be a consequence of PD, because copper deficiencies have been reported in patients with gastric resection and small bowel resection.

Deficient intakes of vitamin D and vitamin E and selenium in post-PD patients have been reported by others. Without wishing to be bound by theory, patients had likely modified their fat intake to limit symptoms of steatorrhoea, leading to a risk of fat-soluble vitamin deficiency and inadequate energy intake. Without wishing to be bound by theory, selenium and vitamin E are antioxidants, and antioxidant deficiencies have been implicated in the pathogenesis of chronic pancreatitis.

With respect to the use of zinc it is noted that additional zinc is preferred in order to avoid loss of hair after the surgery has been carried out.

Besides the above mentioned minerals and vitamins, the pharmaceutical composition for use according to the present invention also comprises a pharmaceutically acceptable excipient.

Such an excipient is chosen from ingredients which are commonly used in the pharmaceutical technology for preparing granulate, solid or liquid oral dosage formulations.

Examples of categories of excipients include, but are not limited to, binders, disintegrants, lubricants, glidants, fillers and diluents. One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granulate e.g. from which capsules / tablets are produced, and/or solid oral dosage form by routine experimentation and without any undue burden. The amount of each excipient used may vary within ranges conventional in the art. The following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms. See “The Handbook of Pharmaceutical Excipients", 4th edition, Rowe et ai, Eds., American Pharmaceuticals Association (2003); and“Remington: The Science and Practice of Pharmacy”, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2000).

In embodiments, the pharmaceutical composition for use according to the invention, is for use in the method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas, wherein the surgical removal of at least part of the patient’s pancreas is pancreaticoduodenectomy (e.g. the Whipple procedure’).

it has been reported previously that patients who underwent PD for pancreatic cancer, e.g. such as peri-ampuliary neoplasia, have relatively low serum micronutrient levels. Deficiency in iron and a relative reduction of antioxidants (selenium and vitamin E) has been observed, as well as vitamin D deficiency. After PD, some patients seem prone to selenium deficiencies, which in profound forms can lead to cardiomyopathy. Both pancreatic resection and duodenal resection are likely to contribute to low vitamin D levels in the serum of post-PD patients. These deficiencies altogether are likely to be a consequence of malabsorption. Micronutrients are most likely absorbed from the upper gastrointestinal tract. After resection of the duodenum and the pancreatic head, the jejunum is used to reconstruct the upper gastrointestinal tract after surgery. In addition to losing the absorptive capacity of the duodenum, the chyme entering the jejunal loop will be altered in composition, with changes in pH and reduced pancreatic enzyme content, further compromising normal function. In many post-PD patients in our cohorts 1 -5, depletion of micronutrients is apparent. See for examples the EXAMPLES section, below.

An embodiment is the pharmaceutical composition for use according to the invention, wherein the patient who has been subjected to the surgical removal of at least part of the patient’s pancreas and/or duodenum, preferably PD, was subjected to said surgical removal between 0 days and 400 months before the pharmaceutical composition is administered to said patient for the first time, preferably 1 week-350 months, more preferably 6 months - 300 months.

The inventors established that in the serum of former pancreatic cancer patients and former pancreatitis patients, micronutrient deficiencies were still apparent as long as 6 months post-PD and longer, such as up to about 280 months post-PD. Surprisingly, for example iron deficiency, vitamin A deficiency, vitamin B6, vitamin B12, vitamin D3, vitamin E, zinc deficiencies were still apparent after half a year to 3 years post-PD, indicating that micronutrient deficiencies are chronically apparent and are not cured by normal diet, perhaps supplemented with a conventional multivitamin / multi-mineral composition comprising for example 33% - 100% of the RDA per unit dose. Therefore, it is part of the invention that the patients in the cohort 4 and cohort 5 are treated by administering to said patients the pharmaceutical composition of the invention comprising 75% of the DRI of vitamin A, or more, and/or comprising 70% of the DRI of vitamin B6 or more, and/or comprising 14.000% of the DRI of vitamin B12 or more, and/or comprising 1 .500% of the DRI of vitamin D3 or more, comprising 200% of the DRI of vitamin E or more, and/or comprising 500% of the DRI of iron or more, and/or comprising 225% of the DRI of zinc or more, and preferably comprising all five of these vitamins at the indicated daily dose and all two of the minerals at the indicated daily dose. Monitoring the blood serum levels of the micronutrients in the weeks to months after the start of the administration of the pharmaceutical composition for use according to the invention, allows for adjustments of the daily dose of any one or more of the micronutrients, if optimal, healthy, natural levels are not reached yet, or when micronutrient serum levels go beyond a level held beneficial for the patient.

Preferred is the pharmaceutical composition for use according to the invention, wherein the pharmaceutical composition is administered to said patient for a period lasting for at least 2 weeks post-surgical removal of at least part of the patient’s pancreas, preferably post-PD, preferably between 4 weeks and rest of the patient’s lifespan, more preferably between 8 weeks and 600 months, most preferably between 12 weeks and 300 months. Of course, the administration of the pharmaceutical composition is continued as long as the results of the monitoring of the micronutrient serum levels in the post-PD patients indicate that said administration is still beneficial to the patient for maintaining desired micronutrient serum levels. See Table 1 for an overview of serum levels for the micronutrients that are aimed for by provision of the pharmaceutical composition to post-PD patients.

In an embodiment, the pharmaceutical composition for use according to the invention is administered at least once daily to the patient in need thereof. As the case may be, for post-PD patients who present with still sub-optimal serum levels of micronutrients once the administration of the pharmaceutical composition of the invention has started post-PD, for example 4 weeks, 3 months, 12 months, daily administration of the pharmaceutical composition may have proven not to be sufficient to treat any one or more of the micronutrient deficiencies, and therefore administration can be increased to e.g. twice, thrice daily, etc., or 1 ,5 times daily, or in an alternating order such as once daily / twice daily in subsequent days.

Table 2 displays a range of typical pharmaceutical compositions of the invention, said compositions being administered to patients who underwent PD and were treated with the pharmaceutical composition of the invention starting directly post-PD or starting 6 months or longer post-PD, wherein the treatment is for at least two weeks such as for example for at least six month, one year, 2 years, the rest of the post-PD patients’ life-span. Table 3 displays a typical pharmaceutical composition for use of the invention, comprising the micronutrients forwhich post- PD patients are most frequently deficient, such as vitamin D, vitamin B6, vitamin A, selenium, zinc, iron, copper, vitamin B12, vitamin E, in particular iron, vitamin A and vitamin D3. Table 3A displays a typical pharmaceutical composition for use of the invention, comprising the micronutrients for which post-PD patients are most frequently deficient, such as vitamin D, vitamin B6, vitamin A, selenium, zinc, vitamin B12, vitamin E, in particular vitamin A and vitamin D3.

Preferred is the pharmaceutical composition for use according to the invention, wherein the unit dose of said pharmaceutical composition comprises vitamin A, iron, vitamin D3, zinc and further one or more of:

- 200 to 1 .000 pg folic acid;

- 1 ,0 mg to 6,0 mg vitamin B1 ;

- 0,5 mg to 2,0 mg vitamin B6;

- 2,5 pg to 700 pg vitamin B12; and

- 10 mg to 50 mg vitamin E,

and preferably, the unit dose of the pharmaceutical composition comprises at least two, three, four, or five of said folic acid, vitamin B1 , vitamin B6, vitamin B12 and vitamin E, more preferably all five. Such a pharmaceutical composition of the invention for use according to the invention encompasses the micronutrients that are determined at relatively high frequency at low levels in serum of post-PD patients, such as iron, zinc, vitamin B6, vitamin A, vitamin B12, vitamin E, vitamin D3. That is to say, the inventors determined that any one or more of these minerals and vitamins are present at below normal (Table 1) values in serum of post-PD patients, even 6 months or longer post-PD. As said before, the amounts of active ingredients administered daily to a patient in need thereof by administering the pharmaceutical composition for use according to the invention, is either administered as a single unit dose, or is administered as two or more, such as two unit doses, preferably containing the same partial amounts of the total daily dose of the pharmaceutical composition, for example two unit doses each containing 50% of the daily administered amount of pharmaceutical composition.

Typically, forthe pharmaceutical composition for use according to the invention, the patient who has been subjected to the surgical removal of at least part of the patient’s pancreas, preferably PD, suffered from any of a neoplastic disease such as liver cancer, a benign cancer, a malignant cancer, cancer of the gastro-intestinal tract accompanied by presence of malignant cells such as invasive cancer cells, pancreatic carcinoma, papillary carcinoma, duodenal carcinoma, cholangiocarcinoma, intraductal papillary mucinous neoplasm, neuroendocrine tumor, pancreatitis, neoplasm of the jejunum such as spindle cell neoplasm of the jejunum, tumor at the ilium such as Ewing’s sarcoma of the ilium, giant cell tumor of the ilium, solitary fibrous tumor of the ilium, neoplasm of the gall bladder, ductal carcinoma, benign or malignant tumor of the duodenum, metastasized kidney cell carcinoma, pancreatic gastro-intestinal stromal tumor (GIST), intraductal oncocytic papillary neoplasm (IOPN) of the pancreas, at the start of the surgical operation, preferably said patient suffered from pancreatic carcinoma, papillary carcinoma, duodenal carcinoma, cholangiocarcinoma, intraductal papillary mucinous neoplasm (IPMN), neuroendocrine tumor (NET), pancreatitis, pancreatic gastro-intestinal stromal tumor (GIST), intraductal oncocytic papillary neoplasm (IOPN) of the pancreas, a benign or malignant cancer of the gastro-intestinal tract. These malignancies and diseases are frequently accompanied by micronutrient deficiencies before and after PD such as the Whipple procedure, and therefore these patients benefit from administration of the pharmaceutical composition of the invention for use according to the invention, since the pharmaceutical composition comprises relatively high amounts of the relevant micronutrients (Table 2, Table 3) for treating the deficiencies, whereas current multivitamin / multimineral compositions that are administered routinely to such patients do not adequately treat the deficiencies.

An embodiment is the pharmaceutical composition for use according to the invention, wherein the composition is formulated as a fixed dose combination, preferably as an oral fixed dose combination which is preferably a solid dosage form, such as a capsule, tablet or powder. Such a tablet or capsule is easily administered to the patient, the more since for most treatment regiments it will suffice to administer a single tablet daily to the post-PD patient. These aspects contribute to the patient compliance, since intake of sufficient food is often coming with difficulties for the patient such that any e.g. multiple units of a food supplement to be taken in addition to regular diet may have a negative impact on compliance. A single tablet once daily, comprising the relatively high amounts per micronutrient compared to common multivitamin preparations, is sufficient and enough for treating the micronutrient deficiencies in most post-PD patients, both those patients treated shortly after the PD surgery, e.g. within one day to 2 weeks post-PD, and those patients who underwent PD for example 2 months to 6 months before at the start of the treatment with the pharmaceutical composition of the invention, or 6 months or longer post-PD.

One embodiment is the pharmaceutical composition for use in a method for the treatment of at least one of a vitamin deficiency and a mineral deficiency according to the invention, wherein the patient suffered pre-treatment from any one or more of headache, skin rash, rheumatoid arthritis, dry skin, deprivement of energy, fatigue, chronical fatigue lasting for at least 3 months, decreased resistance, attention disorder, pale skin, memory disorder, a sensory problem such as deafness and tingling, depression, anxiety, distress, impaired wound healing, impaired haemostasis, declined taste, declined hearing, declined smell, aphthous stomatitis, and hair loss. These health problems and diseases are commonly apparent amongst patients suffering from any one or more of a micronutrient deficiency, such as vitamin A deficiency, and/or iron deficiency, and/or vitamin B6 deficiency, vitamin D3, zinc, vitamin B12 deficiency. Supplementing the diet of post-PD patients suffering from any of these diseases or health problems with the pharmaceutical composition of the invention reliefs the symptoms for these patients, by treating the micronutrient deficiency/deficiencies. Typically, the post-PD patients in cohort 1 -5 suffer from two or more of the listed diseases and health problems, relating to one or more micronutrient deficiencies, of which deficiencies in iron, vitamin D3 and vitamin A, zinc are most frequently observed, including combined deficiencies of two or three or four micronutrients. Since the pharmaceutical composition of the invention, such as the one detailed in Table 3, comprises the indicated relatively high amounts of micronutrients, treatment of post-PD patients with such pharmaceutical compositions effectively reliefs the patient from symptoms and underlying micronutrient deficiencies.

A further aspect of the invention is a therapeutic combination for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas and/or duodenum, wherein the therapeutic combination comprises a combination of at least two of:

(a) a first unit dose comprising 4 pg - 200 pg vitamin D3;

(b) a second unit dose comprising 300 pg - 2500 pg vitamin A;

(c) a third unit dose comprising 5 mg - 70 mg zinc; and

(d) a fourth unit dose comprising 10 mg - 200 mg iron.

In one embodiment, the therapeutic combination for use according to the invention comprises a combination of at least two, preferably at least three, more preferably four of:

(a) the first unit dose comprising 6 pg - 150 pg vitamin D3, preferably 8 pg - 100 pg, more preferably 10 pg - 75 pg;

(b) the second unit dose comprising 400 pg - 2000 pg vitamin A, preferably 500 pg - 1500 pg, more preferably 600 pg - 1200 pg;

(c) the third unit dose comprising 8 mg - 50 mg zinc, preferably 12 mg - 40 mg, more preferably 20 mg - 30 mg, most preferably about 22,5 mg; and

(d) the fourth unit dose comprising 15 mg - 150 mg iron, preferably 20 mg - 100 mg, more preferably 28 mg - 70 mg or 50 mg - 100 mg.

It is part of the invention that any of the unit doses may comprise a combination of micronutrients, including vitamin B6, selenium, copper, vitamin B12, vitamin E. For example, the fourth unit dose comprises a combination of the iron and 1 ,2 - 10 mg copper, such as about 3 mg copper. For example, the first unit dose comprises the vitamin D3 and further comprises vitamin A, zinc, and for example in addition vitamin B6, vitamin B12, vitamin E, selenium at an amount such that a unit dose comprises an amount indicated in Table 2 or Table 3.

An embodiment is the therapeutic combination for use in a method for the treatment or prevention of vitamin and/or mineral deficiencies in a patient who has been subjected PD, such as the Whipple procedure, wherein the patient in need thereof is administered vitamin K, such as a daily dose of 1 mg or less, for example 0,1 mg or less.

It is part of the invention that any one or more of the unit doses of the therapeutic combination for use according to the invention alternatively can also be provided as two unit doses, wherein each of the two unit doses contains 50% of the total dose that is administered daily to the patient in need thereof. Of course, such as single unit dose of the therapeutic combination for use according to the invention can alternatively also be provided as three, four, etc. equal doses.

An embodiment is the therapeutic combination for use in a method for the treatment or prevention of vitamin and/or mineral deficiencies in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas such as PD, wherein the first, second, third and/or fourth unit dose comprises further one or more of:

- 200 pg - 1 .000 pg folic acid;

- 1 ,0 mg - 6,0 mg vitamin B1 ;

- 0,5 mg - 2,0 mg vitamin B6;

- 2,5 pg - 700 pg vitamin B12; and

- 10 mg - 50 mg vitamin E,

and preferably, the first, second, third and/or fourth unit dose of the therapeutic combination comprises at least two, three, four or five of said folic acid, vitamin B1 , vitamin B6, vitamin B12 and vitamin E, more preferably all five.

Preferred is the therapeutic combination for use according to the invention, wherein the patient has been subjected to pancreaticoduodenectomy (e.g. the‘Whipple procedure’).

In one embodiment, the therapeutic combination for use according to the invention is administered at least once daily to the patient in need thereof.

In preferred embodiments, for the therapeutic combination for use according to the invention, the fourth unit dose comprising the 15 mg - 150 mg iron, preferably 20 mg - 100 mg, more preferably 28 mg - 70 mg or 50 mg - 100 mg, such as 28 mg or 70 mg is administered to the patient in need thereof at least 10 minutes, preferably at least 30 minutes and more preferably at least one hour after or before administering the aforementioned first, second and/or third unit dose to said patient, preferably 1 -2 hour after administration of one or more of the first, second and third unit dose to the patient in need thereof, wherein the first unit dose comprises 6 pg - 150 pg vitamin D3, preferably 8 pg - 100 pg, more preferably 10 pg - 75 pg, such as about 10 pg or about 75 pg; the second unit dose comprises 400 pg - 2000 pg vitamin A, preferably 500 pg - 1500 pg, more preferably 600 pg - 1200 pg, such as about 600 pg or about 1200 pg; the third unit dose comprises 8 mg - 50 mg zinc, preferably 12 mg - 40 mg, more preferably 20 mg - 30 mg, most preferably about 22,5 mg zinc. For example, the post-PD patient is first administered a unit dose comprising vitamin A, vitamin B6, vitamin B12, vitamin D3, vitamin E, zinc, present at an amount as indicated in Table 2 or Table 3, and subsequently 30 minutes to 2,5 hours after said first administration the post-PD patient is administered a unit dose comprising 20 mg - 100 mg iron, such as about 28 mg iron or about 70 mg iron, optionally combined with 2 mg - 5 mg copper, such as about 3 mg copper, in the further unit dose. This way, the patient will not suffer from difficulties in swallowing and digesting the combined unit doses, since the delayed administration of the iron comprising unit dose prevents vomiting, stomach pain, unpleasant gut feelings, and the like.

Preferred is the therapeutic combination for use according to the invention, wherein the unit dose(s) is/are a fixed dose combination, preferably an oral fixed dose combination, most preferably a tablet, a capsule or a powder.

It is part of the invention that to the patient in need thereof to whom the therapeutic combination for use according to the invention is administered, in addition any one or more of a composition comprising iron, a composition comprising vitamin A, a composition comprising vitamin D3, a composition comprising copper, a composition comprising selenium, a composition comprising zinc, a composition comprising vitamin B6, a composition comprising vitamin B12 and a composition comprising vitamin E is administered. Preferably, the one or more further compositions administered to the patient in need thereof, comprising iron, vitamin A, vitamin D3, copper, selenium, zinc, vitamin B6, vitamin B12, or vitamin E, are provided as a single unit dose wherein the unit dose comprises the daily amount to be administered to the patient. Typically, such a further composition comprises 14-140 mg iron such as 28 mg or 70 mg, or 300 - 2400 mg vitamin A, such as 600 mg or 1200 mg, or 5 - 75 mg vitamin D3, such as 10 mg or 75 mg, or 1 -6 mg copper, such as 1 ,9 mg or 3 mg, or 52,5 - 210 mg selenium, such as 105 mg, or 1 1 ,3 mg - 45 mg zinc such as 22,5 mg or 30 mg, or 0,49 - 1 ,96 mg vitamin B6, such as 0,98 mg or 1 ,5 mg, or 175 - 700 mg vitamin B12, such as 200 mg, 350 mg, or vitamin E, 12-48 mg, such as 24 mg.

For example, when a post-PD patient is treated with a pharmaceutical composition for use according to the invention or a therapeutic combination for use according to the invention, the patient in need thereof is administered any one or more of the compositions comprising one of iron, vitamin A, vitamin D3, copper, selenium, zinc, vitamin B6, vitamin B12, and vitamin E, when a deficiency for one or more of iron, vitamin A, vitamin D3, copper, selenium, zinc, vitamin B6, vitamin B12, and vitamin E is (still) apparent when the patient in need thereof was previously administered with only the pharmaceutical composition for use according to the invention or the therapeutic combination for use according to the invention. Of course, a patient in need thereof can also be administered with the pharmaceutical composition for use according to the invention or the therapeutic combination for use according to the invention, and any one or more of further compositions comprising iron, vitamin A, vitamin D3, copper, selenium, zinc, vitamin B6, vitamin B12, or vitamin E, directly post-PD, or at any moment in time post-PD, before continuous deficiency for any of these vitamins and minerals has become apparent beforehand.

In embodiments, for the therapeutic combination for use according to the invention, the patient who has been subjected to the surgical removal of at least part of the patient’s pancreas, preferably pancreaticoduodenectomy, was subjected to said surgical removal between 0 days and 400 months before the therapeutic combination is administered to said patient for the first time, preferably 1 week-350 months, more preferably 6 months - 300 months. Thus, according to the invention, post-PD patients are treated directly after the surgical operation, when presented with micronutrient deficiencies or for prophylactic treatment to prevent such deficiencies, or patients who were previously left untreated or who did previously not present with micronutrient deficiencies, are treated with the pharmaceutical composition of the invention for the first time at any number of weeks to months to years post-PD such as 6 months or longer post-PD.

Typically, the therapeutic combination for use according to the invention is administered to said patient for a period lasting for at least 2 weeks post-surgical removal of at least part of the patient’s pancreas, preferably post-pancreaticoduodenectomy, preferably between 4 weeks and rest of the patient’s lifespan, more preferably between 8 weeks and 600 months, most preferably between 12 weeks and 300 months. For preferred embodiments, the therapeutic combination for use according to the invention is administered to the patient who has been subjected to the surgical removal of at least part of the patient’s pancreas, preferably pancreaticoduodenectomy, wherein the patient suffered from any of a neoplastic disease such as liver cancer, a benign cancer, a malignant cancer, cancer of the gastro-intestinal tract accompanied by presence of malignant cells such as invasive cancer cells, pancreatic carcinoma, papillary carcinoma, duodenal carcinoma, cholangiocarcinoma, intraductal papillary mucinous neoplasm, neuroendocrine tumor, pancreatitis, neoplasm of the jejunum such as spindle cell neoplasm of the jejunum, tumor at the ilium such as Ewing’s sarcoma of the ilium, giant cell tumor of the ilium, solitary fibrous tumor of the ilium, neoplasm of the gall bladder, ductal carcinoma, benign or malignant tumor of the duodenum, metastasized kidney cell carcinoma, pancreatic gastro-intestinal stromal tumor (GIST), intraductal oncocytic papillary neoplasm (IOPN) of the pancreas, at the start of the surgical operation, preferably from pancreatic carcinoma, papillary carcinoma, duodenal carcinoma, cholangiocarcinoma, intraductal papillary mucinous neoplasm (IPMN), neuroendocrine tumor (NET), pancreatitis, pancreatic gastrointestinal stromal tumor (GIST), intraductal oncocytic papillary neoplasm (IOPN) of the pancreas, a benign or malignant cancer of the gastro-intestinal tract.

An embodiment is the therapeutic combination for use in a method for the treatment of at least one of a vitamin deficiency and mineral deficiency according to the invention, wherein the patient suffered pre-treatment from any one or more of headache, skin rash, rheumatoid arthritis, dry skin, deprivement of energy, fatigue, chronical fatigue lasting for at least 3 months, decreased resistance, attention disorder, pale skin, memory disorder, a sensory problem such as deafness and tingling, depression, anxiety, distress, impaired wound healing, impaired haemostasis, declined taste, declined hearing, declined smell, aphthous stomatitis, and hair loss.

While the invention has been described in terms of several embodiments, it is contemplated that alternatives, modifications, permutations and equivalents thereof will become apparent to one having ordinary skill in the art upon reading the specification and upon study of the drawings. The invention is not limited in any way to the illustrated embodiments. Changes can be made without departing from the scope which is defined by the appended claims.

An aspect of the present invention features a pharmaceutical composition comprising one or more vitamins and/or one or more minerals, and a physiologically acceptable carrier. A "pharmacological composition" refers to a composition in a form suitable for administration into a mammal, preferably a human. Preferably, the pharmaceutical composition contains a sufficient amount of a compound according to the invention in a proper pharmaceutical form to exert a therapeutic effect on a human.

A preferred embodiment is the pharmaceutical composition according to the invention wherein a unit dose of said composition comprises the compounds listed in Table 3.

A further aspect of the invention is a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas, and/or duodenum, such as pancreaticoduodenectomy (such as the‘Whipple procedure’), wherein the method comprises the daily administration to the patient in need thereof of at least one of:

10 mg - 200 mg iron, preferably 20 mg - 150 mg, more preferably 28 mg - 70 mg or 50 mg - 100 mg, such as about 28 mg or about 70 mg.

Further, it is also part of the invention that the method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to PD such as the Whipple procedure, comprises the daily administration to the patient in need thereof of at least one of vitamin B6, vitamin B12, vitamin E, selenium, copper, and preferably a combination of two or more of these further minerals and vitamins, more preferably all five. In addition, it is also part of the invention that the patient in need thereof is administered a pharmaceutical composition comprising essentially all compounds listed in Table 3.

An embodiment is the method according to the invention, wherein the patient in need thereof is administered a pharmaceutical composition according to any of the previous embodiments or is administered a therapeutic combination according to any of the previous embodiments.

A further aspect of the invention relates to a method of treatment of vitamin- and/or mineral deficiencies in patients who underwent pancreaticoduodenectomy (e.g. the Whipple procedure’), wherein the pharmaceutical composition of the invention is administered to a patient in need thereof. The pharmaceutical composition for example comprises the compounds listed in Table 2 or Table 3.

A further aspect of the present invention relates to the use of the pharmaceutical composition of the invention for the treatment of vitamin- and/or mineral deficiencies in patients who underwent PD.

Another aspect of the invention relates to a method of treating a patient who underwent PD such as the Whipple procedure and who is suffering from vitamin- and/or mineral deficiencies, comprising administering the pharmaceutical composition of the invention to the patient.

A further aspect of the invention relates to the administration of the pharmaceutical composition of the invention for treating vitamin- and/or mineral deficiencies in patients who underwent PD.

An aspect of the invention relates to the pharmaceutical composition of the invention for treating vitamin- and/or mineral deficiencies in patients who underwent PD.

Furthermore, an aspect of the invention relates to use of a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of vitamin- and/or mineral deficiencies in patients who underwent PD. For example, the pharmaceutical composition is the composition exemplified in Table 3.

The invention is further illustrated by the following examples, which should not be interpreted as limiting the present invention in any way. EXAMPLES

Human patients suffering from any of pancreatic carcinoma, papillary carcinoma, duodenal carcinoma, cholangiocarcinoma, intraductal papillary mucinous neoplasm (IPMN), neuroendocrine tumor (NET), pancreatitis, pancreatic gastro-intestinal stromal tumor (GIST), intraductal oncocytic papillary neoplasm (IOPN) of the pancreas, were presented at the clinic. Patients were subjected to surgical removal of at least part of the patient’s pancreas by pancreaticoduodenectomy (e.g the‘Whipple procedure’). Micronutrient levels (vitamins, minerals) in the blood of the patients were determined pre-surgery where indicated and post-surgery at indicated time-points such as directly after surgery ( t = 0), 4 weeks post-surgery, 3 months, 6 months, 12 months post-surgery. At least the levels of vitamin A, vitamin D3, vitamin B6, iron and zinc were measured in the blood serum of the patients during the course of the assessment of micronutrient deficiencies pre- and post-surgery. Table 5 displays the blood parameters that were assessed before and after PD such as the Whipple procedure was and will be applied to the cancer patients and the patients suffering from pancreatitis. Patients suffering from any one or more of a deficiency in iron, zinc, vitamin A, vitamin B6, vitamin D3 are treated by administering the pharmaceutical composition referred to as ΈM’ in Table 3, once daily. Study protocols are outlined in Fig. 1 and Fig. 2.

PATIENTS COHORT 1

For a group of 59 former cancer patients and former pancreatic patients post-PD (Cohort 1), serum levels of various vitamins and minerals (see Table 5) of these patients who underwent the surgery more than six months ago, were assessed retrospectively. Ail patients underwent non- pylorus-preserving PD for a variety of benign and malignant neoplastic lesions. The complete standardized blood test is shown in Table 5. The study protocol is outlined in Fig. 2. The treatment scheme is for post-PD such as post-Whipple procedure patients who previously suffered from cancer or pancreatitis, and who were presented with micronutrient deficiencies, e.g. vitamin A deficiency and/or iron deficiency and/or zinc deficiency and/or vitamin D3 deficiency, at least 6 months post-surgery. Evaluation points during the continued treatment time, at 4 weeks-, 3 months-, 6 months- and 12-months post-surgery, allow for monitoring of previously determined deficiencies and allows for possible adjustments to the treatment scheme and/or to the pharmaceutical composition if necessary.

Twenty six of the 59 patients suffered from iron deficiency (<10,7 pmol/L); nine patients had vitamin A deficiency (<1 ,25 pmol/L); 26 patients had vitamin D3 deficiency (<50 nmol/L); four patients suffered from zinc deficiency (<62 mg/dL); one patient had vitamin B6 deficiency (<35 nmol/L). For the Cohort 1 , 42 patients of the 59 patients suffered from at least one deficiency of vitamin A, vitamin D3, iron, zinc. Patients suffered from either a single deficiency with regard to vitamin A, vitamin D3, iron, zinc, vitamin B6, or suffered from two, three, or four deficiencies in combination. Patients suffered for example from iron deficiency and vitamin A deficiency; iron deficiency and vitamin D deficiency; iron and zinc deficiency; vitamin A and vitamin D3 deficiency; vitamin D and zinc deficiency; iron + vitamin A + vitamin D deficient; vitamin B6 + iron + vitamin D3 deficiency; and iron + vitamin A + vitamin D3 + zinc deficiency.

The patients are treated with the pharmaceutical composition ΈM’ (Table 3), by administering a unit dose once daily, comprising 600 mg vitamin A, 75 mg vitamin D3, 70 mg iron, 22,5 mg zinc, 0,98 mg vitamin B6. Patients do not report any complaints relating to the oral intake of the tablets.

PATIENT COHORT 2

For a group of 64 former cancer patients and former pancreatic patients post-PD (Cohort 2), serum levels of various vitamins and minerals (see Table 5) of these patients who underwent the surgery more than six months ago, were assessed retrospectively. Ail patients underwent non- pylorus-preserving PD for a variety of benign and malignant neoplastic lesions. The study protocol is outlined in Fig. 2. The complete standardized blood test is shown in Table 5. Results showed that almost half of the post PD (post-Whipple procedure) patients (41 .3%) developed iron deficiency resulting in lowered hemoglobin serum levels in 36.5%. Additionally, numerous patients demonstrated vitamin D (vitamin D3) deficiency and/or vitamin A deficiency (42.9% and 15.9%, respectively). The patients are supplemented with the deficient minerals and vitamins by treatment of the patients with the pharmaceutical composition ΈM’ (Table 3, 4), a multivitamin formulation comprising relatively high levels of vitamin A, vitamin D3, iron. Patients are treated for at least three months and serum levels for micronutrient deficiencies are monitored periodically. Additional supplementation for the three most predominant deficiencies (Iron, vitamin A, and vitamin D) is then provided if necessary. Quality of life and health status is assessed by analysis of a questionnaire taken from the patients at baseline and at the end of three months treatment window of multivitamin supplementation by administering pharmaceutical composition ΈM’.

Next, treatment of the patients continues after the initial three months period. Assessment of micronutrient deficiencies is at 6 months and 12 months from the start of the administration of the pharmaceutical composition. The treatment of the patients who are post-6-months PD surgery patients, normalizes micronutrient deficiencies and improves quality of life.

Study population: Patients who underwent a PD operation at least six months before the analysis of a blood sample for micronutrient deficiencies (Table 5), regardless of the diagnosis indicating the Whipple procedure. For the patients vitamin deficiencies post-surgery was assessed and based on the results the treatment protocol was initiated.

PATIENT COHORT 3

Since post-operative complications are decreasing post-PD such as post-Whipple procedure for former cancer patients and former pancreatitis patients, PD-related comorbidities are increasingly important for the patient’s functional status and quality of life. Inadequate dietary intake combined with absorption loss due to altered Gl-tract anatomy and physiology, may result in multifactorial micronutrient deficiencies. Evaluating long-term effects (>1 year post resection) of deficiencies and assessment of supplementation efficacy in larger study populations is lacking. The aim of the study, outlined in Fig. 2, with patients of cohort 3 was to identify which deficiencies are most common in a large group of patients who underwent PD-surgery more than 6 months ago. All patients underwent non-pylorus-preserving PD for a variety of benign and malignant neoplastic lesions.

Serum from 65 patients who underwent PD (6-264 months ago) was analyzed for common electrolyte and vitamin deficiencies (see Table 5 for parameters assessed). PD indications included malignant disease (n=55), benign conditions (n=6) and other (n=4) (GIST, IOPN). Patients with recurrent disease or high C-reactive protein levels (>10 mg/L) were excluded from the study.

Blood serum analyses revealed that 42.19% of the patients had vitamin D (vitamin D3) deficiency (<50 nmol/L), 41 ,3% had ferritin deficiency (<30 mhioI/I_), resulting in microcytic anemia (36.5%) (iron deficiency) and 15.9% of the patients had vitamin A deficiency (<1 .25 mhioI/I_). Deficiencies in vitamin B6 and zinc were also apparent for some patients.

Patients who underwent PD are deficient in vitamin A and vitamin D and show iron deficiencies which correspond to low hemoglobin levels. In addition, some patients suffered from vitamin B6 deficiency and zinc deficiency. Measuring the micronutrient status routinely in pre- and post-PD patients is thus an important assessment when monitoring the health status of the former cancer patients and former pancreatitis patients. PD patients benefit from vitamin and mineral supplementation, to improve quality of life and health status. Patients suffering from any one or more of the deficiencies are therefore treated by administering the pharmaceutical composition ΈM’, depicted in Table 3 and 4.

PATIENT COHORT 4

Serum obtained from a fourth cohort of 72 patients who underwent PD (6 - 264 months before the first blood draw) was analyzed for common electrolyte and vitamin deficiencies and mineral deficiencies according to Table 5. All patients underwent non-pylorus-preserving PD for a variety of benign and malignant neoplastic lesions PD indications included malignant disease, benign conditions and other of which the distribution was pancreatic carcinoma (40%), papillary carcinoma (22%), duodenal carcinoma (7%), cholangiocarcinoma (8%), intraductal papillary mucinous neoplasm (IPMN) (10%), neuroendocrine tumor (NET) (4%), pancreatitis (3%), and in total 6% of the patients suffered before the PD (Whipple procedure) from any of pancreatic gastrointestinal stromal tumor (GIST), intraductal oncocytic papillary neoplasm (IOPN) of the pancreas. All patients underwent baseline serum tests and those with deficiencies are supplemented with minerals and vitamins by administering to the patients in need thereof the pharmaceutical composition ΈM’ outlined in Table 3 and 4. The study protocol was according to the scheme depicted in Fig. 2.

Preliminary analyses of the blood samples of the 72 patients revealed four main deficiencies: 44% of patients demonstrated vitamin D deficiency (vitamin D3 deficiency) (<50 nmol/L), 14% had ferritin deficiency (<30 ng/mL), resulting in microcytic anemia (iron deficiency) (40%) and 18% of patients had vitamin A deficiency (<1 .25 mhioI/L). In addition, at least four patients suffered from zinc deficiency. Moreover, at least one patient suffered from vitamin B6 deficiency. Hb deficiency was observed for 35% of the patients 6-264 months PD (post-Whipple procedure).

Typical complaints by the patients and health issues of the patients, related to the observed vitamin and mineral deficiencies are headache, skin rash, rheumatoid arthritis, dry skin, deprivement of energy, fatigue, chronical fatigue lasting for at least 3 months, decreased resistance, attention disorder, pale skin, memory disorder, a sensory problem such as deafness and tingling, depression, anxiety, distress, impaired wound healing, impaired haemostasis, declined taste, declined hearing, declined smell, aphthous stomatitis, and hair loss.

These results showed that PD-surgery patients are susceptible to developing micronutrient deficiencies; Common deficiencies include iron, vitamin A, vitamin D (vitamin D3), zinc, and to a lesser extent vitamin B6; PD-surgery patients benefit from supplementation and routine serum evaluations.

PATIENTS COHORT 5

Study population: Patients who are subjected to PD operation or will be subjected to a PD operation regardless of the diagnosis indicating the procedure (cancer, pancreatitis). All patients will undergo or underwent non-pylorus-preserving PD for a variety of benign and malignant neoplastic lesions. The future surgery patients are treated with a vitamins/minerals supplement. Pre-operation baseline measurements are performed for the patient (Table 5). Post-operatively, blood levels of the compounds listed in Table 5 are determined after two weeks post-Whipple procedure (post-PD), and then every four weeks. At 4 and 12 weeks the micronutrient deficiency status is evaluated and the supplementation of individual micronutrients or the pharmaceutical composition is adjusted according to the patient’s requirements. That is to say, for example individual vitamins and/or minerals are administered at an adjusted level compared to the initial level administered by the daily dose of pharmaceutical composition ΈM’, and/or for example the dosing and/or dosing frequency of pharmaceutical composition ΈM’ is adjusted in accordance of the micronutrient blood levels that are monitored periodically for each individual patient post-PD.

Fig. 1 outlines the protocol for the patient study. The outlined treatment scheme is for patients undergoing pancreaticoduodenectomy surgery, i.e. Whipple procedure, who are subsequently administered a pharmaceutical composition comprising vitamins and minerals, i.e. pharmaceutical composition ΈM’ (Table 3). Pre-surgery deficiencies for minerals and vitamins are determined in the blood of the patients, and values obtained are used to determine which mineral(s) and which vitamin(s) require supplementation post-surgery, if pre-surgery deficiencies are apparent. Evaluation time-points post-surgery allow for monitoring of (declining or effectively treated) deficiencies and the monitoring allows for timely adjustments to supplementation if necessary by amending the treatment schedule and/or amending the pharmaceutical composition. Post-PD patients start the treatment scheme at baseline post-surgery with an evaluation of the results of the treatment after weeks of the start of the treatment, which is an adjustment check at 4 weeks of supplementation.

Endpoints of the study - Primary endpoint: improvement in serum/plasma levels of micronutrients; Secondary endpoint: improved quality of life assessment scores.

EXAMPLE - PATIENT CASE STUDY

A 59 years old female pancreas cancer patient underwent surgery and was subjected to pancreaticoduodenectomy (Whipple procedure). As part of the Whipple procedure, lymph nodes were resected. At six days before the subjection to the Whipple procedure, the blood parameters for the patient were determined: see Table 6. The patient suffered from a reduced vitamin A level, amongst others.

At day +24 post Whipple procedure, twice daily administration of a unit dose of the pharmaceutical composition EM started. At day +62 after the start of the twice daily administration of a unit dose of the pharmaceutical composition EM (see Table 3), which was day +86 post Whipple procedure, the patient had a blood iron level that returned to a normal value of 1 1 ,5 mhioI/L. At day +1 10 after the start of the twice daily administration of a unit dose of the pharmaceutical composition EM, which was day +134 post Whipple procedure, the patient reported an overall and gradually health improvement since the start of the twice daily intake of the unit dose of the pharmaceutical composition EM, resulting in reaching a plateau status of complete recovery relating to overall health. The quality and duration of sleep improved compared to the period preceding the start of the intake of the pharmaceutical composition EM. Concentration improved as well. In addition, upon twice daily intake of pharmaceutical composition EM, her feelings of fatigue and apathy gradually diminished.

These health improvements are attributed to the twice daily intake of the pharmaceutical composition EM by the patient, starting at day +24 post Whipple procedure. Symptoms like sleepiness, apathy, fatigue disappeared, overall fitness and overall health improved and reached ‘normal’ levels, all indicative for efficient treatment of the vitamin A deficiency, iron deficiency and/or the reduced vitamin B1 (thiamine) levels, due to the twice daily intake of the pharmaceutical composition EM by the patient.

EXAMPLE - PATIENT COHORT STUDY

In a cohort of patients with pancreatic tumors, blood levels of different vitamins and trace elements were determined. Preoperative deficiencies were found in half of the patients. In the cohort of more than 100 patients, for whom the deficiencies were assessed for longer than 6 months after a pancreatoduodenectomy, it was determined that one or more deficiencies are apparent in more than 80% of the patients.

Based on these important findings, it was decided to supplement all patients postoperatively with one or two unit doses of pharmaceutical composition EM (see Table 3) per day. Upon daily administration, several patients have indicated that they feel considerably better after a few weeks and the previously observed vitamin deficiencies had also improved considerably, including vitamin A deficiency, zinc deficiency, vitamin D3 deficiency, and iron deficiency.

Claims

1 . Pharmaceutical composition for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas, comprising at least one of:

- vitamin A or a source thereof;

- vitamin D3 or a source thereof;

- iron or a source thereof; and

- zinc or a source thereof;

and further comprising a pharmaceutically acceptable carrier, wherein the patient in need thereof is administered by means of said pharmaceutical composition per day at least one of: 300 pg - 2500 pg vitamin A, 4 pg - 200 pg vitamin D3, 10 mg - 200 mg zinc and 10 mg - 200 mg iron.

2. Pharmaceutical composition for use according to claim 1 , wherein the patient in need thereof is at least administered by means of said pharmaceutical composition per day 300 pg - 2500 pg vitamin A.

3. Pharmaceutical composition for use according to claim 1 or 2, wherein the patient in need thereof is at least administered by means of said pharmaceutical composition per day 10 mg - 200 mg iron.

4. Pharmaceutical composition for use according to any one of the claims 1 -3, wherein a unit dose of the pharmaceutical composition comprises at least one of:

5. Pharmaceutical composition for use according to any one of the claims 1 -4, wherein a unit dose of the pharmaceutical composition comprises at least two, preferably at least three, more preferably four of:

10 mg - 200 mg iron, preferably 20 mg - 150 mg, more preferably 28 mg - 70 mg or 50 mg - 100 mg; and 10 mg - 200 mg zinc, preferably 15 mg - 40 mg, more preferably 20 mg - 30 mg, most preferably about 22,5 mg.

6. Pharmaceutical composition for use according to any one of the claims 1 -5, wherein a unit dose of the pharmaceutical composition comprises at least:

300 pg - 2500 pg vitamin A, preferably 450 pg - 1800 pg, more preferably 600 pg - 1200 pg; and/or

7. Pharmaceutical composition for use according to any one of the claims 1 -6, wherein the surgical removal of at least part of the patient’s pancreas is pancreaticoduodenectomy, such as Whipple procedure.

8. Pharmaceutical composition for use according to any one of the claims 1 -7, wherein the patient who has been subjected to the surgical removal of at least part of the patient’s pancreas, preferably pancreaticoduodenectomy, was subjected to said surgical removal between 0 days and 400 months before the pharmaceutical composition is administered to said patient for the first time, preferably 1 week-350 months, more preferably 6 months - 300 months.

9. Pharmaceutical composition for use according to any one of the claims 1 -8, wherein the pharmaceutical composition is administered to said patient for a period lasting for at least 2 weeks post-surgical removal of at least part of the patient’s pancreas, preferably postpancreaticoduodenectomy, preferably between 4 weeks and rest of the patient’s lifespan, more preferably between 8 weeks and 600 months, most preferably between 12 weeks and 300 months.

10. Pharmaceutical composition for use according to any one of the previous claims, wherein the pharmaceutical composition is administered at least once daily to the patient in need thereof.

1 1 . Pharmaceutical composition for use according to any of the claims 4-10, wherein the unit dose of said pharmaceutical composition comprises further one or more of:

- 200 to 1 .000 pg folic acid;

- 1 ,0 mg to 6,0 mg vitamin B1 ;

- 0,5 mg to 2,0 mg vitamin B6;

- 2,5 microgram to 700 microgram vitamin B12; and

- 10 mg to 50 mg vitamin E,

and preferably, the unit dose of the pharmaceutical composition comprises at least two, three, four, or five of said folic acid, vitamin B1 , vitamin B6, vitamin B12 and vitamin E, more preferably all five.

12. Pharmaceutical composition for use according to any of the previous claims, wherein the patient who has been subjected to the surgical removal of at least part of the patient’s pancreas, preferably pancreaticoduodenectomy, suffered from any of a neoplastic disease such as liver cancer, a benign cancer, a malignant cancer, cancer of the gastro-intestinal tract accompanied by presence of malignant cells such as invasive cancer cells, pancreatic carcinoma, papillary carcinoma, duodenal carcinoma, cholangiocarcinoma, intraductal papillary mucinous neoplasm, neuroendocrine tumor, pancreatitis, neoplasm of the jejunum such as spindle cell neoplasm of the jejunum, tumor at the ilium such as Ewing’s sarcoma of the ilium, giant cell tumor of the ilium, solitary fibrous tumor of the ilium, neoplasm of the gall bladder, ductal carcinoma, benign or malignant tumor of the duodenum, metastasized kidney cell carcinoma, pancreatic gastrointestinal stromal tumor (GIST), intraductal oncocytic papillary neoplasm (IOPN) of the pancreas, at the start of the surgical operation,

preferably from pancreatic carcinoma, papillary carcinoma, duodenal carcinoma, cholangiocarcinoma, intraductal papillary mucinous neoplasm (IPMN), neuroendocrine tumor (NET), pancreatitis, pancreatic gastro-intestinal stromal tumor (GIST), intraductal oncocytic papillary neoplasm (IOPN) of the pancreas, a benign or malignant cancer of the gastro-intestinal tract.

13. Pharmaceutical composition for use according to any one of the previous claims, wherein the composition is formulated as a fixed dose combination, preferably as an oral fixed dose combination which is preferably a solid dosage form, such as a capsule, tablet or powder.

14. Pharmaceutical composition for use in a method for the treatment of at least one of a vitamin deficiency and a mineral deficiency according to any one of the previous claims, wherein the patient suffered pre-treatment from any one or more of headache, skin rash, rheumatoid arthritis, dry skin, deprivement of energy, fatigue, chronical fatigue lasting for at least 3 months, decreased resistance, attention disorder, pale skin, memory disorder, a sensory problem such as deafness and tingling, depression, anxiety, distress, impaired wound healing, impaired haemostasis, declined taste, declined hearing, declined smell, aphthous stomatitis, and hair loss.

15. Therapeutic combination for use in a method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas, wherein the therapeutic combination comprises a combination of at least two of:

(a) a first unit dose comprising 4 pg - 200 pg vitamin D3;

(b) a second unit dose comprising 300 pg - 2500 pg vitamin A;

(c) a third unit dose comprising 5 mg - 70 mg zinc; and

(d) a fourth unit dose comprising 10 mg - 200 mg iron.

16. Therapeutic combination for use according to claim 15, wherein the therapeutic combination comprises a combination of at least two, preferably at least three, more preferably four of:

17. Therapeutic combination for use according to claim 15 or 16, wherein the therapeutic combination comprises a combination of at least:

18. Therapeutic combination for use according to any one of the claims 15 or 17, wherein the patient has been subjected to pancreaticoduodenectomy.

19. Therapeutic combination for use according to any one of the claims 15-18, wherein the therapeutic combination is administered at least once daily to the patient in need thereof.

20. Therapeutic combination for use according to any one of the claims 15-19, wherein the fourth unit dose is administered to the patient in need thereof at least 10 minutes, preferably at least 30 minutes and more preferably at least one hour after or before administering the first, second and/or third unit dose to said patient, preferably 1 -2 hour after administration of one or more of the first, second and third unit dose to the patient in need thereof.

21 . Therapeutic combination for use according to any one of the claims 15-20, wherein the unit dose(s) is/are a fixed dose combination, preferably an oral fixed dose combination, most preferably a tablet, a capsule or a powder.

22. Therapeutic combination for use according to any one of the claims 15-21 , wherein the patient who has been subjected to the surgical removal of at least part of the patient’s pancreas, preferably pancreaticoduodenectomy, was subjected to said surgical removal between 0 days and 400 months before the therapeutic combination is administered to said patient for the first time, preferably 1 week-350 months, more preferably 6 months - 300 months.

23. Therapeutic combination for use according to any one of the claims 15-22, wherein the therapeutic combination is administered to said patient for a period lasting for at least 2 weeks post- surgical removal of at least part of the patient’s pancreas, preferably postpancreaticoduodenectomy, preferably between 4 weeks and rest of the patient’s lifespan, more preferably between 8 weeks and 600 months, most preferably between 12 weeks and 300 months.

24. Therapeutic combination for use according to any one of the claims 15-23, wherein the patient who has been subjected to the surgical removal of at least part of the patient’s pancreas, preferably pancreaticoduodenectomy, suffered from any of a neoplastic disease such as liver cancer, a benign cancer, a malignant cancer, cancer of the gastro-intestinal tract accompanied by presence of malignant cells such as invasive cancer cells, pancreatic carcinoma, papillary carcinoma, duodenal carcinoma, cholangiocarcinoma, intraductal papillary mucinous neoplasm, neuroendocrine tumor, pancreatitis, neoplasm of the jejunum such as spindle cell neoplasm of the jejunum, tumor at the ilium such as Ewing’s sarcoma of the ilium, giant cell tumor of the ilium, solitary fibrous tumor of the ilium, neoplasm of the gall bladder, ductal carcinoma, benign or malignant tumor of the duodenum, metastasized kidney cell carcinoma, pancreatic gastrointestinal stromal tumor (GIST), intraductal oncocytic papillary neoplasm (IOPN) of the pancreas, at the start of the surgical operation, preferably from pancreatic carcinoma, papillary carcinoma, duodenal carcinoma, cholangiocarcinoma, intraductal papillary mucinous neoplasm (IPMN), neuroendocrine tumor (NET), pancreatitis, pancreatic gastro-intestinal stromal tumor (GIST), intraductal oncocytic papillary neoplasm (IOPN) of the pancreas, a benign or malignant cancer of the gastro-intestinal tract.

25. Therapeutic combination for use in a method for the treatment of at least one of a vitamin deficiency and mineral deficiency according to any one of the claims 15-24, wherein the patient suffered pre-treatment from any one or more of headache, skin rash, rheumatoid arthritis, dry skin, deprivement of energy, fatigue, chronical fatigue lasting for at least 3 months, decreased resistance, attention disorder, pale skin, memory disorder, a sensory problem such as deafness and tingling, depression, anxiety, distress, impaired wound healing, impaired haemostasis, declined taste, declined hearing, declined smell, aphthous stomatitis, and hair loss.

26. Method for the treatment or prevention of at least one of a vitamin deficiency and a mineral deficiency in a patient who has been subjected to surgical removal of at least part of the patient’s pancreas such as pancreaticoduodenectomy, wherein the method comprises the daily administration to the patient in need thereof of at least one of:

4 pg - 200 pg vitamin D3, preferably 6 pg - 150 pg, more preferably 10 pg - 75 pg; 4 mg - 70 mg zinc, preferably 8 mg - 60 mg, more preferably 15 mg - 40 mg, most preferably 20 mg - 30 mg, such as 22,5 mg; and

27. Method according to claim 26, wherein said patient in need thereof is administered a pharmaceutical composition according to any of the claims 1 -14 or a therapeutic combination according to any of the claims 15-25.

28. Method according to claim 26 or 27, wherein the method comprises the daily administration to the patient in need thereof of at least: